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Abstract Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

Following intensive care unit hospitalization, survivors of acute neurological injury often experience debilitating short-term and long-term impairments. Although the physical/motor impairments experienced by survivors of acute neurological injury have been described extensively, fewer studies have examined cognitive, mental health, health-related quality of life (HRQoL), and employment outcomes. This scoping review describes the publication landscape beyond physical and/or motor sequelae in neurocritical care survivors. Databases were searched for terms related to critical illness, intensive care, and outcomes from January 1970 to March 2022. English-language studies of critically ill adults with a primary neurological diagnosis were included if they reported on at least one outcome of interest: cognition, mental health, HRQoL or employment. Data extraction was performed in duplicate for prespecified variables related to study outcomes. Of 16,036 abstracts screened, 74 citations were identified for inclusion. The studies encompassed seven worldwide regions and eight neurocritical diagnosis categories. Publications reporting outcomes of interest increased from 3 before the year 2000 to 71 after. Follow-up time points included ≤ 1 (n = 15 [20%] citations), 3 (n = 28 [38%]), 6 (n = 28 [38%]), and 12 (n = 21 [28%]) months and 1 to 5 (n = 19 [26%]) and > 5 years (n = 8 [11%]), with 28 (38%) citations evaluating outcomes at multiple time points. Sixty-six assessment tools were used to evaluate the four outcomes of interest: 22 evaluating HRQoL (56 [76%] citations), 21 evaluating cognition (20 [27%] citations), 21 evaluating mental health (18 [24%] citations), and 2 evaluating employment (9 [12%] citations). This scoping review aimed to better understand the literature landscape regarding nonphysical outcomes in survivors of neurocritical care. Although a rising number of publications highlight growing awareness, future efforts are needed to improve study consistency and comparability and characterize outcomes in a disease-specific manner, including outlining of a minimum core outcomes set and associated assessment tools. [ABSTRACT FROM AUTHOR]

Additive manufacturing enables new processing domains due to its rapid cooling rates and variety of novel parameters, but their effects on the Ti–6Al–4V solid-state phase transformation and consequent mechanical properties are not well understood. Optimal processing requires accurate models of these thermomechanical processes that are parameterized by high-fidelity kinetic and mechanistic data. In this work, these data are acquired with in-situ synchrotron x-ray diffraction during the β → α/α′ transformation in controlled isothermal and continuous cooling experiments that provide time evolution of α phase fraction ( f α ) and β phase V concentration ( V β ). Equilibrium, time-temperature-transformation, and continuous cooling diagrams are constructed for both f α and V β . The in-situ determination of V β shows that completion of the structural transformation precedes V redistribution for isothermal temperatures ≤ 865 °C and all continuous cooling rates, indicating that diffusional processes alone cannot be responsible for the transformation. A diffusional–displacive mechanism is proposed by thermally activated nucleation of α lath subunits and their displacive growth, which is consistent with observations. These data both inform the selection of novel processing routes and alloy compositions for materials with improved mechanical and functional properties, as well as provide valuable calibration data for microstructure simulation. [ABSTRACT FROM AUTHOR]

The Restriction Spectrum Imaging restriction score (RSIrs) has been shown to improve the accuracy for diagnosis of clinically significant prostate cancer (csPCa) compared to standard DWI. Both diffusion and T2 properties of prostate tissue contribute to the signal measured in DWI, and studies have demonstrated that each may be valuable for distinguishing csPCa from benign tissue. The purpose of this retrospective study was to (1) determine whether prostate T2 varies across RSI compartments and in the presence of csPCa, and (2) evaluate whether csPCa detection with RSIrs is improved by acquiring multiple scans at different TEs to measure compartmental T2 (cT2). Data includes two cohorts scanned for csPCa with 3T multi-b-value diffusion-weighted sequences acquired at multiple TEs. cT2 values were computed from multi-TE RSI data and compared by compartment. CsPCa detection was compared between RSIrs and a logistic regression model (LRM) to predict the probability of csPCa using cT2 in combination with RSI measurements. Two-sample t-tests (α = 0.05) and the area under the receiver operating characteristic curve (AUC) were used for the statistical analyses. In both cohorts, T2 was different (p < 0.05) across the four RSI compartments (C1, C2, C3, C4). Voxel-level, cohort 1: T2 was different in csPCa for C1, C2, C3 (p < 0.001). Patient-level, cohort 1: T2 was different in csPCa patients in C3 (p = 0.02); cohort 2: T2 differed in csPCa patients in C1 (p = 0.01), C3 (p = 0.01) and C4 (p < 0.01). Voxel-level csPCa detection: cT2 did not improve discrimination over RSIrs alone (p = 0.9). Patient-level: RSIrs and the LRM performed better than diffusion alone (p < 0.001), but the difference in AUCs between RSIrs and the LRM was not significantly different (p = 0.54). In conclusion, significant differences in cT2 were observed between normal and cancerous prostatic tissue. With our data, however, consideration of cT2 in addition to diffusion did not significantly improve cancer detection performance. [ABSTRACT FROM AUTHOR]

In recent years, additive manufacturing (AM), especially large-format additive manufacturing (LFAM), has gained momentum in the manufacturing industry. While LFAM offers benefits over conventional manufacturing processes, such as minimizing material waste and providing vast geometric freedom, assessing its sustainability remains challenging due to limited data, particularly on energy consumption. Most existing data pertain to small-scale or desktop AM and are not directly applicable to LFAM. In this study, we conducted real-time measurements of electricity usage for a type of LFAM known as big area additive manufacturing (BAAM), which typically uses fiber-reinforced polymer pellets as feedstock. We collected electricity usage data from fifteen printing jobs over two months in an industrial production setting. These data fill the existing gap and can be reused to enhance the community's understanding of LFAM electricity usage, support further research, and promote sustainable development in advanced manufacturing technologies. [ABSTRACT FROM AUTHOR]

Pesticides and farming have been associated with increased rheumatoid arthritis (RA) risk, but the role of specific pesticides remains unknown. We examined RA risk among licensed pesticide applicators (97% white male farmers), from North Carolina and Iowa, in the Agricultural Health Study, in relation to lifetime use of 45 pesticides reported at enrollment (1993–1997, updated 1999–2003). In 22,642 applicators ages ≥ 67 years with ≥ 24 months Fee for Service Medicare data (1999–2016), we identified 161 (0.7%) incident cases with ≥ 2 RA claims (including ≥ 1 by a rheumatologist), ≥ 30 days apart, after ≥ 12 months without RA claims. Relative risks (RR) and 95% Confidence Intervals (CI) were calculated using log-binomial models adjusted for age, state, education, smoking, and correlated pesticides. Risk was elevated (RR > 1.5 or lower CI > 0.95) for use of nine pesticides: four insecticides [malathion (RR = 1.77;95%CI = 1.14–2.73), phorate (1.40;0.96–2.04), carbaryl (1.65;1.10–2.46), carbofuran (1.41;0.99–2.01)], four herbicides [alachlor (RR = 1.40;95%CI 0.99–1.98), metolachlor (1.57;1.11–2.23), S-Ethyl dipropylthiocarbamate (1.57;1.00-2.44), metribuzin (1.45; 1.01, 2.08)], and one fungicide [benomyl (1.56;0.99–2.44)]. Exposure-response was seen for greater intensity-weighted lifetime days use of malathion and carbofuran (p-trends = 0.03 and 0.05). Some specific pesticides, including several currently approved and commonly used in agricultural, public health, or residential settings may increase RA risk among older adults. [ABSTRACT FROM AUTHOR]

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Understanding the origins of mechanical failures is critical to the prevention of future failures. In this study, additively manufactured Charpy bars, commonly used to measure the impact toughness of materials, were produced over a wide range of process conditions. The Charpy V-Notch toughness was measured on over 200 samples alongside corresponding optical images of both sides of the fracture surface. Convolutional neural network models were trained to correlate the fractographic images with quantitative toughness values. Several different neural network architectures were compared, along with other strategies for data cleaning and downsampling. The best models predicted Charpy toughness values from imagery with a mean absolute percent error of 8.5%. The neural network results were interpreted through a Grad-CAM saliency map; toughness values were correlated with expected physical characteristics such as porosity, shear lips, and fracture surface edges. A model trained on data from a Kovar alloy was found to maintain predictivity when applied to other similar alloy systems (300-series stainless steels) without any additional training. The primary optical images used in this study were macrofractography images spanning the entire fracture surface; a follow-on study using microfractographic images was less predictive but retained some utility. This work illustrates opportunities for developing data-driven approaches to provide quantitative assessment and qualitative interpretations of fracture surfaces. [ABSTRACT FROM AUTHOR]

Background: In Malawi approximately, 88.3% people living with HIV are aware of their HIV status. Significant gaps are among men aged 15–34 years; only 72% know their HIV status. To reach men, Jhpiego, in collaboration with the Ministry of Health (MOH), implemented the Men's Mobile Wellness Clinic (MMWC) at workplace settings in Blantyre, Malawi between October 2019 and March 2020. Methods: We conducted a descriptive qualitative study to understand motivators and barriers to MMWC service uptake by employees and employers. Primary data was drawn from in-depth telephone interviews from four study populations: employers who accepted or declined to host the MMWC at their worksite, and employees who accessed or did not access the services. We performed a thematic analysis using Nvivo 12 software to identify patterns and themes across the dataset. Findings: Main reasons given for using the service among male employees were a desire to know their health status, availability of free health services at the workplace, and good quality services offered by MMWC staff, and support from their supervisor. Men who did not access services stated reasons such as work-clinic scheduling conflicts, lack of adequate promotion of the service, and miscommunication on the criteria about who should attend the MMWC. Employers who accepted to host the MMWC stated convenience and employee's rights to know their health status. Those who declined either stated that employees did not want the services or COVID-19 preventive measures by the MOH between October 2019 and March 2020 restricted participation. Conclusion: This study underscores the potential utility of MMWC services including HIV testing among men. The desire to know their health status, availability of free MMWC services at the workplace, good quality services offered by MMWC staff, and the endorsement of MMWC by supervisors were main motivators to access the MMWC services. Sensitizing supervisors and employees about the benefits of the MMWC services, strengthening demand creation, and clarifying eligibility are important to facilitate MMWC uptake among men in Malawi. [ABSTRACT FROM AUTHOR]

To examine the associations between adverse childhood experiences (ACEs) and children's obesogenic behaviors (meeting recommendations for sleep duration and screen time) in a representative sample of U.S. children and adolescents. This study assessed data from the 2019–2020 National Survey of Children's Health. Separate multinomial logistic regressions examined the likelihood of failing to meet sleep and screen time recommendations given individual and cumulative ACE scores. 15,581 children (48% female, 32% non-White) experienced one ACE, representing 32% of the analyzed sample. Parents reported financial hardship as the most prevalent ACE (48%). After adjusting for child race/ethnicity, sex of the child, highest education in the household, and child age, we found that participants with four or more ACEs were (1) age-specific sleep recommendations compared with participants with zero ACEs (OR 1.96; 95%CI = 1.64–2.35), and (2) more likely to fall short of meeting screen use recommendations compared with participants with zero ACEs (OR 1.61; 95%CI = 1.26–2.07). U.S. children and adolescents who have experienced four or more ACEs are significantly more likely to fall short of sleep and screen time recommendations compared to their counterparts who experienced zero ACEs. Given the strong associations between ACEs and health outcomes in adulthood, screening for ACEs may better inform practitioners when attempting to improve youth health outcomes. [ABSTRACT FROM AUTHOR]

Purpose of Review: Disulfide bonds provide a convenient method for chemoselective alteration of peptide and protein structure and function. We previously reported that mild oxidation of a p53-derived bisthiol peptide (CTFANLWRLLAQNC) under dilute non-denaturing conditions led to unexpected disulfide-linked dimers as the exclusive product. The dimers were antiparallel, significantly α-helical, resistant to protease degradation, and easily reduced back to the original bisthiol peptide. Recent Findings: Here we examine the intrinsic factors influencing peptide dimerization using a combination of amino acid substitution, circular dichroism (CD) spectroscopy, and X-ray crystallography. CD analysis of peptide variants suggests critical roles for Leu6 and Leu10 in the formation of stable disulfide-linked dimers. The 1.0 Å resolution crystal structure of the peptide dimer supports these data, revealing a leucine-rich LxxLL dimer interface with canonical knobs-into-holes packing. Two levels of higher-order oligomerization are also observed in the crystal: an antiparallel “dimer of dimers” mediated by Phe3 and Trp7 residues in the asymmetric unit and a tetramer of dimers mediated by Trp7 and Leu10. In CD spectra of Trp-containing peptide variants, minima at 227 nm provide evidence for the dimer of dimers in dilute aqueous solution. Summary: Importantly, and in contrast to the original dimer model, the canonical leucine-rich core and robust dimerization of most peptide variants suggests a tunable molecular architecture to target various proteins and evaluate how folding and oligomerization impact various properties, such as cell permeability. [ABSTRACT FROM AUTHOR]

Background: Preoperative patient frailty (i.e., aging-related functional decline across multiple physiological systems) has been linked to greater perioperative complications following metabolic bariatric surgery (MBS). This study evaluated whether preoperative patient frailty predicts 1-year suboptimal weight loss response after primary sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Methods: The Bariatric Frailty Score (BFS), an adapted version of the Canadian Study of Health and Aging-Frailty Index based on 10 variables from MBSAQIP, assessed degree of frailty based on number of deficits (i.e., 0–10). Suboptimal response to MBS was defined as < 20% and < 30% percentage total weight loss (%TWL) at 1 year following SG and RYGB, respectively. Multiple linear and logistic regression models evaluated associations of preoperative BFS score with %TWL and %TWL response thresholds, respectively. Results: Patients (n = 1574; 78.9% female, 28.3% non-white, mean age 45 ± 12 year; 67% SG) had a mean BFS of 1.6 ± 1.3 (range = 0–7). Overall, higher BFS related to lower %TWL after SG and RYGB (ß = − 0.12 and ß = − 0.17, respectively, p = 0.001). Compared to patients with 0–1 deficits (BFS score ≤ 1; n = 785, 49.9%), those with multiple deficits (BFS score ≥ 2; n = 789, 50.1%) had higher odds of suboptimal weight loss response after SG (OR 1.88, 95% CI 1.40–2.52, p < 0.001) and RYGB (OR 2.18, 95% CI 1.43–3.32, p < 0.001). Conclusion: Having multiple preoperative frailty deficits is associated with higher odds of suboptimal weight loss response after MBS. These findings point to the need for increased frailty screening and appropriate adjunctive interventions (i.e., exercise, nutrition, and cognitive), as these interventions may improve frailty status and MBS outcomes. [ABSTRACT FROM AUTHOR]

Swim tests are highly effective for identifying vestibular deficits in rodents by offering significant vestibular motor challenges with reduced proprioceptive input, unlike rotarod and balance beam tests. Traditional swim tests rely on subjective assessments, limiting objective quantification and reproducibility. We present a novel instrumented swim test using a miniature motion sensor with a 3D accelerometer and 3D gyroscope affixed to the rodent's head. This setup robustly quantifies six-dimensional motion—three translational and three rotational axes—during swimming with high temporal resolution. We demonstrate the test's capabilities by comparing head movements of Gpr156-/- mutant mice, which have impaired otolith organ development, to their heterozygous littermates. Our results show axis-specific differences in head movement probability distribution functions and dynamics that identify mice with the Gpr156 mutation. Axis-specific power spectrum analyses reveal selective movement alterations within distinct frequency ranges. Additionally, our spherical visualization and 3D analysis quantifies swimming performance based on head vector distance from upright. We use this analysis to generate a single classifier metric—a weighted average of an animal's head deviation from upright during swimming. This metric effectively distinguishes animals with vestibular dysfunction from those with normal vestibular function. Overall, this instrumented swim test provides quantitative metrics for assessing performance and identifying subtle, axis- and frequency-specific deficits not captured by existing systems. This novel quantitative approach can enhance understanding of rodent sensorimotor function including enabling more selective and reproducible studies of vestibular-motor deficits. [ABSTRACT FROM AUTHOR]

Bone-anchored percutaneous implants, commonly referred to as osseointegrated implants, are gaining popularity as an alternative to sockets for attaching a prosthetic limb to an amputated femur. While these implants have several advantages, femoral fractures are relatively common in these patients, occurring in 6.3% of femurs within 4 years. This study aimed to develop a novel method to quantify femoral strength under all possible external loads acting on the distal implant. Finite element analysis was used to explore combinations of forces and moments that, when applied on the bone-anchored implant, were just sufficient to fracture the femur. The 6-dimensional envelope generated in the current study provided a quantitative description of the strength of the femur-implant construct. All the femoral fractures were predicted in the trochanteric region, corresponding to where most in vivo fractures have been reported. The 6-dimensional envelopes developed in the current study may be useful in the design of fail-safe devices that could reduce femoral fractures in patients with bone-anchored percutaneous femoral implants. The framework presented may also be used for determining patient suitability for bone-anchored percutaneous implants, and for evaluating the functional performance of implant designs. [ABSTRACT FROM AUTHOR]

Many animals convergently evolved photosynthetic symbioses. In bivalves, giant clams (Cardiidae: Tridacninae) gape open to irradiate their symbionts, but heart cockles (Cardiidae: Fraginae) stay closed because sunlight passes through transparent windows in their shells. Here, we show that heart cockles (Corculum cardissa and spp.) use biophotonic adaptations to transmit sunlight for photosynthesis. Heart cockles transmit 11–62% of photosynthetically active radiation (mean = 31%) but only 5–28% of potentially harmful UV radiation (mean = 14%) to their symbionts. Beneath each window, microlenses condense light to penetrate more deeply into the symbiont-rich tissue. Within each window, aragonite forms narrow fibrous prisms perpendicular to the surface. These bundled "fiber optic cables" project images through the shell with a resolution of >100 lines/mm. Parameter sweeps show that the aragonite fibers' size (~1 µm diameter), morphology (long fibers rather than plates), and orientation (along the optical c-axis) transmit more light than many other possible designs. Heart cockle shell windows are thus: (i) the first instance of fiber optic cable bundles in an organism to our knowledge; (ii) a second evolution, with epidermal cells in angiosperm plants, of condensing lenses for photosynthesis; and (iii) a photonic system that efficiently transmits useful light while protecting photosymbionts from UV radiation. Some bivalves have evolved photosynthetic symbioses. Here, the authors show that heart cockles transmit light through their upper shell to internal photosynthetic symbionts, using mineral fiber optic cables to maximize light transmission. [ABSTRACT FROM AUTHOR]

This study presents a comprehensive multimodal analytical study of an Egyptian ritual Bes-vase, of the 2nd century BCE employing cutting-edge proteomics, metabolomics, genetics techniques, and synchrotron radiation-based Fourier Transformed Infrared microSpectroscopy (SR µ-FTIR) to characterize organic residues of its content. We successfully identified the presence of various functional, bioactive, psychotropic, and medicinal substances, shedding light on the diverse components of a liquid concoction used for ritual practices in Ptolemaic Egypt. Using LC-MS/MS with a new methodological approach, we identified key proteins and metabolites, enabling the identification of botanical sources, confirmed by genetic sequences. Our analyses revealed traces of Peganum harmala, Nimphaea nouchali var. caerulea, and a plant of the Cleome genus, all of which are traditionally proven to have psychotropic and medicinal properties. Additionally, the identification of human fluids suggests their direct involvement in these rituals. Furthermore, metabolomics and SR µ-FTIR analyses also revealed the presence of fermented fruit-based liquid and other ingredients such as honey or royal jelly. The identification of specific chemical compounds, such as alkaloids and flavonoids, provides insight into the psychoactive and therapeutic uses of these in ancient ritual practices. This multidisciplinary study highlights the complexity of ancient cultures and their interactions with psychoactive, medicinal, and bioactive substances. These findings contribute to our understanding of ancient belief systems, cultural practices, and the utilization of natural resources, ultimately enhancing our knowledge of past societies and their connection to the natural world. [ABSTRACT FROM AUTHOR]

Community dynamics within microbial mat assemblages are complex, likely involving intricate metabolic linkages. Interactions between microbes shape these communities, particularly in extreme habitats such as those found in the Middle Island Sinkhole (MIS), Lake Huron. Herein, euxinic waters resemble early-Earth ocean conditions, and diverse microbial groups form benthic mats. The goal of this study was to examine interspecific relationships among culturable cyanobacteria (two strains of Anagnostidinema) and diatoms (Craticula cuspidata and Nitzschia palea) isolated from MIS mats in a co-culture factorial experiment. Although most crosses showed limited interactions, a significant increase in abundance of one Anagnostidinema strain was found when grown with Craticula cuspidata compared to other taxa (P < 0.0001). Nitzschia palea growth was significantly reduced when grown with either strain of cyanobacteria (P = 0.0040). Addition of both cells and filtrates from C. cuspidata cultures caused increases in Anagnostidinema percent cover. Unique metabolic capabilities of C. cuspidata may benefit some cyanobacteria, and cyanobacteria may inhibit N. palea growth via interference competition. These interactions may be masked in the mat community in situ by environmental factors or other interspecific interactions, or allow species to survive in low abundance in an otherwise unfavorable habitat. [ABSTRACT FROM AUTHOR]

Relativistic field theory for a vector field on a curved space-time is considered assuming that the Lagrangian field density is quadratic and contains field derivatives of first order at most. By applying standard variational calculus, the general Euler–Lagrange equations for the field are derived and the existence of a conserved current is achieved. The field equations are also analysed from an eikonal-like point of view. The Hilbert energy-momentum tensor of the field is also derived and the influence of each one of the irreducible pieces appearing in the Lagrangian is studied. Particular values of the free parameters allow to retrieve known results. [ABSTRACT FROM AUTHOR]

Internationally, governments and scientists are bound by legal and treaty rights when working with Indigenous nations. These rights include the right of Indigenous people to control the conduct of science with Indigenous nations. Unfortunately, in some cases, individual scientists and scientific teams working with biological and genetic data collected from Indigenous people have not respected these international rights. Here, we argue that the scientific community should understand and acknowledge the historical harms experienced by Indigenous people under the veil of scientific progress (truth) and implement existing standards for ethical conduct of research and sovereign control of data collected within Indigenous communities (reconciliation). Specifically, we outline the rationale for why scientists, scientific journals and research integrity and institutional review boards/ethics committees should adopt, and be held accountable for upholding, current international standards of Indigenous data sovereignty and ethical use of Indigenous biological samples. [ABSTRACT FROM AUTHOR]

Background: Medical devices for fluorescence-guided surgery (FGS) are becoming available at a fast pace. The main challenge for surgeons lies in the lack of in-depth knowledge of optical imaging, different technical specifications and poor standardisation, and the selection of the best device based on clinical application. Methods: This manuscript aims to provide an up-to-date description of the commercially available fluorescence imaging platforms by comparing their mode of use, required settings, image types, compatible fluorophores, regulatory approval, and cost. We obtained this information by performing a broad literature search on PubMed and by contacting medical companies directly. The data for this review were collected up to November 2023. Results: Thirty-two devices made by 19 medical companies were identified. Ten systems are surgical microscopes, 5 can be used for both open and minimally invasive surgery (MIS), 6 can only be used for open surgery, and 10 only for MIS. One is a fluorescence system available for the Da Vinci robot. Nineteen devices can provide an overlay between fluorescence and white light image. All devices are compatible with Indocyanine Green, the most common fluorescence dye used intraoperatively. There is significant variability in the hardware and software of each device, which resulted in different sensitivity, fluorescence intensity, and image quality. All devices are CE-mark regulated, and 30 were FDA-approved. Conclusion: There is a prolific market of devices for FGS and healthcare professionals should have basic knowledge of their technical specifications to use it at best for each clinical indication. Standardisation across devices must be a priority in the field of FGS, and it will enhance external validity for future clinical trials in the field. [ABSTRACT FROM AUTHOR]

Evolution results from the interaction of stochastic and deterministic processes that create a web of historical contingency, shaping gene content and organismal function. To understand the scope of this interaction, we examine the relative contributions of stochasticity, determinism, and contingency in shaping gene inactivation in 34 lineages of endosymbiotic bacteria, Sodalis, found in parasitic lice, Columbicola, that are independently undergoing genome degeneration. Here we show that the process of genome degeneration in this system is largely deterministic: genes involved in amino acid biosynthesis are lost while those involved in providing B-vitamins to the host are retained. In contrast, many genes encoding redundant functions, including components of the respiratory chain and DNA repair pathways, are subject to stochastic loss, yielding historical contingencies that constrain subsequent losses. Thus, while selection results in functional convergence between symbiont lineages, stochastic mutations initiate distinct evolutionary trajectories, generating diverse gene inventories that lack the functional redundancy typically found in free-living relatives. Endosymbionts often have small genomes that maintain minimal functions required to serve their hosts. This study examines cases of new endosymbiont acquisition and finds genome degeneration involves both stochastic and deterministic processes that shape gene content and organismal function. [ABSTRACT FROM AUTHOR]

The heavy chain of an antibody is crucial for mediating antigen binding. IGHV genes, which partially encode the heavy chain of antibodies, exhibit vast genetic diversity largely through polymorphism and copy number variation (CNV). These genetic variations impact population-level expression levels. In this study, we analyzed expressed antibody transcriptomes and matched germline IGHV genes from donors from KwaZulu-Natal, South Africa. Amplicon NGS targeting germline IGHV sequences was performed on genomic DNA from 70 participants, eight of whom had matched datasets of expressed antibody transcriptomes. Germline IGHV sequencing identified 161 unique IGHV alleles, of which 32 were novel. A further 21 novel IGHV alleles were detected in the expressed transcriptomes of these donors. We also examined the datasets for CNV, uncovering gene duplications of 10 IGHV genes from germline sequencing and 33 genes in the expressed transcriptomes. Many of the IGHV gene duplications have not been described in other populations. This study expands our understanding of genetic differences in distinct populations and suggests the potential impact of genetic diversity on immune responses. [ABSTRACT FROM AUTHOR]

The accuracy of electron-excited X-ray microanalysis with energy-dispersive spectrometry (EDS) has been tested in the low beam energy range, specifically at an incident beam energy of 5 keV, which is the lowest beam energy for which a useful characteristic X-ray peak can be excited for all elements of the periodic table, excepting H and He. Elemental analysis results are reported for certified reference materials (CRM), stoichiometric compounds, minerals, and metal alloys of independently known or measured composition which had microscopic homogeneity suitable for microanalysis. Two-hundred sixty-three concentration measurements for 39 elements in 113 materials were determined following the k-ratio protocol and using the EDS analytical software NIST DTSA-II. The accuracy of the results, as characterized by the relative deviation from expected value (RDEV) metric, was such that more than 98% of the results were found to be captured within a range of ±5% RDEV, while 82% of the results fell in the range -2% to 2% RDEV. [ABSTRACT FROM AUTHOR]

αβ T cell receptors (αβTCRs) co-recognise antigens when bound to Major Histocompatibility Complex (MHC) or MHC class I-like molecules. Additionally, some αβTCRs can bind non-MHC molecules, but how much intact antigen reactivities are achieved remains unknown. Here, we identify an αβ T cell clone that directly recognises the intact foreign protein, R-phycoerythrin (PE), a multimeric (αβ)6γ protein complex. This direct αβTCR–PE interaction occurs in an MHC-independent manner, yet triggers T cell activation and bound PE with an affinity comparable to αβTCR–peptide–MHC interactions. The crystal structure reveals how six αβTCR molecules simultaneously engage the PE hexamer, mediated by the complementarity-determining regions (CDRs) of the αβTCR. Here, the αβTCR mainly binds to two α-helices of the globin fold in the PE α-subunit, which is analogous to the antigen-binding platform of the MHC molecule. Using retrogenic mice expressing this TCR, we show that it supports intrathymic T cell development, maturation, and exit into the periphery as mature CD4/CD8 double negative (DN) T cells with TCR-mediated functional capacity. Accordingly, we show how an αβTCR can recognise an intact foreign protein in an antibody-like manner. Certain specific antigens have been shown to activate T cells in an MHC independent manner. Here the authors show a phycoerythrin reactive mouse TCR which recognises native protein and characterise the molecular nature of this interaction and that this specific TCR can be selected in the thymus. [ABSTRACT FROM AUTHOR]

As part of the advancement in therapeutic decision-making for brain tumor patients at St. Jude Children's Research Hospital (SJCRH), we developed three robust classifiers, a deep learning neural network (NN), k-nearest neighbor (kNN), and random forest (RF), trained on a reference series DNA-methylation profiles to classify central nervous system (CNS) tumor types. The models' performance was rigorously validated against 2054 samples from two independent cohorts. In addition to classic metrics of model performance, we compared the robustness of the three models to reduced tumor purity, a critical consideration in the clinical utility of such classifiers. Our findings revealed that the NN model exhibited the highest accuracy and maintained a balance between precision and recall. The NN model was the most resistant to drops in performance associated with a reduction in tumor purity, showing good performance until the purity fell below 50%. Through rigorous validation, our study emphasizes the potential of DNA-methylation-based deep learning methods to improve precision medicine for brain tumor classification in the clinical setting. [ABSTRACT FROM AUTHOR]

Bird species depending on seeds from masting trees face large temporal and spatial variation in food availability and perform nomadic or irruptive movements to locate food. In northern Europe, the Common Crossbill (Loxia curvirostra) is specialized on seeds from Norway Spruce (Picea abies) which usually has peak years followed by crop failure. Common Crossbills breed in mast years and emigrate when spruce seeds are no longer available. On the other hand, the Parrot Crossbill (L. pytyopsittacus) is specialized on seeds from Scots Pine (Pinus sylvestris) in which seed production is more stable from year to year. The Parrot Crossbill is therefore thought to be more sedentary. However, both species may switch food if there is low abundance of their 'own' seed type, but little is known about the relative importance of crop size of the two tree species on breeding population size and migration of the two crossbill species. Here, we analyse time series (up to 36 years) of crossbills and crop size of spruce and pine in Norway and Sweden to investigate this. We found that breeding population sizes of both species were positively related to spruce crop size. Surprisingly, pine crop size had no positive influence, not even on the Parrot Crossbill. Emigration of both crossbill species (based on autumn migration counts in southern Sweden) increased when there were small seed crops of spruce, but pine crop size had no influence, not even on the Parrot Crossbill. There was no influence of population size on emigration. These results suggest that alternative food resources had an asymmetric effect, only influencing the Parrot Crossbill. This asymmetry explains why the two crossbill species often have synchronous eruptions despite being specialized on different tree species with different seed crop size dynamics. [ABSTRACT FROM AUTHOR]

Black women living with HIV (BWLWH) face adversities associated with lower HIV medication adherence, viral non-suppression, and mental health symptoms (e.g., post-traumatic stress disorder) such as trauma/violence, racism, HIV-related discrimination/stigma, and gender-related stressors. We developed the first intervention based in cognitive behavioral therapy and culturally congruent coping for BWLWH to increase medication adherence and decrease PTSD symptoms by enhancing resilience, self-care, engagement in care, and coping for trauma, racism, HIV-related discrimination/stigma, and gender-related stressors. A pilot randomized control trial was conducted with BWLWH and histories of trauma who were at risk for their HIV viral load remaining or becoming detectable (i.e., below 80% medication adherence, detectable viral load in the past year, and/or missed HIV-related appointments). 119 BWLWH were assessed at baseline and 70 met inclusion criteria, completed one session of Life-Steps adherence counseling, and were randomized to either nine sessions of STEP-AD (Striving Towards EmPowerment and Medication Adherence) or ETAU (enhanced treatment as usual consisting of biweekly check-ins). Women completed a post intervention follow up assessment (3 months post baseline) and 3-month post intervention follow-up (6 months post baseline). Via STATA the difference-in-difference methodology with mixed models compared STEP-AD to ETAU on changes in outcomes over time. BWLWH in STEP-AD compared to E-TAU had significantly higher ART adherence (estimate = 9.36 p = 0.045) and lower likelihood of being clinically diagnosed with PTSD (OR =.07, estimate = − 2.66, p = 0.03) as well as borderline significance on higher CD4 count (estimate = 161.26, p = 0.05). Our findings suggest preliminary efficacy of STEP-AD in improving ART adherence, mental health, and immune function. [ABSTRACT FROM AUTHOR]

Thomas Hurka’s recursive account of value appeals to certain intuitions to expand the class of intrinsic values, placing concepts of virtue and desert within the realm of second and third order intrinsic goods, respectively. This is a formalization of a tradition of thought extending back to Aristotle and Kant via the British moralists, G. E. Moore, and W. D. Ross. However, the evidential status of such intuitions vis a vis the real, intrinsic value of virtue and desert is hostage to alternative explanations. If there is a plausible competing explanation for these intuitions, then the (putative) fact that desert and virtue are intrinsic (rather than instrumental or derivative) goods seems a much less obvious choice for the best explanation. As it turns out, there are plausible evolutionary explanations for these intuitions about desert and virtue. These evolutionary explanations suggest that it is adaptive to value desert and virtue separately from their instrumentality for other goods. Consequently, these explanations debunk intuitions about the intrinsic value of desert and virtue. [ABSTRACT FROM AUTHOR]

Legumes are notorious for coevolutionary arms races where chemical defenses are employed to ward off herbivores—particularly insect seed predators. Locoweeds are legumes containing the toxic alkaloid swainsonine which can poison livestock, but its role as a deterrent for insects is unknown. Swainsonine is produced by the fungal endophyte Alternaria section Undifilum, and the chemical composition of the toxin has been well characterized. Despite this knowledge, the ecological roles and evolutionary drivers of swainsonine toxins in locoweeds remain uncertain. Here, we quantify swainsonine concentrations and herbivory levels in the hyper-diverse locoweed Astragalus lentiginosus to evaluate its role as an evolved chemical defense. We found that A. lentiginosus shows considerable variation in swainsonine concentrations according to variety, in particular showing presence/absence variation at both population and local geographic scales. Surprisingly, herbivory levels from presumed generalist insects emerging from fruits showed no correlation with swainsonine concentrations. Conversely, seed and fruit herbivory levels linked to specialist Acanthoscelides seed beetles increased with concentrations of swainsonine—suggesting a possible coevolutionary arms race. Our results highlight that variation in endophyte-produced toxin systems may not follow classical expectations for geographic variation and ecological roles of plant chemicals. We discuss the implications of these results on plant-endophytic toxin systems and coevolutionary dynamics more broadly, highlighting a considerable need for more research in these systems. [ABSTRACT FROM AUTHOR]

This article, published in Obesity Surgery, explores the impact of metabolic bariatric surgery (MBS) on cognitive functioning in individuals with severe obesity. The study specifically focuses on the effect of MBS on planning and problem-solving abilities, which are important for postoperative adherence to recommendations. The researchers compared the performance of patients who underwent sleeve gastrectomy (SG) with a control group of individuals with severe obesity who did not undergo obesity treatment. The results showed that the SG group demonstrated improved planning and problem-solving performance compared to the control group. However, the study has limitations, and further research is needed to fully understand the relationship between MBS, cognitive functioning, and adherence to postoperative guidelines. [Extracted from the article]

Complexity, uncertainty, and conflict characterize contemporary environmental challenges. Addressing these issues is beyond the purview of any one actor. A collaborative approach to environmental management is required; participation in collaboration is needed. However, participation in collaborative environmental management is a persistent challenge in practice. This research examines tactics used to engender participation in collaborations. Tactics constitute a strategy for communications with an intended goal and encompass the framing (i.e., wording, imagery) and platform of dissemination. This research examined the influence of tactics on an intention to participate in an environmental management collaboration. Eight tactics were empirically tested on 300 individuals aged 18–29. Descriptive and inferential statistical analysis was undertaken. Results uncovered the effectiveness of contextual and personal framings in engendering participation and deepened the understanding about past participation, tactics, and an individual's intention to participate. Opportunities to engender participation in collaborations using tactics are abundant. The research emphasizes the need for greater attention to tactics in environmental management and contributes to a greater understanding of tactics, identifying effective practices for engendering participation and broad dissemination. [ABSTRACT FROM AUTHOR]

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Purpose: Musculoskeletal disorders (MSDs) are common worldwide and gender differences exist in terms of prevalence and disability. MSDs are a leading cause of sick leave and physical work exposures. To assess the association between physical exposures assessed by the gender-specific CONSTANCES Job-Exposure Matrix (JEM) and musculoskeletal pain in six areas: neck pain, shoulder pain, elbow/arm pain, hand/wrist pain, low back pain, knee/leg pain; and to compare the results with those obtained using the non-gendered CONSTANCES JEM and with individual self-report exposures. Methods: We included 48,736 male and 63,326 female workers from the CONSTANCES cohort (France). The association between 27 physical exposures and musculoskeletal self-reported pain in six body areas was assessed using logistic regression. We conducted the analysis with three types of exposures: (1) individual self-reported exposures; (2) gender-specific CONSTANCES JEM; (3) non-gendered CONSTANCES JEM, and adjusted for age and Body Mass Index (BMI). Analyses were stratified by gender. Results: The associations to the gender-specific and non-gendered JEM were similar. The odds ratios using individual self-reported exposures were comparable to the JEM-based associations, with the exceptions of the exposures 'change tasks', 'rest eyes' and 'reach behind'. In some comparisons, there were differences in the direction and/or significance of effects between genders (regardless of whether the JEM used was gender-specific or not). Conclusion: The gender-specific and non-gendered JEMs gave similar results, hence, developing physical work exposures JEMs that are gender-specific may not be essential. However, when predicting musculoskeletal pain, it seems relevant to stratify the analysis by gender. [ABSTRACT FROM AUTHOR]

Purpose of Review: Black women's sexual well-being is predicated upon having the autonomy, resources, and access to define, explore, and safely enjoy their sexuality and intimacy. Black cisgender and transgender women have been placed at disproportional risk for HIV due to structural and health specific inequities. Pre-exposure prophylaxis (PrEP), an effective biomedical intervention, reduces HIV transmission from sex or injection drug use by 99%, however the uptake of PrEP remains low among Black cisgender and transgender women. Using the PRISMA technique, we conducted a review of literature on Black women, cisgender and transgender, and PrEP. We used Google Scholar and PubMed to conduct the search. Recent Findings: Our initial search garnered 2,221 sources across the two databases. However, n = 197 articles were included in this review based on the screening process and our inclusion criteria. Socio-cultural factors, provider factors, low HIV risk awareness, limited PrEP awareness and knowledge, communication, motivation, concerns about PrEP, barriers, and sexual agency, power, and pleasure may impact utilization of PrEP among Black transgender and cisgender women. However, facilitators were highlighted as well as interventions, though limited. Summary: To adequately meet the needs of Black women and increase PrEP uptake, there is a need to address these factors that may impact utilization and develop effective interventions for Black women surrounding PrEP. [ABSTRACT FROM AUTHOR]

Purpose of Review: Oxytocin plays many diverse roles in physiological and behavioral processes, including social activity, parental nurturing, stress responses, and sexual function. In this narrative review, we provide an update on the most noteworthy recent findings in this fascinating field. Recent Findings: The development of techniques such as serial two-photon tomography and fiber photometry have provided a window into oxytocin neuroanatomy and real-time neuronal activity during social interactions. fMRI and complementary mapping techniques offer new insights into oxytocin's influence on brain activity and connectivity. Indeed, oxytocin has recently been found to influence the acquisition of maternal care behaviors and to mediate the influence of social touch on brain development and social interaction. Additionally, oxytocin plays a crucial role in male sexual function, affecting erectile activity and ejaculation, while its role in females remains controversial. Recent studies also highlight oxytocin's interaction with other neuropeptides, such as melanin-concentrating hormone, serotonin, and arginine vasopressin, influencing social and affective behaviors. Finally, an update is provided on the status of clinical trials involving oxytocin as a therapeutic intervention. Summary: The exploration of oxytocin's complexities and its interplay with other neuropeptides holds promise for targeted treatment in various health and disease contexts. Overall, these findings contribute to the discovery of new and specific pathways to allow therapeutic targeting of oxytocin to treat disorders. [ABSTRACT FROM AUTHOR]

For a family of self-adjoint Dirac operators - i c (α · ∇) + c 2 2 subject to generalized MIT bag boundary conditions on domains in R 3 , it is shown that the nonrelativistic limit in the norm resolvent sense is the Dirichlet Laplacian. This allows to transfer spectral geometry results for Dirichlet Laplacians to Dirac operators for large c. [ABSTRACT FROM AUTHOR]

Purpose: Uncertainty exists if post-resistance exercise hydrotherapy attenuates chronic inflammatory and hormone responses. The effects of repeated post-resistance exercise water immersion on inflammatory and hormone responses in athletes were investigated. Methods: Male, academy Super Rugby players (n = 18, 19.9 ± 1.5 y, 1.85 ± 0.06 m, 98.3 ± 10.7 kg) participated in a 12-week programme divided into 3 × 4-week blocks of post-resistance exercise water immersion (either, no immersion control [CON]; cold [CWI]; or hot [HWI] water immersion), utilising a randomised cross-over pre-post design. Fasted, morning blood measures were collected prior to commencement of first intervention block, and every fourth week thereafter. Linear mixed-effects models were used to analyse main (treatment, time) and interaction effects. Results: Repeated CWI (p = 0.025, g = 0.05) and HWI (p < 0.001, g = 0.62) reduced creatine kinase (CK), compared to CON. HWI decreased (p = 0.013, g = 0.59) interleukin (IL)-1ra, compared to CON. HWI increased (p < 0.001–0.026, g = 0.06–0.17) growth factors (PDGF-BB, IGF-1), compared to CON and CWI. CWI increased (p = 0.004, g = 0.46) heat shock protein-72 (HSP-72), compared to HWI. Conclusion: Post-resistance exercise CWI or HWI resulted in trivial and moderate reductions in CK, respectively, which may be partly due to hydrostatic effects of water immersion. Post-resistance exercise HWI moderately decreased IL-1ra, which may be associated with post-resistance exercise skeletal muscle inflammation influencing chronic resistance exercise adaptive responses. Following post-resistance exercise water immersion, CWI increased HSP-72 suggesting a thermoregulatory response indicating improved adaptive inflammatory responses to temperature changes, while HWI increased growth factors (PDGF-BB, IGF-1) indicating different systematic signalling pathway activation. Our data supports the continued use of post-resistance exercise water immersion recovery strategies of any temperature during in-season competition phases for improved inflammatory adaptive responses in athletes. [ABSTRACT FROM AUTHOR]

Background and aims: Agricultural activities can degrade soils and promote weeds, posing challenges to native species restoration. In agricultural restoration, removing contaminated topsoil is a method designed to reduce elevated soil nutrients caused by fertilisation. This strategy targets weed control by eliminating both aboveground weeds and their soil seed bank before direct seeding. However, it also diminishes native soil seed banks and beneficial soil microbes. We investigated the potential of fresh topsoil pellets containing seeds to improve seedling performance in a degraded grassy woodland where topsoil had been removed. Methods: We tested various pellet recipes, including one using commercial ingredients and three with different topsoil proportions (30%, 50%, and 70%). The study was conducted in a degraded grassy woodland in southeastern Australia, where topsoil was removed for restoration. We explored the effect of these pellet varieties on seedling emergence and growth of six native species common in this community, as well as microbial activity in the soil surrounding the seedlings. Results: Pellets significantly improved the emergence of Chrysocephalum apiculatum, providing evidence of their effectiveness. However, pellets significantly reduced Arthropodium milleflorum and Glycine tabacina emergence. Linum marginale and Rytidosperma caespitosum emergence remained unaffected by pellets. One species, Bothriochloa macra, had insufficient emergence for analysis. The microbial activity of the soil surrounding Rytidosperma caespitosum seedlings was significantly improved by pellets, with no significant effects observed for other species. Conclusion: Our results demonstrate that topsoil pellets improved the emergence of one native species, but reduced emergence for two others, indicating species-specific responses to pelleting. [ABSTRACT FROM AUTHOR]

Purpose: Surfactant therapy incorporates liquid bolus instillation via endotracheal tube catheter and a mechanical ventilator in preterm neonates with respiratory distress syndrome (RDS). Aerosolized surfactants have generated interest and conflicting data on the efficacy of phospholipid (PL) dose requirements. We developed and characterized a synthetic lung surfactant excipient enhanced growth (SLS-EEG) dry powder aerosol product. In this study, we compare the in vivo performance of the new aerosol product with standard-of-care liquid instillation. Methods: Juvenile rabbits were sedated, anesthetized, intubated, and ventilated. Endogenous surfactant was depleted via whole lung lavage. Animals received either a standard dose of liquid Curosurf (200 mg PL/kg) instilled via a tracheal catheter, SLS-EEG powder aerosol (60 mg device loaded dose; equivalent to 24 mg PL/kg), or sham control. Gas exchange, lung compliance, and indices of disease severity were recorded every 30 min for 3.5 h and macro- and microscopy images were acquired at necropsy. Results: While aerosol was administered at an approximately tenfold lower PL dose, both liquid-instilled and aerosol groups had similar, nearly complete recoveries of arterial oxygenation (PaO2; 96–100% recovery) and oxygenation index, and the aerosol group had superior recovery of compliance (P < 0.05). The SLS-EEG aerosol group showed less lung tissue injury, greater uniformity in lung aeration, and more homogenous surfactant distribution at the alveolar surfaces compared with liquid Curosurf. Conclusions: The new dry powder aerosol SLS product (which includes the delivery strategy, formulation, and delivery system) has the potential to be a safe, effective, and economical alternative to the current clinical standard of liquid bolus surfactant instillation. [ABSTRACT FROM AUTHOR]

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of ‘early T cell precursor-like’ leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Improving the deep lung delivery of aerosol surfactant therapy (AST) with a dry powder formulation may enable significant reductions in dose while providing improved efficacy. The objective of Part I of this two-part study was to present the development of a new dry powder aerosol synthetic lung surfactant (SLS) product and to characterize performance based on aerosol formation and realistic in vitro airway testing leading to aerosol delivery recommendations for subsequent in vivo animal model experiments. Methods: A new micrometer-sized SLS excipient enhanced growth (EEG) dry powder formulation was produced via spray drying and aerosolized using a positive-pressure air-jet dry powder inhaler (DPI) intended for aerosol delivery directly to intubated infants with respiratory distress syndrome (RDS) or infant-size test animals. Results: The best-case design (D2) of the air-jet DPI was capable of high emitted dose (> 80% of loaded) and formed a < 2 µm mass median aerodynamic diameter (MMAD) aerosol, but was limited to ≤ 20 mg mass loadings. Testing with a realistic in vitro rabbit model indicated that over half of the loaded dose could penetrate into the lower lung regions. Using the characterization data, a dose delivery protocol was designed in which a 60 mg total loaded dose would be administered and deliver an approximate lung dose of 14.7–17.7 mg phospholipids/kg with a total aerosol delivery period < 5 min. Conclusions: A high-efficiency aerosol SLS product was designed and tested that may enable an order of magnitude reduction in administered phospholipid dose, and provide rapid aerosol administration to infants with RDS. [ABSTRACT FROM AUTHOR]

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3′,5′-monophosphate–protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.This study explores how adenosine A2B receptors can act as astrocytic sensors of brain metabolic activity and how cAMP signalling in astrocytes may support core brain functions such as sleep and memory. [ABSTRACT FROM AUTHOR]

Key message: De novo genotyping in potato using methylation-sensitive GBS discovers SNPs largely confined to genic or gene-associated regions and displays enhanced effectiveness in estimating LD decay rates, population structure and detecting GWAS associations over ‘fixed’ SNP genotyping platform. Study also reports the genetic architectures including robust sequence-tagged marker–trait associations for sixteen important potato traits potentially carrying higher transferability across a wider range of germplasm. This study deploys recent advancements in polyploid analytical approaches to perform complex trait analyses in cultivated tetraploid potato. The study employs a ‘fixed’ SNP Infinium array platform and a ‘flexible and open’ genome complexity reduction-based sequencing method (GBS, genotyping-by-sequencing) to perform genome-wide association studies (GWAS) for several key potato traits including the assessment of population structure and linkage disequilibrium (LD) in the studied population. GBS SNPs discovered here were largely confined (~ 90%) to genic or gene-associated regions of the genome demonstrating the utility of using a methylation-sensitive restriction enzyme (PstI) for library construction. As compared to Infinium array SNPs, GBS SNPs displayed enhanced effectiveness in estimating LD decay rates and discriminating population subgroups. GWAS using a combined set of 30,363 SNPs identified 189 unique QTL marker–trait associations (QTL-MTAs) covering all studied traits. The majority of the QTL-MTAs were from GBS SNPs potentially illustrating the effectiveness of marker-dense de novo genotyping platforms in overcoming ascertainment bias and providing a more accurate correction for different levels of relatedness in GWAS models. GWAS also detected QTL ‘hotspots’ for several traits at previously known as well as newly identified genomic locations. Due to the current study exploiting genome-wide genotyping and de novo SNP discovery simultaneously on a large tetraploid panel representing a greater diversity of the cultivated potato gene pool, the reported sequence-tagged MTAs are likely to have higher transferability across a wider range of potato germplasm and increased utility for expediting genomics-assisted breeding for the several complex traits studied. [ABSTRACT FROM AUTHOR]

Purpose: Chiari I malformation (CM-I) in pediatric patients can impose substantial neurologic and functional impairment. Additionally, the presence of syrinx is often a harbinger of clinical compromise, but little attention has been devoted to identifying features associated with syrinx development and the clinical impact of syrinx resolution. Therefore, this study aims to identify clinical and radiographic variables associated with preoperative syrinx presence and postoperative syrinx reduction in pediatric patients with CM-I and determine the relationship between postoperative syrinx reduction and clinical symptom improvement. Methods: The authors performed a retrospective analysis of 435 consecutive pediatric patients who underwent surgical treatment of CM-I from 2001 to 2021 at a single tertiary pediatric medical center. All patients underwent pre- and postoperative MRI, and clinical and radiographic variables were recorded and subject to inferential analysis. Results: Syrinx at presentation was independently associated with symptoms of spinal cord dysfunction at presentation (OR 2.17 (95% CI 1.05–4.48); p = 0.036), scoliosis (OR 5.33 (2.34–10.86); p = 0.001), and greater pB-C2 (posterior basion to C2 distance) measurement length (OR 1.14 (95% CI 1.01–1.30); p = 0.040). Syrinx at presentation was inversely associated with tussive headaches at presentation (OR 0.27 (95% CI 0.16–0.47); p = 0.001) and cranial nerve deficits at presentation (OR 0.49 (95% CI 0.26–0.92); p = 0.025). Postoperatively, patients with radiographic evidence of syrinx improvement had greater rates of symptom improvement (93.1% vs 82.1%; p = 0.049), better CCOS scores (15.4 vs 14.2; p = 0.001), and decreased rates of readmission (6.0% vs 25.0%, p = 0.002) and reoperation (0.5% vs 35.7%; p = 0.001). The difference in syrinx resolution was similar but not statistically significant (10.3% vs 16.7%; p = 0.251). AO joint anomaly (OR 0.20, 95% CI 0.04–0.95; p = 0.026) and foramen magnum diameter (OR 1.12, 95% CI 1.00–1.25; p = 0.049) were the only independent predictors of syrinx improvement, and surgical technique was the only predictor for syrinx resolution (OR 2.44, 95% CI 1.08–5.50; p = 0.031). Patients that underwent tonsil reduction surgery whose syrinx improved had a wider foramen magnum diameter than those whose did not improve (34.3 vs 31.7; p = 0.028). Conclusions: Radiographic syrinx improvement is associated with greater rates of symptom improvement and less readmissions and reoperations for CM-I. AO joint anomalies and narrower foramen magnums were independent risk factors for the lack of syrinx improvement. These novel insights will help guide preoperative patient counseling, pre- and intraoperative surgical decision-making, and postoperative clinical prognostication in the treatment of pediatric CM-I. [ABSTRACT FROM AUTHOR]

Urban bird species represent a subset of the regional species pool, consisting of species that have been able to survive in, or colonise, urban areas. Urban birds are typically resident non-forest species with a broad diet and nesting high in trees or in cavities, and some studies have also claimed that they are large-brained. However, little is known about how urban bird communities change over time. Does the urban environment impose specific selective pressures favouring particular species or ecological groups, or do birds in urban areas simply have population changes reflecting population trends at larger scales? We assessed population changes of 45 breeding land bird species in Oslo, the capital of Norway, based on surveys conducted ca. 15 years apart. Population changes within Oslo most closely matched changes occurring at the regional level (national population trends from Norway and Sweden). Thus, species increasing in Oslo were those that also increased at the regional level. We found no evidence that relative brain size, diet or habitat preferences influenced population trends. However, controlling for regional population trends, there were additional residual effects of nest site and migration: species nesting on the ground or low in bushes had more positive changes than species nesting high in trees or in cavities, and resident species did better than long- or short-distance migrants. These results indicate that urban environments are not isolated islands only influenced by own selection pressures, but are connected with regional population dynamics, most likely through immigration. [ABSTRACT FROM AUTHOR]