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The hippocampus is functionally specialized along its longitudinal axis with intricate interactions with cortical systems, which is crucial for understanding development and cognition. Using a well-established connectopic mapping technique on two large resting-state functional MRI datasets, we systematically quantified topographic organization of the hippocampal functional connectivity (hippocampal gradient) and its cortical interaction in developing brains. We revealed hippocampal functional hierarchy within the large-scale cortical brain systems, with the anterior hippocampus preferentially connected to an anterior temporal (AT) pathway and the posterior hippocampus embedded in a posterior medial (PM) pathway. We examined the developmental effects of the primary gradient and its whole-brain functional interaction. We observed increased functional specialization along the hippocampal long axis and found a general whole-brain connectivity shift from the posterior to the anterior hippocampus during development. Using phenotypic predictive modeling, we further delineated how the hippocampus is differentially integrated into the whole-brain cortical hierarchy underlying episodic memory and identified several key nodes within PM/AT systems. Our results highlight the importance of hippocampal gradient and its cortical interaction in development and for supporting episodic memory., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Early detection of Alzheimer's disease (AD) is essential for timely management and consideration of therapeutic options; therefore, detecting the risk of conversion from mild cognitive impairment (MCI) to AD is crucial during neurodegenerative progression. Existing neuroimaging studies have mostly focused on group differences between individuals with MCI (or AD) and cognitively normal (CN), discarding the temporal information of conversion time. Here, we aimed to develop a prognostic model for AD conversion using functional connectivity (FC) and Cox regression suitable for conversion event modeling., Methods: We developed a prognostic model using a large-scale Alzheimer's Disease Neuroimaging Initiative dataset, and it was validated using external data obtained from the Open Access Series of Imaging Studies. We considered individuals who were initially CN or had MCI but progressed to AD and those with MCI with no progression to AD during the five-year follow-up period. As the exact conversion time to AD is unknown, we inferred this information using imputation approaches. We generated cortex-wide principal FC gradients using manifold learning techniques and computed subcortical-weighted manifold degrees from baseline functional magnetic resonance imaging data. A penalized Cox regression model with an elastic net penalty was adopted to define a risk score predicting the risk of conversion to AD, using FC gradients and clinical factors as regressors., Results: Our prognostic model predicted the conversion risk and confirmed the role of imaging-derived manifolds in the conversion risk. The brain regions that largely contributed to predicting AD conversion were the heteromodal association and visual cortices, as well as the caudate and hippocampus. Our risk score based on Cox regression was consistent with the expected disease trajectories and correlated with positron emission tomography tracer uptake and symptom severity, reinforcing its clinical usefulness. Our findings were validated using an independent dataset. The cross-sectional application of our model showed a higher risk for AD than that for MCI, which correlated with symptom severity scores in the validation dataset., Conclusion: We proposed a prognostic model predicting the risk of conversion to AD. The associated risk score may provide insights for early intervention in individuals at risk of AD conversion., (© 2024. The Author(s).)

Land cover is recognized as an important determinant of mosquito community assemblages and pathogen transmission, but few studies have investigated the role of land cover in populations of La Crosse virus (LACV) vectors. La Crosse virus is a zoonotic disease primarily maintained by native Aedes triseriatus , with accessory transmission by invasive vectors Ae. albopictus and Ae. japonicus. The objective of this study was to investigate the association between land cover composition and the egg abundances of LACV vectors in a city with endemic LACV transmission. Oviposition cups were deployed at sites ranging from recreational forests to urban areas. Mixed-effects regression models were used to test the relationships between land cover composition and species abundances. Sites characterized by large percentages of impervious and built surfaces were dominated by Ae. albopictus , but Ae. triseriatus was the most abundant species in forested areas. Aedes japonicus was rare at all sites, but its presence was associated with higher percentages of forested land. These results indicate that forested areas may allow Ae. triseriatus to maintain large populations near urban areas that are dominated by Ae. albopictus . Further research should explore the potential for these land cover-dependent population dynamics to influence LACV transmission cycles.

Lightweight porous ceramics with a unique combination of superior mechanical strength and damage tolerance are in significant demand in many fields such as energy absorption, aerospace vehicles, and chemical engineering; however, it is difficult to meet these mechanical requirements with conventional porous ceramics. Here, we report a graded structure design strategy to fabricate porous ceramic nanowire networks that simultaneously possess excellent mechanical strength and energy absorption capacity. Our optimized graded nanowire networks show a compressive strength of up to 35.6 MPa at a low density of 540 mg·cm -3 , giving rise to a high specific compressive strength of 65.7 kN·m·kg -1 and a high energy absorption capacity of 17.1 kJ·kg -1 , owing to a homogeneous distribution of stress upon loading. These values are top performance compared to other porous ceramics, giving our materials significant potential in various engineering fields.

Current biofabrication strategies are limited in their ability to replicate native shape-to-function relationships, that are dependent on adequate biomimicry of macroscale shape as well as size and microscale spatial heterogeneity, within cell-laden hydrogels. In this study, a novel diffusion-based microfluidics platform is presented that meets these needs in a two-step process. In the first step, a hydrogel-precursor solution is dispersed into a continuous oil phase within the microfluidics tubing. By adjusting the dispersed and oil phase flow rates, the physical architecture of hydrogel-precursor phases can be adjusted to generate spherical and plug-like structures, as well as continuous meter-long hydrogel-precursor phases (up to 1.75 m). The second step involves the controlled introduction a small molecule-containing aqueous phase through a T-shaped tube connector to enable controlled small molecule diffusion across the interface of the aqueous phase and hydrogel-precursor. Application of this system is demonstrated by diffusing co-initiator sodium persulfate (SPS) into hydrogel-precursor solutions, where the controlled SPS diffusion into the hydrogel-precursor and subsequent photo-polymerization allows for the formation of unique radial stiffness patterns across the shape- and size-controlled hydrogels, as well as allowing the formation of hollow hydrogels with controllable internal architectures. Mesenchymal stromal cells are successfully encapsulated within hollow hydrogels and hydrogels containing radial stiffness gradient and found to respond to the heterogeneity in stiffness through the yes-associated protein mechano-regulator. Finally, breast cancer cells are found to phenotypically switch in response to stiffness gradients, causing a shift in their ability to aggregate, which may have implications for metastasis. The diffusion-based microfluidics thus finds application mimicking native shape-to-function relationship in the context of tissue engineering and provides a platform to further study the roles of micro- and macroscale architectural features that exist within native tissues., (Creative Commons Attribution license.)

High magnetic field homogeneity is critical for magnetic resonance imaging (MRI), functional MRI, and magnetic resonance spectroscopy (MRS) applications. B 0 inhomogeneity during MR scans is a long-standing problem resulting from magnet imperfections and site conditions, with the main issue being the inhomogeneity across the human body caused by differences in magnetic susceptibilities between tissues, resulting in signal loss, image distortion, and poor spectral resolution. Through a combination of passive and active shim techniques, as well as technological advances employing multi-coil techniques, optimal coil design, motion tracking, and real-time modifications, improved field homogeneity and image quality have been achieved in MRI/MRS. The integration of RF and shim coils brings a high shim efficiency due to the proximity of participants. This technique will potentially be applied to high-density RF coils with a high-density shim array for improved B 0 homogeneity. Simultaneous shimming and image encoding can be achieved using multi-coil array, which also enables the development of novel encoding methods using advanced magnetic field control. Field monitoring enables the capture and real-time compensation for dynamic field perturbance beyond the static background inhomogeneity. These advancements have the potential to better use the scanner performance to enhance diagnostic capabilities and broaden applications of MRI/MRS in a variety of clinical and research settings. The purpose of this paper is to provide an overview of the latest advances in B 0 magnetic field shimming and magnetic field control techniques as well as MR hardware, and to emphasize their significance and potential impact on improving the data quality of MRI/MRS., Competing Interests: One of the authors, Hui Han, is also the editor board member of Psychoradiology. He was blinded from reviewing or making decisions on the manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of West China School of Medicine/West China Hospital (WCSM/WCH) of Sichuan University.)

Background: Data regarding the impact of reduced left ventricular ejection fraction (LVEF) and/or reduced mean aortic valve gradient (AVG) on outcomes following transcatheter aortic valve intervention (TAVI) have been conflicting. We sought to assess the relationship between LVEF, AVG, and 1-year mortality in patients undergoing TAVI., Methods: We prospectively evaluated 298 consecutive adults undergoing TAVI from 2015 to 2018 at an academic tertiary medical center. Patients were categorized according to LVEF and mean AVG. The primary outcome of interest was all-cause mortality at 1 year., Results: Of 298 adults undergoing TAVI, 66 (22.1%) had baseline LVEF ≤45% while 232 (77.9%) had baseline LVEF >45%; 173 (58.1%) had baseline AVG < 40mmHg while 125 (41.9%) had baseline AVG ≥ 40mmHg. Rates of 1-year all-cause mortality were significantly higher in patients with LVEF ≤45% (28.8% vs 12.1%, p = 0.001) and those with AVG < 40mmHg (19.7% vs 10.4%, p = 0.031) compared to those with LVEF >45% and AVG ≥ 40mmHg respectively. In multivariable analysis, higher AVG (per mmHg) (OR 0.97, 95% CI 0.94-0.99, p = 0.026) was noted to be independently associated with lower rates of 1-year mortality, while LVEF was not (OR 0.98, 95% CI 0.96-1.01)., Conclusions: In this prospective, contemporary registry of adults undergoing TAVI, while 1-year unadjusted mortality rates are significantly higher in patients with reduced LVEF and reduced AVG, risk-adjusted mortality at 1 year is only higher in those with reduced AVG - not in those with reduced LVEF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Puja Parikh, MD reports a relationship with Medtronic Inc. that includes: consulting or advisory and speaking and lecture fees. Puja Parikh, MD reports a relationship with Edwards Lifesciences Corporation that includes: funding grants. Smadar Kort, MD reports a relationship with Medtronic Inc. that includes: board membership., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An efficient method for the synthesis of a self-supporting carbon framework (denoted Gra-GC-MoSe 2 ) is proposed with a triple-gradient structure-in sodiophilic sites, pore volume, and electrical conductivity-which facilitates the highly efficient regulation of Na deposition. In situ and ex situ measurements, together with theoretical calculations, reveal that the gradient distribution of Se heteroatoms in MoSe 2 , and its derivatives tailor the sodiophilicity, while the gradient distribution of porous nanostructures homogenizes the Na + diffusion. Therefore, Na deposition occurs from the bottom to the top of the Gra-GC-MoSe 2 framework without dendrite formation. In addition, the gradient in electrical conductivity ensures the stripping process does not lead to dead Na. As a result, a Gra-GC-MoSe 2 modified Na anode (Na@Gra-GC-MoSe 2 ) shows impressive cycling stability with a high average Coulombic efficiency in an asymmetric cell. In symmetric cells, it also exhibits a long cycling life of 2000 h with a low polarization voltage and works stably even under a large capacity of 10 mAh cm -2 . Moreover, a Na@Gra-GC-MoSe 2 || Na 3 V 2 (PO 4 ) 3 full cell delivers a high energy density with an excellent cycling performance., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Lung images often have the characteristics of strong noise, uneven grayscale distribution, and complex pathological structures, which makes lung image segmentation a challenging task. To solve this problems, this paper proposes an initial lung mask extraction algorithm that combines threshold and gradient. The gradient used in the algorithm is obtained by the time series feature extraction method based on differential memory (TFDM), which is obtained by the grayscale threshold and image grayscale features. At the same time, we also proposed a lung contour repair algorithm based on the improved convex hull method to solve the contour loss caused by solid nodules and other lesions. Experimental results show that on the COVID-19 CT segmentation dataset, the advanced lung segmentation algorithm proposed in this article achieves better segmentation results and greatly improves the consistency and accuracy of lung segmentation. Our method can obtain more lung information, resulting in ideal segmentation effects with improved accuracy and robustness., (© 2024. The Author(s).)

The bone-cartilage interface is defined by a unique arrangement of cells and tissue matrix. Injury to the interface can contribute to the development of arthritic joint disease. Attempts to repair osteochondral damage through clinical trials have generated mixed outcomes. Tissue engineering offers the potential of integrated scaffold design with multiregional architecture to assist in tissue regeneration, such as the bone-cartilage interface. Challenges remain in joining distinct materials in a single scaffold mass while maintaining integrity and avoiding delamination. The aim of the current work is to examine the possibility of joining two closely related acrylamide derivatives such as, poly n-isopropyl acrylamide (pNIPAM) and poly n‑tert‑butyl acrylamide (pNTBAM). The target is to produce a single scaffold unit with distinct architectural regions in the favour of regenerating the osteochondral interface. Longitudinal phosphate glass fibres (PGFs) with the formula 50P 2 O 5 .30CaO.20Na 2 O were incorporated to provide additional bioactivity by degradation to release ions such as calcium and phosphate which are considered valuable to assist the mineralization process. Polymers were prepared via atom transfer radical polymerization (ATRP) and solutions cast to ensure the integration of polymers chains. Scaffold was characterized using scanning electron microscope (SEM) and Fourier transform infra-red (FTIR) techniques. The PGF mass degradation pattern was inspected using micro computed tomography (µCT). Biological assessment of primary human osteoblasts (hOBs) and primary human chondrocytes (hCHs) upon scaffolds was performed using alizarin red and colorimetric calcium assay for mineralization assessment; alcian blue staining and dimethyl-methylene blue (DMMB) assay for glycosaminoglycans (GAGs); immunostaining and enzyme-linked immunosorbent assay (ELISA) to detect functional proteins expression by cells such as collagen I, II, and annexin A2. FTIR analysis revealed an intact unit with gradual transformation from pNIPAM to pNTBAM. SEM images showed three distinct architectural regions with mean pore diameter of 54.5 µm (pNIPAM), 16.5 µm (pNTBAM) and 118 µm at the mixed interface. Osteogenic and mineralization potential by cells was observed upon the entire scaffold's regions. Chondrogenic activity was relevant on the pNTBAM side of the scaffold only with minimal evidence in the pNIPAM region. PGFs increased mineralization potential of both hOBs and hCHs, evidenced by elevated collagens I, X, and annexin A2 with reduction of collagen II in PGFs scaffolds. In conclusion, pNIPAM and pNTBAM integration created a multiregional scaffold with distinct architectural regions. Differential chondrogenic, osteogenic, and mineralized cell performance, in addition to the impact of PGF, suggests a potential role for phosphate glass-incorporated, acrylamide-derivative scaffolds in osteochondral interface regeneration., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zaid M. Younus reports financial support was provided by The Higher Committee for Education Development in Iraq. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Scaffolds have garnered considerable attention for enhancing neural repairment for spinal cord injury (SCI) treatment. Both microstructural features and biochemical modifications play pivotal roles in influencing the interaction of cells with the scaffold, thereby affecting tissue regeneration. Here, a scaffold is designed with spiral structure and gradient peptide modification (GS) specifically for SCI treatment. The spiral structure provides crucial support and space, while the gradient peptide isoleucine-lysine-valine-alanine-valine (IKVAV) modification imparts directional guidance for neuronal and axonal extension. GS scaffold shows a significant nerve extension induction effect through its interlayer gap and gradient peptide density to dorsal root ganglia in vitro, while in vivo studies reveal its substantial promotion for functional recovery and neural repair. Additionally, the GS scaffold displays impressive drug-loading capacity, mesenchymal stem cell-derived exosomes can be efficiently loaded into the GS scaffold and delivered to the injury site, thereby synergistically promoting SCI repair. Overall, the GS scaffold can serve as a versatile platform and present a promising multifunctional approach for SCI treatment., (© 2024 Wiley‐VCH GmbH.)

Aims: Spinocerebellar Ataxia Type 3 (SCA3) is a rare genetic ataxia that impacts the entire brain and is characterized as a neurodegenerative disorder affecting the neural network. This study explores how alterations in the functional hierarchy, connectivity, and structural changes within specific brain regions significantly contribute to the heterogeneity of symptom manifestations in patients with SCA3., Methods: We prospectively recruited 51 patients with SCA3 and 59 age-and sex-matched healthy controls. All participants underwent comprehensive multimodal neuroimaging and clinical assessments. In SCA3 patients, an innovative approach utilizing gradients in resting-state functional connectivity (FC) was employed to examine atypical patterns of hierarchical processing topology from sensorimotor to supramodal regions in the cerebellum and cerebrum. Coupling analyses of abnormal FC and structural connectivity among regions of interest (ROIs) in the brain were also performed to characterize connectivity alterations. Additionally, relationships between quantitative ROI values and clinical variables were explored., Results: Patients with SCA3 exhibited either compression or expansion within the primary sensorimotor-to-supramodal gradient through four distinct calculation methods, along with disruptions in FC and structural connectivity coupling. A comprehensive correlation was identified between the altered gradients and the clinical manifestations observed in patients. Notably, altered fractional anisotropy values were not significantly correlated with clinical variables., Conclusion: Abnormal gradients and connectivity in the cerebellar and cerebral cortices in SCA3 patients may contribute to disrupted motor-to-supramodal functions. Moreover, these findings support the potential utility of FCG analysis as a biomarker for diagnosing SCA3 and assessing treatment efficacy., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Secreted chemokines form concentration gradients in target tissues to control migratory directions and patterns of immune cells in response to inflammatory stimulation; however, how the gradients are formed is much debated. Heparan sulfate (HS) binds to chemokines and modulates their activities. In this study, we investigated the roles of HS in the gradient formation and chemoattractant activity of CCL5 that is known to bind to HS. CCL5 and heparin underwent liquid-liquid phase separation and formed gradient, which was confirmed using CCL5 immobilized on heparin-beads. The biological implication of HS in CCL5 gradient formation was established in CHO-K1 (wild-type) and CHO-677 (lacking HS) cells by Transwell assay. The effect of HS on CCL5 chemoattractant activity was further proved by Transwell assay of human peripheral blood cells. Finally, peritoneal injection of the chemokines into mice showed reduced recruitment of inflammatory cells either by mutant CCL5 (lacking heparin-binding sequence) or by addition of heparin to wild-type CCL5. Our experimental data propose that co-phase separation of CCL5 with HS establishes a specific chemokine concentration gradient to trigger directional cell migration. The results warrant further investigation on other heparin-binding chemokines and allows for a more elaborate insight into disease process and new treatment strategies., Competing Interests: XY, GD, PP, LC, RG, WH, HZ, YW, LG, LL, TC, JL, SL No competing interests declared, (© 2024, Yu, Duan et al.)

Socio-economic differences in mortality are among the most pervasive characteristics of Western societies. While the mortality gradient by income is well established for the period after 1970, knowledge about the origins of this gradient is still rudimentary. We analyse the association between income and cause-specific adult mortality during the period 1905-2014 in an area of southern Sweden, using competing-risk hazard models with individual-level longitudinal data for over 2.2 million person-years and over 35,000 deaths. We find that the present-day income gradient in adult mortality emerged only in the period after the Second World War and did so for the leading causes of death and for men and women largely simultaneously.

Dynamic functional network connectivity (dFNC) analysis is a widely used approach for studying brain function and offering insight into how brain networks evolve over time. Typically, dFNC studies utilized fixed spatial maps and evaluate transient changes in coupling among time courses estimated from independent component analysis (ICA). This manuscript presents a complementary approach that relaxes this assumption by spatially reordering the components dynamically at each timepoint to optimize for a smooth gradient in the FNC (i.e., a smooth gradient among ICA connectivity values). Several methods are presented to summarize dynamic FNC gradients (dFNGs) over time, starting with static FNC gradients (sFNGs), then exploring the reordering properties as well as the dynamics of the gradients themselves. We then apply this approach to a dataset of schizophrenia (SZ) patients and healthy controls (HC). Functional dysconnectivity between different brain regions has been reported in schizophrenia, yet the neural mechanisms behind it remain elusive. Using resting state fMRI and ICA on a dataset consisting of 151 schizophrenia patients and 160 age and gender-matched healthy controls, we extracted 53 intrinsic connectivity networks (ICNs) for each subject using a fully automated spatially constrained ICA approach. We develop several summaries of our functional network connectivity gradient analysis, both in a static sense, computed as the Pearson correlation coefficient between full time series, and a dynamic sense, computed using a sliding window approach followed by reordering based on the computed gradient, and evaluate group differences. Static connectivity analysis revealed significantly stronger connectivity between subcortical (SC), auditory (AUD) and visual (VIS) networks in patients, as well as hypoconnectivity in sensorimotor (SM) network relative to controls. sFNG analysis highlighted distinctive clustering patterns in patients and HCs along cognitive control (CC)/ default mode network (DMN), as well as SC/ AUD/ SM/ cerebellar (CB), and VIS gradients. Furthermore, we observed significant differences in the sFNGs between groups in SC and CB domains. dFNG analysis suggested that SZ patients spend significantly more time in a SC/ CB state based on the first gradient, while HCs favor the SM/DMN state. For the second gradient, however, patients exhibited significantly higher activity in CB domains, contrasting with HCs' DMN engagement. The gradient synchrony analysis conveyed more shifts between SM/ SC networks and transmodal CC/ DMN networks in patients. In addition, the dFNG coupling revealed distinct connectivity patterns between SC, SM and CB domains in SZ patients compared to HCs. To recap, our results advance our understanding of brain network modulation by examining smooth connectivity trajectories. This provides a more complete spatiotemporal summary of the data, contributing to the growing body of current literature regarding the functional dysconnectivity in schizophrenia patients. By employing dFNG, we highlight a new perspective to capture large scale fluctuations across the brain while maintaining the convenience of brain networks and low dimensional summary measures., Competing Interests: Competing Interest The authors declare no competing interests.

Migrasomes, newly identified extracellular organelles produced by migrating cells, are observed widely across both in vivo and in vitro studies. These organelles, rich in signaling and bioactive molecules, are pivotal in a range of physiological functions. This opinion summarizes current understanding of migrasomes, highlighting their importance as a versatile mechanism for cell-cell communication. Furthermore, it examines their roles in health and disease and potential diagnostic and therapeutic applications, and addresses the emerging challenges and open questions in this developing field., Competing Interests: Declaration of interests L.Y. is the scientific founder of Migrasome Therapeutics. The remaining authors have no interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Flexible sensors are prone to the problems of slow recovery rate and large residual strain in practical use. In this paper, a polyurethane functional composite with a gradient change in elastic modulus is proposed as a flexible sensor to meet the recovery rate and residual strain without affecting the motion. Different hard and soft segment ratios are used to synthesize a gradient polyurethane structure. The conductive percolation threshold was obtained between 45 wt% and 50 wt% of flake silver powder. Both gradient polyurethane and gradient polyurethane composites demonstrated that gradient materials can increase the recovery rate and reduce residual strain. The gradient polyurethane composites had a tensile strength of 3.26 MPa, an elastic modulus of 2.58 MPa, an elongation at break of 245%, a sensitivity coefficient of 1.20 at 0-25% deformation, a sensitivity coefficient of 11.38 at 25-75% deformation, a rate of recovery of 1.95 s at a time, and a resistance to fatigue (over 1000 cycles at a fixed strain of 20% showed a stable electrical response). The sensing performance under different cyclic strain frequencies was also investigated. The process has practical applications in the field of wearable skin motion and health monitoring.

To assess cellular behavior within heterogeneous tissues, such as bone, skin, and nerves, scaffolds with biophysical gradients are required to adequately replicate the in vivo interaction between cells and their native microenvironment. In this study, we introduce a strategy for depositing ultrathin films comprised of laminin-111 with precisely controlled biophysical gradients onto planar substrates using the Langmuir-Blodgett (LB) technique. The gradient is created by controlled desynchronization of the barrier compression and substrate withdrawal speed during the LB deposition process. Characterization of the films was performed using techniques such as atomic force microscopy and confocal fluorescence microscopy, enabling the comprehensive analysis of biophysical parameters along the gradient direction. Furthermore, human adipose-derived stem cells were seeded onto the gradient films to investigate the influence of protein density on cell attachment, showing that the distribution of the cells can be modulated by the arrangement of the laminin at the air-water interface. The presented approach not only allowed us to gain insights into the intricate interplay between biophysical cues and cell behavior within complex tissue environments, but it is also suited as a screening approach to determine optimal protein concentrations to achieve a target cellular output., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Bone scaffolds are widely employed for treating various bone disorders, including defects, fractures, and accidents. Gradient bone scaffolds present a promising approach by incorporating gradients in shape, porosity, density, and other properties, mimicking the natural human body structure. This design offers several advantages over traditional scaffolds. A key advantage is the enhanced matching of human tissue properties, facilitating cell adhesion and migration. Furthermore, the gradient structure fosters a smooth transition between scaffold and surrounding tissue, minimizing the risk of inflammation or rejection. Mechanical stability is also improved, providing better support for bone regeneration. Additionally, gradient bone scaffolds can integrate drug delivery systems, enabling controlled release of drugs or growth factors to promote specific cellular activities during the healing process. This comprehensive review examines the design aspects of gradient bone scaffolds, encompassing structure and drug delivery capabilities. By optimizing the scaffold's inherent advantages through gradient design, bone regeneration outcomes can be improved. The insights presented in this article contribute to the academic understanding of gradient bone scaffolds and their applications in bone tissue engineering., (© 2024 IOP Publishing Ltd.)

Background: Previous studies have shown that women with hypertrophic obstructive cardiomyopathy (HCM) have worse long-term outcomes irrespective of intervention. However, the outcomes of patients undergoing alcohol septal ablation (ASA) based on sex have not been described. Hence, this study aimed to evaluate pressure changes and long-term mortality in patients with HCM undergoing ASA based on sex., Methods and Results: This is a single-center retrospective study evaluating hemodynamic changes and long-term mortality in patients with HCM treated with ASA according to sex. A total of 259 patients were included (aged 68.4±11.9 years, 62.2% women). Women had higher age and baseline pressures at the time of ASA, with a greater percent reduction in mean left atrial pressure (men versus women: 2.2% versus 15.9%, respectively; P =0.02). Women had better survival (median survival rate of men versus women: 8.6 versus 12.5 years, respectively; P =0.011). On Cox multivariable regression, predictors of mortality were age (per group change <60 years, 61-70 years, 71-80 years, and >80 years; hazard ratio [HR], 1.45 [95% CI, 1.10-1.91], P =0.008), female sex (HR, 0.59 [95% CI, 0.35-0.99], P =0.048), chronic kidney disease (HR, 1.88 [95% CI, 1.06-3.33], P =0.031), and left ventricular outflow tract gradient reduction ≤86% (HR, 1.91 [95% CI, 1.14-3.19], P =0.014)., Conclusions: Women with HCM undergoing ASA are older and have higher left-sided baseline pressures compared with men yet have better survival. Further studies exploring the mechanisms of differential outcomes according to sex in patients with HCM undergoing ASA are needed.

The RNA-silencing effector ARGONAUTE10 influences cell fate in plant shoot and floral meristems. ARGONAUTE10 also accumulates in the root apical meristem (RAM), yet its function(s) therein remain elusive. Here, we show that ARGONAUTE10 is expressed in the root cell initials where it controls overall RAM activity and length. ARGONAUTE10 is also expressed in the stele, where post-transcriptional regulation confines it to the root tip's pro-vascular region. There, variations in ARGONAUTE10 levels modulate metaxylem-vs-protoxylem specification. Both ARGONAUTE10 functions entail its selective, high-affinity binding to mobile miR165/166 transcribed in the neighboring endodermis. ARGONAUTE10-bound miR165/166 is degraded, likely via SMALL-RNA-DEGRADING-NUCLEASES1/2, thus reducing miR165/166 ability to silence, via ARGONAUTE1, the transcripts of cell fate-influencing transcription factors. These include PHABULOSA (PHB), which controls meristem activity in the initials and xylem differentiation in the pro-vasculature. During early germination, PHB transcription increases while dynamic, spatially-restricted transcriptional and post-transcriptional mechanisms reduce and confine ARGONAUTE10 accumulation to the provascular cells surrounding the newly-forming xylem axis. Adequate miR165/166 concentrations are thereby channeled along the ARGONAUTE10-deficient yet ARGONAUTE1-proficient axis. Consequently, inversely-correlated miR165/166 and PHB gradients form preferentially along the axis despite ubiquitous PHB transcription and widespread miR165/166 delivery inside the whole vascular cylinder., (© 2024. The Author(s).)

The default mode network (DMN) lies towards the heteromodal end of the principal gradient of intrinsic connectivity, maximally separated from the sensory-motor cortex. It supports memory-based cognition, including the capacity to retrieve conceptual and evaluative information from sensory inputs, and to generate meaningful states internally; however, the functional organisation of DMN that can support these distinct modes of retrieval remains unclear. We used fMRI to examine whether activation within subsystems of DMN differed as a function of retrieval demands, or the type of association to be retrieved, or both. In a picture association task, participants retrieved semantic associations that were either contextual or emotional in nature. Participants were asked to avoid generating episodic associations. In the generate phase, these associations were retrieved from a novel picture, while in the switch phase, participants retrieved a new association for the same image. Semantic context and emotion trials were associated with dissociable DMN subnetworks, indicating that a key dimension of DMN organisation relates to the type of association being accessed. The frontotemporal and medial temporal DMN showed a preference for emotional and semantic contextual associations, respectively. Relative to the generate phase, the switch phase recruited clusters closer to the heteromodal apex of the principal gradient-a cortical hierarchy separating unimodal and heteromodal regions. There were no differences in this effect between association types. Instead, memory switching was associated with a distinct subnetwork associated with controlled internal cognition. These findings delineate distinct patterns of DMN recruitment for different kinds of associations yet common responses across tasks that reflect retrieval demands., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Temporal lobe epilepsy (TLE) is the most common pharmaco-resistant epilepsy in adults. While primarily associated with mesiotemporal pathology, recent evidence suggests that brain alterations in TLE extend beyond the paralimbic epicenter and impact macroscale function and cognitive functions, particularly memory. Using connectome-wide manifold learning and generative models of effective connectivity, we examined functional topography and directional signal flow patterns between large-scale neural circuits in TLE at rest. Studying a multisite cohort of 95 patients with TLE and 95 healthy controls, we observed atypical functional topographies in the former group, characterized by reduced differentiation between sensory and transmodal association cortices, with most marked effects in bilateral temporo-limbic and ventromedial prefrontal cortices. These findings were consistent across all study sites, present in left and right lateralized patients, and validated in a subgroup of patients with histopathological validation of mesiotemporal sclerosis and post-surgical seizure freedom. Moreover, they were replicated in an independent cohort of 30 TLE patients and 40 healthy controls. Further analyses demonstrated that reduced differentiation related to decreased functional signal flow into and out of temporolimbic cortical systems and other brain networks. Parallel analyses of structural and diffusion-weighted MRI data revealed that topographic alterations were independent of TLE-related cortical thinning but partially mediated by white matter microstructural changes that radiated away from paralimbic circuits. Finally, we found a strong association between the degree of functional alterations and behavioral markers of memory dysfunction. Our work illustrates the complex landscape of macroscale functional imbalances in TLE, which can serve as intermediate markers bridging microstructural changes and cognitive impairment., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Systemic systolic (SAP) and mean (MAP) arterial pressure monitoring is the cornerstone in hemodynamic management of the cardiac surgical patient, and the radial artery is the most common site of catheter placement. The present study compared 3 different arterial line procedures. It is hypothesized that a 20-G 12.7- cm catheter inserted into the radial artery will be equal to a 20-G 12.7- cm angiocath placed in the brachial artery, and superior to a 20-G 5.00 cm angiocath placed in the radial artery., Design: A prospective randomized control study was performed., Setting: Single academic university hospital., Participants: Adult patients ≥18 years old undergoing nonemergent cardiac surgery using cardiopulmonary bypass (CPB)., Interventions: After approval by the Rhode Island Hospital institutional review board, a randomized prospective control study to evaluate 3 different peripheral intraarterial catheter systems was performed: (1) Radial Short (RS): 20-G 5- cm catheter; (2) Radial Long (RL): 20-G 12- cm catheter; and (3) Brachial Long (BL): 20-G 12- cm catheter., Measurements and Results: Gradients between central aortic and peripheral catheters (CA-P) were compared and analyzed before CPB and 2 and 10 minutes after separation from CPB. The placement of femoral arterial lines and administration of vasoactive medications were recorded. After exclusions, 67 BL, 61 RL, and 66 RS patients were compared. Before CPB, CA-P SAP and MAP gradients were not significant among the 3 groups. Two minutes after CPB, the CA-P SAP gradient was significant for the RS group (p = 0.005) and insignificant for BL (p = 0.47) and RL (p = 0.39). Two-group analysis revealed that CA-P SAP gradients are similar between BL and RL (p = 0.84), both of which were superior to RS (p = 0.02 and p = 0.04, respectively). At 10 minutes after CPB, the CA-P SAP gradient for RS remained significant (p = 0.004) and similar to the gradient at 2 minutes. The CA-P SAP gradients increased from 2 to 10 minutes for BL (p = 0.13) and RL (p = 0.06). Two minutes after CPB, the CA-P MAP gradients were significant for the BL (p = 0.003), RL (p < 0.0001), and RS (p < 0.0001) groups. Two-group analysis revealed that the CA-P MAP gradients were lower for the BL group compared with the RL (p = 0.054) and RS (p< 0.05) groups. Ten minutes after CPB, the CA-P MAP gradients in the RL and RS groups remained significant (p < 0.0001) and both greater than the BL group (p = 0.002). A femoral arterial line was placed more frequently in the RS group (8/66 = 12.1%) than in the RL group (3/61 = 4.9%) and the BL group (2/67 = 3.0%). Vasopressin was administered significantly more frequently in the RS group., Conclusion: Regarding CA-P SAP gradients, the RL group performed equally to the BL group, both being superior to RS. Regarding CA-P MAP gradients, BL was superior to RL and RS. Clinically, femoral line placement and vasopressin administration were fewer for the BL and RL groups when compared with the RS group. This study demonstrated the benefits of a long (12.7 cm) 20- G angiocath placed in the radial artery., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hair cells in the cochlear sensory epithelia serve as mechanosensory receptors, converting sound into neuronal signals. The basal sensory epithelia are responsible for transducing high-frequency sounds, while the apex handles low-frequency sounds. Age-related hearing loss predominantly affects hearing at high frequencies and is indicative of damage to the basal sensory epithelia. However, the precise mechanism underlying this site-selective injury remains unclear. In this study, we employed a microscale proteomics approach to examine and compare protein expression in different regions of the cochlear sensory epithelia (upper half and lower half) in 1.5-month-old (normal hearing) and 6-month-old (severe high-frequency hearing loss without hair cell loss) C57BL/6J mice. A total of 2,386 proteins were detected, and no significant differences in protein expression were detected in the upper half of the cochlear sensory epithelia between the two age groups. The expression of 20 proteins in the lower half of the cochlear sensory epithelia significantly differed between the two age groups (e.g., MATN1, MATN4, and AQP1). Moreover, there were 311 and 226 differentially expressed proteins between the upper and lower halves of the cochlear sensory epithelia in 1.5-month-old and 6-month-old mice, respectively. The expression levels of selected proteins were validated by Western blotting. These findings suggest that the spatial differences in protein expression within the cochlear sensory epithelia may play a role in determining the susceptibility of cells at different sites of the cochlea to age-related damage., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heparan sulfate (HS) is a glycosaminoglycan, polysaccharides that are considered to have arisen in the last common unicellular ancestor of multicellular animals. In this light, the large interactome of HS and its myriad functions in relation to the regulation of cell communication are not surprising. The binding of proteins to HS determines their localisation and diffusion, essential for embryonic development and homeostasis. Following the biosynthesis of the initial heparosan polymer, the subsequent modifications comprise an established canonical pathway and a minor pathway. The more frequent former starts with N-deacetylation and N-sulfation of GlcNAc residues, the latter with C-5 epimerisation of a GlcA residue adjacent to a GlcNAc. The binding of proteins to HS is driven by ionic interactions. The multivalent effect arising from the many individual ionic bonds between a single protein and a polysaccharide chain results in a far stronger interaction than would be expected from an ion-exchange process. In many instances, upon binding, both parties undergo substantial conformational change, the resulting hydrogen and van der Waal bonds contributing significant free energy to the binding reaction. Nevertheless, ionic bonds dominate the protein-polysaccharide interaction kinetically. Together with the multivalent effect, this provides an explanation for the observed trapping of HS-binding proteins in extracellular matrix. Importantly, individual ionic bonds have been observed to be dynamic; breaking and reforming, while the protein remains bound to the polysaccharide. These considerations lead to a model for 1D diffusion of proteins in extracellular matrix on HS, involving mechanisms such as sliding, chain switching and rolling., (© 2024 The Author(s).)

Purpose: When performing single-point dose verification in VMAT, it is necessary to avoid the regions with steep dose gradient. We propose a method to obtain the estimated value ( U plan ) of uncertainty of the absolute dose measurement due to the phantom setup error by using dose gradient calculated from treatment planning system (TPS), for evaluating the appropriate measurement points., Methods: The dose gradient was calculated from the planned dose values in the vicinity of the isocenter point using TPS. The phantom setup error was estimated. The U plan was calculated using the proposed formula after estimating the phantom setup error. Then, the dose gradient was calculated from the measured dose values in the vicinity of the isocenter point specified by TPS using the Tough water phantom with ionization chamber (IC), and U meas was calculated as in U plan ., Results: The correlation coefficient between U plan and U meas was 0.984, which indicates a high correlation. The average of the difference between U meas and U plan was -0.24%. We considered that this result was caused by the influence of volume averaging effect of IC., Conclusion: The U plan obtained from this proposed method reflects the uncertainty of the absolute dose measurement due to the phantom setup error and is useful for evaluating the appropriate measurement points for absolute dose measurement.

Due to its high sensitivity and specificity, Micro-Raman spectroscopy has emerged as a vital technique for molecular recognition and identification. As a weakly scattered signal, ensuring the accurate focus of the sample is essential for acquiring high quality Raman spectral signal and its analysis, especially in some complex microenvironments such as intracellular settings. Traditional autofocus methods are often time consuming or necessitate additional hardware, limiting real-time sample observation and device compatibility. Here, we propose an adaptive focusing method based on residual network to realize rapid and accurate focusing on Micro-Raman measurements. Using only a bright field image of the sample acquired on any image plane, we can predict the defocus distance with a residual network trained by Resnet50, in which the focus position is determined by combining the gradient and discrete cosine transform. Further, detailed regional division of the bright field map used for characterizing the height variation of actual sample surface is performed. As a result, a focus prediction map with 1μm accuracy is obtained from a bright field image in 120 ms. Based on this method, we successfully realize Raman signal optimization and the necessary correction of spectral information. This adaptive focusing method based on residual network is beneficial to further enhance the sensitivity and accuracy of Micro-Raman spectroscopy technology, which is of great significance in promoting the wide application of Raman spectroscopy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Achieving non-invasive spatiotemporal control over cellular functions, tissue organization, and behavior is a desirable aim for advanced therapies. Magnetic fields, due to their negligible interaction with biological matter, are promising for in vitro and in vivo applications, even in deep tissues. Particularly, the remote manipulation of paramagnetic (including superparamagnetic and ferromagnetic, all with a positive magnetic susceptibility) entities through magnetic instruments has emerged as a promising approach across various biological contexts. However, variations in the properties and descriptions of these instruments have led to a lack of reproducibility and comparability among studies. This article addresses the need for standardizing the characterization of magnetic instruments, with a specific focus on their ability to control the movement of paramagnetic objects within organisms. While it is well known that the force exerted on magnetic particles depends on the spatial variation (gradient) of the magnetic field, the magnitude of the field is often overlooked in the literature. Therefore, we comprehensively analyze and discuss both actors and propose a novel descriptor, termed 'effective gradient', which combines both dependencies. To illustrate the importance of both factors, we characterize different magnet systems and relate them to experiments involving superparamagnetic nanoparticles. This standardization effort aims to enhance the reproducibility and comparability of studies utilizing magnetic instruments for biological applications., (© 2024. The Author(s).)

Objective: To assess the possible influence of third-order shim coils on the behavior of the gradient field and in gradient-magnet interactions at 7 T and above., Materials and Methods: Gradient impulse response function measurements were performed at 5 sites spanning field strengths from 7 to 11.7 T, all of them sharing the same exact whole-body gradient coil design. Mechanical fixation and boundary conditions of the gradient coil were altered in several ways at one site to study the impact of mechanical coupling with the magnet on the field perturbations. Vibrations, power deposition in the He bath, and field dynamics were characterized at 11.7 T with the third-order shim coils connected and disconnected inside the Faraday cage., Results: For the same whole-body gradient coil design, all measurements differed greatly based on the third-order shim coil configuration (connected or not). Vibrations and gradient transfer function peaks could be affected by a factor of 2 or more, depending on the resonances. Disconnecting the third-order shim coils at 11.7 T also suppressed almost completely power deposition peaks at some frequencies., Discussion: Third-order shim coil configurations can have major impact in gradient-magnet interactions with consequences on potential hardware damage, magnet heating, and image quality going beyond EPI acquisitions., (© 2024. The Author(s).)

Objective: Here we aimed to explore the differences in individual gray matter (GM) networks at baseline in mild cognitive impairment patients who converted to Alzheimer's disease (AD) within 3 years (MCI-C) and nonconverters (MCI-NC)., Materials and Methods: Data from 461 MCI patients (180 MCI-C and 281 MCI-NC) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For each subject, a GM network was constructed using 3D-T1 imaging and the Kullback-Leibler divergence method. Gradient and topological analyses of individual GM networks were performed, and partial correlations were calculated to evaluate relationships among network properties, cognitive function, and apolipoprotein E (APOE) €4 alleles. Subsequently, a support vector machine (SVM) model was constructed to discriminate the MCI-C and MCI-NC patients at baseline., Results: The gradient analysis revealed that the principal gradient score distribution was more compressed in the MCI-C group than in the MCI-NC group, with scores for the left lingual gyrus, right fusiform gyrus and left middle temporal gyrus being increased in the MCI-C group (p < 0.05, FDR corrected). The topological analysis showed significant differences in nodal efficiency in four nodes between the two groups. Furthermore, the regional gradient scores or nodal efficiency were found to be significantly related to the neuropsychological test scores, and the left middle temporal gyrus gradient scores were positively associated with the number of APOE €4 alleles (r = 0.192, p = 0.002). Ultimately, the SVM model achieved a balanced accuracy of 79.4% in classifying MCI-C and MCI-NC patients (p < 0.001)., Conclusion: The whole-brain GM network hierarchy in the MCI-C group was more compressed than that in the MCI-NC group, suggesting more serious cognitive impairments in the MCI-C group. The left middle temporal gyrus gradient scores were related to both cognitive function and APOE €4 alleles, thus serving as potential biomarkers distinguishing MCI-C from MCI-NC at baseline., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Functional traits influence the assembly of microbial communities, but identifying these traits in the environment has remained challenging. We studied ectomycorrhizal fungal (EMF) communities inhabiting Populus trichocarpa roots distributed across a precipitation gradient in the Pacific Northwest, USA. We profiled these communities using taxonomic (meta-barcoding) and functional (metagenomic) approaches. We hypothesized that genes involved in fungal drought-stress tolerance and fungal mediated plant water uptake would be most abundant in drier soils. We were unable to detect support for this hypothesis; instead, the abundance of genes involved in melanin synthesis, hydrophobins, aquaporins, trehalose-synthases, and other gene families exhibited no significant shifts across the gradient. Finally, we studied variation in sequence homology for certain genes, finding that fungal communities in dry soils are composed of distinct aquaporin and hydrophobin gene sequences. Altogether, our results suggest that while EMF communities exhibit significant compositional shifts across this gradient, coupled functional turnover, at least as inferred using community metagenomics is limited. Accordingly, the consequences of these distinct EMF communities on plant water uptake remain critically unknown, and future studies targeting the expression of genes involved in drought stress tolerance are required., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Therapeutic options for staphylococcus infections have been raised due to the emergence of VISA and VRSA. Six isolates of Staphylococcus aureus of clinical origin which were previously confirmed to carry vanG were selected for this study. Antimicrobial susceptibility was performed by disc diffusion method. Transcriptional expression of vanG and vanS G showed down regulation against vancomycin and teicoplanin but expression was increased with increasing concentration of antibiotics. vanU G , vanR G showed up regulation against glycopeptide exposure. The present study underscored that expression of vanG and its regulatory gene operons are dependent on concentration of vancomycin and teicoplanin exposure in S.aureus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

Antireflection coatings (ARCs) enhance optical clarity and improve light transmission by reducing glare and reflections. The application of conventional ARCs in flexible devices, however, is impeded by their lack of durability, particularly under bending deformation. We develop ARCs that withstand delamination and fracture, remaining intact even after 1000 bending cycles with a 5 cm bending radius. We fabricate integrated ARCs (iARCs) on a poly(methyl methacrylate) (PMMA) substrate by inducing free polymers to infiltrate the interstices of a disordered assembly of hollow silica nanochains and nanospheres. The polydispersity of PMMA creates a refractive index gradient, yielding a broadband antireflection capability. The nanochain-based iARCs are superior to the nanosphere-based coatings in both antireflection properties and mechanical durability, owing to the lower packing density and mechanical interlocking of the nanochains, respectively. Additionally, these nanochain iARCs display antifogging properties stemming from their superhydrophilicity. While our demonstrations are based on PMMA as a model substrate, this methodology is potentially extendable to other polymers, enhancing the iARC's applicability across various practical applications, including flexible and wearable devices.

Introduction: Plant growth is a plastic phenomenon controlled both by endogenous genetic programs and by environmental cues. The embryonic stem, the hypocotyl, is an ideal model system for the quantitative study of growth due to its relatively simple geometry and cellular organization, and to its essentially unidirectional growth pattern. The hypocotyl of Arabidopsis thaliana has been studied particularly well at the molecular-genetic level and at the cellular level, and it is the model of choice for analysis of the shade avoidance syndrome (SAS), a growth reaction that allows plants to compete with neighboring plants for light. During SAS, hypocotyl growth is controlled primarily by the growth hormone auxin, which stimulates cell expansion without the involvement of cell division., Methods: We assessed hypocotyl growth at cellular resolution in Arabidopsis mutants defective in auxin transport and biosynthesis and we designed a mathematical auxin transport model based on known polar and non-polar auxin transporters (ABCB1, ABCB19, and PINs) and on factors that control auxin homeostasis in the hypocotyl. In addition, we introduced into the model biophysical properties of the cell types based on precise cell wall measurements., Results and Discussion: Our model can generate the observed cellular growth patterns based on auxin distribution along the hypocotyl resulting from production in the cotyledons, transport along the hypocotyl, and general turnover of auxin. These principles, which resemble the features of mathematical models of animal morphogen gradients, allow to generate robust shallow auxin gradients as they are expected to exist in tissues that exhibit quantitative auxin-driven tissue growth, as opposed to the sharp auxin maxima generated by patterning mechanisms in plant development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Favre, van Schaik, Schorderet, Yerly and Reinhardt.)

Background: Few data exist on the comparative long-term outcomes of severe aortic stenosis (AS) patients with different flow-gradient patterns undergoing transcatheter aortic valve implantation (TAVI). This study sought to evaluate the impact of the pre-TAVI flow-gradient pattern on long-term clinical outcomes after TAVI and assess changes in the left ventricular ejection fraction (LVEF) of different subtypes of AS patients following TAVI. Methods: Consecutive patients with severe AS undergoing TAVI in our institution were screened and prospectively enrolled. Patients were divided into four subgroups according to pre-TAVI flow/gradient pattern: (i) low flow-low gradient (LF-LG): stroke volume indexed (SVi) ≤ 35 mL/m 2 and mean gradient (MG) < 40 mmHg); (ii) normal flow-low gradient (NF-LG): SVi > 35 mL/m 2 and MG < 40 mmHg; (iii) low flow-high gradient (LF-HG): Svi 35 mL/m 2 and MG ≥ 40 mmHg and (iv) normal flow-high gradient (NF-HG): SVi > 35 mL/m 2 and MG ≥ 40 mmHg. Transthoracic echocardiography was repeated at 1-year follow-up. Clinical follow-up was obtained at 12 months, and yearly thereafter until 5-year follow-up was complete for all patients. Results: A total of 272 patients with complete echocardiographic and clinical follow-up were included in our analysis. Their mean age was 80 ± 7 years and the majority of patients (N = 138, 50.8%) were women. 62 patients (22.8% of the study population) were distributed in the LF-LG group, 98 patients (36%) were LF-HG patients, 95 patients (34.9%) were NF-HG, and 17 patients (6.3%) were NF-LG. There was a greater prevalence of comorbidities among LF-LG AS patients. One-year all-cause mortality differed significantly between the four subgroups of AS patients (log-rank p: 0.022) and was more prevalent among LF-LG patients (25.8%) compared to LF-HG (11.3%), NF-HG (6.3%) and NF-LG patients (18.8%). At 5-year follow-up, global mortality remained persistently higher among LF-LG patients (64.5%) compared to LF-HG (47.9%), NF-HG (42.9%), and NF-LG patients (58.8%) (log-rank p: 0.029). At multivariable Cox hazard regression analysis, baseline SVi (HR: 0.951, 95% C.I.; 0.918-0.984), the presence of at least moderate tricuspid regurgitation at baseline (HR: 3.091, 95% C.I: 1.645-5.809) and at least moderate paravalvular leak (PVL) post-TAVI (HR: 1.456, 95% C.I.: 1.106-1.792) were significant independent predictors of late global mortality. LF-LG patients and LF-HG patients exhibited a significant increase in LVEF at 1-year follow-up. A lower LVEF ( p < 0.001) and a lower Svi ( p < 0.001) at baseline were associated with LVEF improvement at 1-year. Conclusions: Patients with LF-LG AS have acceptable 1-year outcomes with significant improvement in LVEF at 1-year follow-up, but exhibit exceedingly high 5-year mortality following TAVI. The presence of low transvalvular flow and at least moderate tricuspid regurgitation at baseline and significant paravalvular leak post-TAVI were associated with poorer long-term outcomes in the entire cohort of AS patients. The presence of a low LVEF or a low SVi predicts LVEF improvement at 1-year.

Background: The timely diagnosis of medical conditions, particularly diabetic retinopathy, relies on the identification of retinal microaneurysms. However, the commonly used retinography method poses a challenge due to the diminutive dimensions and limited differentiation of microaneurysms in images., Problem Statement: Automated identification of microaneurysms becomes crucial, necessitating the use of comprehensive ad-hoc processing techniques. Although fluorescein angiography enhances detectability, its invasiveness limits its suitability for routine preventative screening., Objective: This study proposes a novel approach for detecting retinal microaneurysms using a fundus scan, leveraging circular reference-based shape features (CR-SF) and radial gradient-based texture features (RG-TF)., Methodology: The proposed technique involves extracting CR-SF and RG-TF for each candidate microaneurysm, employing a robust back-propagation machine learning method for training. During testing, extracted features from test images are compared with training features to categorize microaneurysm presence., Results: The experimental assessment utilized four datasets (MESSIDOR, Diaretdb1, e-ophtha-MA, and ROC), employing various measures. The proposed approach demonstrated high accuracy (98.01%), sensitivity (98.74%), specificity (97.12%), and area under the curve (91.72%)., Conclusion: The presented approach showcases a successful method for detecting retinal microaneurysms using a fundus scan, providing promising accuracy and sensitivity. This non-invasive technique holds potential for effective screening in diabetic retinopathy and other related medical conditions., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

A major factor driving stem cell decline is stem cell niche aging, but its molecular mechanism remains elusive. We use the Caenorhabditis elegans distal tip cell (DTC), the mesenchymal niche that employs Notch signaling to regulate germline stem cells (GSCs), as an in vivo niche aging model and delineate the molecular details of the DTC/niche aging process. Here, we demonstrate that a drastic decrease in C. elegans germline fecundity, which begins even in early adulthood, is mainly due to an age-induced disruption in spatial regulation of Notch-dependent transcription in the germline combined with a moderate reduction in Notch transcription at both tissue and cellular levels. Consequently, the Notch-responsive GSC pool shifts from the distal end of the gonad to a more proximal region, disrupting the distal-to-proximal germline polarity. We find that this GSC pool shift is due to a dislocation of the DTC/niche nucleus, which is associated with age-induced changes in the structure and morphology of the DTC/niche. Our findings reveal a critical link between physiological changes in the aging niche, their consequences in stem cell regulation, and germline tissue functions., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Hierarchy is the organizing principle of human brain network. How network hierarchy changes in subthreshold depression (StD) is unclear. The aim of this study was to investigate the altered brain network hierarchy and its clinical significance in patients with StD., Methods: A total of 43 patients with StD and 43 healthy controls matched for age, gender and years of education participated in this study. Alterations in the hierarchy of StD brain networks were depicted by connectome gradient analysis. We assessed changes in network hierarchy by comparing gradient scores in each network in patients with StD and healthy controls. The study compared different brain subdivisions if there was a different network. Finally, we analysed the relationship between the altered gradient scores and clinical characteristics., Results: Patients with StD had contracted network hierarchy and suppressed cortical range gradients. In the principal gradient, the gradient scores of default mode network were significantly reduced in patients with StD compared to controls. In the default network, the subdivisions of reduced gradient scores were mainly located in the precuneus, superior temporal gyrus, and anterior and posterior cingulate gyrus. Reduced gradient scores in the default mode network, the anterior and posterior cingulate gyrus were correlated with severity of depression., Conclusions: The network hierarchy of the StD changed and was significantly correlated with depressive symptoms and severity. These results provided new insights into further understanding of the neural mechanisms of StD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In mountain forests, tree regeneration is limited by increasingly frequent frosts with increasing elevation. We investigated the effects of exposure to freezing temperature on early life stages of two native trees of different elevational origin in a seasonally dry mountain forest. We hypothesized that the negative effects of freezing exposure on performance of early life stages increases as freezing temperature decreases, and that frost resistance increases in plants of high elevational origin. We collected seeds of two tree species (Kageneckia lanceolata and Lithraea molleoides) from populations located at different elevations and grew seedlings and saplings in a greenhouse. Dry seeds, imbibed seeds and 1-month-old seedlings were exposed to seven temperature treatments ranging from 4 °C to -20 °C, while 12-month-old saplings were exposed to four temperature treatments from -8 °C to -20 °C. After freezing exposure in a climate chamber, we monitored seed germination and seedling and sapling survival. Germination of K. lanceolata decreased with decreasing temperature only for imbibed seeds from mid- and high elevations, whereas germination of L. molleoides slightly increased with decreasing temperature only for imbibed seeds from high elevations. For both species, seedling survival decreased with decreasing temperature. For K. lanceolata, the negative effects of freezing temperatures were weaker as elevational origin of seeds increased, whereas L. molleoides showed the opposite pattern. For both species, saplings only survived at the mildest applied freezing temperature (-8 °C). We conclude that effects of climatic variation associated with elevation depend on the study species and life stage. The observed patterns could be caused by maternal effects, which are absent at the sapling stage. Moreover, temperatures below -8 °C can limit recruitment since partial mortality of seedlings and saplings occurred at such values., (© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Internal tibial loading is influenced by modifiable factors with implications for the risk of stress injury. Runners encounter varied surface steepness (gradients) when running outdoors and may adapt their speed according to the gradient. This study aimed to quantify tibial bending moments and stress at the anterior and posterior peripheries when running at different speeds on surfaces of different gradients., Methods: Twenty recreational runners ran on a treadmill at 3 different speeds (2.5 m/s, 3.0 m/s, and 3.5 m/s) and gradients (level: 0%; uphill: +5%, +10%, and +15%; downhill: -5%, -10%, and -15%). Force and marker data were collected synchronously throughout. Bending moments were estimated at the distal third centroid of the tibia about the medial-lateral axis by ensuring static equilibrium at each 1% of stance. Stress was derived from bending moments at the anterior and posterior peripheries by modeling the tibia as a hollow ellipse. Two-way repeated-measures analysis of variance were conducted using both functional and discrete statistical analyses., Results: There were significant main effects for running speed and gradient on peak bending moments and peak anterior and posterior stress. Higher running speeds resulted in greater tibial loading. Running uphill at +10% and +15% resulted in greater tibial loading than level running. Running downhill at -10% and -15% resulted in reduced tibial loading compared to level running. There was no difference between +5% or -5% and level running., Conclusion: Running at faster speeds and uphill on gradients ≥+10% increased internal tibial loading, whereas slower running and downhill running on gradients ≥-10% reduced internal loading. Adapting running speed according to the gradient could be a protective mechanism, providing runners with a strategy to minimize the risk of tibial stress injuries., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Recent studies support a model in which the progeny of SOX9 + epithelial progenitors at the distal tip of lung branches undergo cell allocation and differentiation sequentially along the distal-to-proximal axis. Concomitant with the elongation and ramification of lung branches, the descendants of the distal SOX9 + progenitors are distributed proximally, express SOX2, and differentiate into cell types in the conducting airways. Amid subsequent sacculation, the distal SOX9 + progenitors generate alveolar epithelial cells to form alveoli. Sequential cell allocation and differentiation are integrated with the branching process to generate a functional branching organ. This review focuses on the roles of SOX9 + cells as precursors for new branches, as the source of various cell types in the conducting airways, and as progenitors of the alveolar epithelium. All of these processes are controlled by multiple signaling pathways. Many mouse mutants with defective lung branching contain underlying defects in one or more steps of cell allocation and differentiation of SOX9 + progenitors. This model provides a framework to understand the molecular basis of lung phenotypes and to elucidate the molecular mechanisms of lung patterning. It builds a foundation on which comparing and contrasting the mechanisms employed by different branching organs in diverse species can be made., (© 2023 The Authors. BioEssays published by Wiley Periodicals LLC.)

fMRI of the human brain reveals spatiotemporal patterns of functional connectivity (FC), forming distinct cortical networks. Lately, subcortical contributions to these configurations are receiving renewed interest, but investigations rarely focus explicitly on their effects on cortico-cortical FC. Here, we employ a straightforward multivariable approach and graph-theoretic tools to assess subcortical impact on topological features of cortical networks. Given recent evidence showing that structures like the thalamus and basal ganglia integrate input from multiple networks, we expect increased segregation between cortical networks after removal of subcortical effects on their FC patterns. We analyze resting state data of young and healthy participants (male and female; N = 100) from the human connectome project. We find that overall, the cortical network architecture becomes less segregated, and more integrated, when subcortical influences are accounted for. Underlying these global effects are the following trends: 'Transmodal' systems become more integrated with the rest of the network, while 'unimodal' networks show the opposite effect. For single nodes this hierarchical organization is reflected by a close correspondence with the spatial layout of the principal gradient of FC (Margulies et al., 2016). Lastly, we show that the limbic system is significantly less coherent with subcortical influences removed. The findings are validated in a (split-sample) replication dataset. Our results provide new insight regarding the interplay between subcortex and cortical networks, by putting the integrative impact of subcortex in the context of macroscale patterns of cortical organization., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial or personal interests that might have influenced the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

The cost of walking and running on uneven terrain is not directly explained by external mechanical work. Although metabolic cost of transport increases linearly with gradient at uphill and downhill gradients exceeding 15%, at shallower gradients, the relationship is nonlinear, with the minimum cost occurring at ∼10% downhill grade. Given these nonlinear relationships between grade and metabolic cost, we projected a significant difference in the total metabolic cost of two walking conditions that required the same total external mechanical work be performed over the same total period of time; in one condition, time was spent walking to gradients that were fixed at +10.5% and -10.5% and in the other condition time was spent walking to gradients that varied from 0 to +21% and from -21 to 0%. We compared these two conditions experimentally, using an approach to quantify nonsteady-state oxidative energy expenditure. In line with our projection, the "variable" grade condition resulted in an 8.3 ± 2.2% higher total cumulative oxidative energy expenditure (J·kg -1 ) compared with the "fixed" grade condition ( P < 0.001). Future work should aim to apply our approach across different gradients, speeds, and forms of locomotion; especially those that might provide insight into how humans optimize locomotion on variable grade routes. NEW & NOTEWORTHY We use a method for quantifying nonsteady-state energetics to show that regardless of whether the same total gain and loss in elevation (i.e., same total external mechanical work) is achieved over the same period of time, the total energy expenditure of different graded walking conditions can vary depending on the grades that are walked at and for how long they are walked at.

A key element to ensuring driving safety is to provide a sufficient braking distance. Inspired by the nature triply periodic minimal surface (TPMS), a gradient and multimodal triboelectric nanogenerator (GM-TENG) is proposed with high sensitivity and excellent multimodal monitoring. The gradient TPMS structure exhibits the multi-stage stress-strain properties of typical porous metamaterials. Significantly, the multimodal monitoring capability depends on the implicit function of the defined level constant c , which directly contributes to the multimodal driving safety monitoring. The mechanical and electrical responsive behavior of the GM-TENG is analyzed to identify the applied speed, load, and working mode. In addition, optimized peak open-circuit voltage ( V oc ) is demonstrated for self-awareness of the braking condition. The braking distance factor ( L ) is conceived to construct the self-aware equation of the friction coefficient based on the integration of V oc with respect to time. Importantly, R -squared up to 94.29 % can be obtained, which improves self-aware accuracy and real-time capabilities. This natural structure and self-aware device provide an effective strategy to improve driving safety, which contributes to the improvement of road safety and presents self-powered sensing with potential applications in an intelligent transportation system.

Numerous technological advancements in the 21st century depend on the creation of novel materials possessing enhanced properties; there is a growing reliance on materials that can be optimized to serve multiple functions. To efficiently save time and meet the requirements of diverse applications, high-throughput and combinatorial approaches are increasingly employed to explore and design superior materials. Among them, gradient thin-film deposition is one of the most mature and widely used technologies for high-throughput preparation of material libraries. This review summarizes recent progress in gradient thin-film deposition fabricated by magnetron sputtering, multi-arc ion plating, e-beam evaporation, additive manufacturing, and chemical bath deposition, providing readers with a fundamental understanding of this research field. First, high-throughput synthesis methods for gradient thin films are emphasized. Subsequently, we present the characteristics of combinatorial films, including microstructure, oxidation, corrosion tests, and mechanical properties. Next, the screening methods employed for evaluating these properties are discussed. Furthermore, we delve into the limitations of high-throughput preparation and characterization techniques for combinatorial films. Finally, we provide a summary and offer our perspectives.

Fibroblast growth factor (FGF) signaling is conserved from cnidaria to mammals (Ornitz and Itoh, 2022) and it regulates several critical processes such as differentiation, proliferation, apoptosis, cell migration, and embryonic development. One pivotal process FGF signaling controls is the division of vertebrate paraxial mesoderm into repeated segmented units called somites (i.e., somitogenesis). Somite segmentation occurs periodically and sequentially in a head-to-tail manner, and lays down the plan for compartmentalized development of the vertebrate body axis (Gomez et al. , 2008). These somites later give rise to vertebrae, tendons, and skeletal muscle. Somite segments form sequentially from the anterior end of the presomitic mesoderm (PSM). The periodicity of somite segmentation is conferred by the segmentation clock, comprising oscillatory expression of Hairy and enhancer-of-split (Her/Hes) genes in the PSM. The positional information for somite boundaries is instructed by the double phosphorylated extracellular signal-regulated kinase (ppERK) gradient, which is the relevant readout of FGF signaling during somitogenesis (Sawada et al. , 2001; Delfini et al. , 2005; Simsek and Ozbudak, 2018; Simsek et al. , 2023). In this review, we summarize the crosstalk between the segmentation clock and FGF/ppERK gradient and discuss how that leads to periodic somite boundary formation. We also draw attention to outstanding questions regarding the interconnected roles of the segmentation clock and ppERK gradient, and close with suggested future directions of study.

The dorsolateral prefrontal cortex (dlPFC) is composed of multiple anatomically defined regions involved in higher-order cognitive processes, including working memory and selective attention. It is organized in an anterior-posterior global gradient where posterior regions track changes in the environment, whereas anterior regions support abstract neural representations. However, it remains unknown if such a global gradient results from a smooth gradient that spans regions or an emergent property arising from functionally distinct regions, that is, an areal gradient. Here, we recorded single neurons in the dlPFC of nonhuman primates trained to perform a memory-guided saccade task with an interfering distractor and analyzed their physiological properties along the anterior-posterior axis. We found that these physiological properties were best described by an areal gradient. Further, population analyses revealed that there is a distributed representation of spatial information across the dlPFC. Our results validate the functional boundaries between anatomically defined dlPFC regions and highlight the distributed nature of computations underlying working memory across the dlPFC. SIGNIFICANCE STATEMENT Activity of frontal lobe regions is known to possess an anterior-posterior functional gradient. However, it is not known whether this gradient is the result of individual brain regions organized in a gradient (like a staircase), or a smooth gradient that spans regions (like a slide). Analysis of physiological properties of individual neurons in the primate frontal regions suggest that individual regions are organized as a gradient, rather than a smooth gradient. At the population level, working memory was more prominent in posterior regions, although it was also present in anterior regions. This is consistent with the functional segregation of brain regions that is also observed in other systems (i.e., the visual system)., (Copyright © 2023 the authors.)

The impact mechanical properties of graded hourglass lattice sandwich structures under impact compression were studied using experiments and numerical simulations. The influence of the gradient distribution on the deformation mode, peak load, and energy absorption capacity of the hourglass lattice sandwich structure under the same impact energy level, different impact masses, and different impact velocities is discussed. The results show that the difference in impact mass and velocity has a significant effect on the impact mechanical properties of the graded hourglass lattice sandwich structure under the same impact energy level. The gradient distribution mode is a factor that requires careful consideration in the design. A reasonable gradient distribution design can control the initial and compression peak loads to achieve similarly low values and improve the load consistency of the hourglass lattice sandwich structure. The total energy absorption of the hourglass lattice sandwich structures with different gradient distributions is the same; however, the energy absorption capacity is different at different deformation stages. When the moving distance is 0.005 m, the gradient hourglass lattice sandwich structures with the mass decline distribution can absorb 1 kJ/kg more energy than the gradient hourglass lattice sandwich structures with the mass increment distribution. When the moving distance is 0.037 m, the mass decline distribution gradient hourglass lattice sandwich structures absorb 1 kJ/kg less energy than the mass increment distribution gradient hourglass lattice sandwich structures.