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Abstract Riboswitches are ligand-responsive gene-regulatory RNA elements that perform key roles in maintaining cellular homeostasis. Understanding how riboswitch sensitivity to ligand (EC50) is controlled is critical to explain how highly conserved aptamer domains are deployed in a variety of contexts with different sensitivity demands. Here we uncover roles by which RNA folding dynamics control riboswitch sensitivity in cells. By investigating the Clostridium beijerinckii pfl ZTP riboswitch, we identify multiple mechanistic routes of altering expression platform sequence and structure to slow RNA folding, all of which enhance riboswitch sensitivity. Applying these methods to riboswitches with diverse aptamer architectures and regulatory mechanisms demonstrates the generality of our findings, indicating that any riboswitch that operates in a kinetic regime can be sensitized by slowing expression platform folding. Our results add to the growing suite of knowledge and approaches that can be used to rationally program cotranscriptional RNA folding for biotechnology applications, and suggest general RNA folding principles for understanding dynamic RNA systems in other areas of biology.

Abstract Tuberculosis (TB) killed approximately 1.3 million people in 2022 and remains a leading cause of death from the bacteria Mycobacterium tuberculosis (M.tb); this number of deaths was surpassed only by COVID-19, caused by the SARS-CoV-2 virus. The alarming emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M.tb strains presents an urgent need for effective new treatments. Our study aimed to determine the synergistic effects of antibiotic combinations against M.tb. Using a high-throughput in vitro checkerboard assay, we evaluated the interactions of Bedaquiline (BDQ) and other antibiotics including Capreomycin (CAP), Linezolid (LIN), and Sutezolid (SUT) against M.tb H37Rv. BDQ and CAP demonstrated in vitro enhanced effect, which prompted further investigation in vivo using the murine low dose aerosol (LDA) model. After aerosol challenge with M.tb, C57BL/6 mice were treated with BDQ, CAP, or their combination, starting 28 days post-infection. The antimicrobial treatment lasted four weeks, and the bacterial burden in lung and spleen tissues was assessed at the end of treatment. At 4 weeks post-treatment, a significant reduction in bacterial load was observed within the lungs and spleens of mice given BDQ alone or given as a BDQ/CAP combination compared to the untreated group. In contrast, CAP monotherapy led to an increase in bacterial load within the lung and no significant difference in bacterial burden in the spleen in comparison to the untreated mice. These results were confirmed in the guinea pig model of TB, where both BDQ and the BDQ/CAP combination treatment led to a decrease in bacterial burden in the lung and spleen, whereas CAP had no significant effect on bacterial burden at the 4-week post treatment timepoint. We next determined whether there may be differences in vitro with the BDQ/CAP combination against M.tb lineages 1, 2 and 4. We determined that in vitro enhanced effect was not observed in some representative strains of M.tb lineage 4, indicating variability in drug effectiveness across M.tb lineages. This research underscores the complexity of TB treatment and the critical need for innovative approaches to combat this global health threat.

Abstract Binding-activated optical sensors are powerful tools for imaging, diagnostics, and biomolecular sensing. However, biosensor discovery is slow and requires tedious steps in rational design, screening, and characterization. Here we report on a platform that streamlines biosensor discovery and unlocks directed nanosensor evolution through genetically encodable fluorogenic amino acids (FgAAs). Building on the classical knowledge-based semisynthetic approach, we engineer ~15 kDa nanosensors that recognize specific proteins, peptides, and small molecules with up to 100-fold fluorescence increases and subsecond kinetics, allowing real-time and wash-free target sensing and live-cell bioimaging. An optimized genetic code expansion chemistry with FgAAs further enables rapid (~3 h) ribosomal nanosensor discovery via the cell-free translation of hundreds of candidates in parallel and directed nanosensor evolution with improved variant-specific sensitivities (up to ~250-fold) for SARS-CoV-2 antigens. Altogether, this platform could accelerate the discovery of fluorogenic nanosensors and pave the way to modify proteins with other non-standard functionalities for diverse applications.

The multi-material components formed by laser powder bed fusion (LPBF) have shown potential in advanced equipment due to their superior performance. The uneven distribution of immiscible in the molten pool is a challenge for the performance of multi-material components. In this study, a thermo-fluidic particle scale numerical model coupled with a ray-tracing method is established to understand the formation of the immiscible CuCrZr/316L multi-material. The impact of process parameters on the distribution of CuCrZr and 316L is investigated. Results reveal that the experimental and simulation results agree well with a maximum molten pool width and depth difference of 7%. The recoil pressure and Marangoni convection contribute to the mixing of 316L and CuCrZr. As the scanning speed decreases or the scanning power increases, a longer molten pool lifetime is obtained, which increases the immiscible CuCrZr/316L mixing. A large number of CuCrZr islands are formed inside the molten pool at high energy density with improved homogeneity. This work can provide fundamental insights into understanding the distribution of immiscible metal material in the multi-materials LPBF process.

Hydrodynamic separators are commonly used to control the total suspended solid concentration in stormwater before being discharged to natural water bodies. The separator studied in this paper, featuring a swirling flow generated by tangential inlet and outlet connections, was analyzed for its sediment removal efficiency in relation to sediment and flow rates. For the separator studied in this paper, the numerical model showed that the flow field was favorable for the sediments to gather at the center and settle. A higher flow rate or a smaller sediment diameter corresponded to a lower removal rate and vice versa. The dimension improvement for increasing the sediment removal rate was also studied. It was found that increasing the diameter of the separator showed a higher sediment removal rate compared with corresponding increase in the height of the separator. A dimensionless parameter J was proposed to assess the sediment removal rate of a separator, which may be used for designing and optimizing such a device. The removal rate is positively correlated with the J value. When the J value reaches 0.5 or above, the sediment removal rate exceeds 80%, which is a good initial target value for designing this type of separator. HIGHLIGHTS Provided an experimentally validated computational fluid dynamics model.; Changing the diameter has a greater impact on the removal rate of hydrodynamic separators than changing the height.; The J value can be used to evaluate the solids removal efficiency of a hydrodynamic separator.;

BackgroundCardiac monitoring strategies to detect occult atrial fibrillation (AF) post-stroke differ among healthcare institutions. This may be related to discrepancies in stroke subtype classification/adjudication, and/or consultation of cardiology specialists at Community Hospitals (CoH) and Academic Centers (AcC). Identifying the degree of heterogeneity may encourage development of guideline-directed monitoring protocols, result in higher AF detection rates and treatments, and fewer strokes.MethodsThe DiVERT (SeconDary Stroke PreVEntion ThRough Pathway ManagemenT) study was designed to characterize post-stroke cardiac monitoring practices in a hospital setting. Care pathways were assessed with in-person stakeholder interviews; patient-level data were reviewed using electronic medical records.ResultsDiVERT identified 2,475 patients with diagnoses of cryptogenic (83.6% vs. 33.1%, p

IntroductionHair cells (HCs) are the sensory receptors of the auditory and vestibular systems in the inner ears of vertebrates that selectively transduce mechanical stimuli into electrical activity. Although all HCs have the hallmark stereocilia bundle for mechanotransduction, HCs in non-mammals and mammals differ in their molecular specialization in the apical, basolateral, and synaptic membranes. HCs of non-mammals, such as zebrafish (zHCs), are electrically tuned to specific frequencies and possess an active process in the stereocilia bundle to amplify sound signals. Mammalian HCs, in contrast, are not electrically tuned and achieve amplification by somatic motility of outer HCs (OHCs).MethodsTo understand the genetic mechanisms underlying differences between adult zebrafish and mammalian HCs, we compared their RNA-seq-characterized transcriptomes, focusing on protein-coding orthologous genes related to HC specialization.ResultsThere was considerable shared expression of gene orthologs among the HCs, including those genes associated with mechanotransduction, ion transport/channels, and synaptic signaling. However, there were some notable differences in expression among zHCs, OHCs, and inner HCs (IHCs), which likely underlie the distinctive physiological properties of each cell type. For example, OHCs highly express Slc26a5 which encodes the motor protein prestin that contributes to OHC electromotility. However, zHCs have only weak expression of slc26a5, and subsequently showed no voltage-dependent electromotility when measured. Notably, the zHCs expressed more paralogous genes including those associated with HC-specific functions and transcriptional activity, though it is unknown whether they have functions similar to their mammalian counterparts. There was overlap in the expressed genes associated with a known hearing phenotype.DiscussionOur analyses unveil substantial differences in gene expression patterns that may explain phenotypic specialization of zebrafish and mouse HCs. This dataset also includes several protein-coding genes to further the functional characterization of HCs and study of HC evolution from non-mammals to mammals.

Abstract The aim of this study was to develop a dynamic model-based approach to separately quantify the exogenous and endogenous contributions to total plasma insulin concentration and to apply it to assess the effects of inhaled-insulin administration on endogenous insulin secretion during a meal test. A three-step dynamic in-silico modeling approach was developed to estimate the two insulin contributions of total plasma insulin in a group of 21 healthy subjects who underwent two equivalent standardized meal tests on separate days, one of which preceded by inhalation of a Technosphere® Insulin dose (22U or 20U). In the 30–120 min test interval, the calculated endogenous insulin component showed a divergence in the time course between the test with and without inhaled insulin. Moreover, the supra-basal area-under-the-curve of endogenous insulin in the test with inhaled insulin was significantly lower than that in the test without (2.1 ± 1.7 × 104 pmol·min/L vs 4.2 ± 1.8 × 104 pmol·min/L, p

Rainfall-derived inflow/infiltration (RDII) modelling during heavy rainfall events is essential for sewer flow management. In this study, two machine learning algorithms, random forest (RF) and long short-term memory (LSTM), were developed for sewer flow prediction and RDII estimation based on field monitoring data. The study implemented feature engineering for extracting physically significant features in sewer flow modelling and investigated the importance of the relevant features. The results from two case studies indicated the superior capability of machine learning models in RDII estimation in the combined and separated sewer systems, and LSTM model outperformed the two models. Compared to traditional methods, machine learning models were capable of simulating the temporal variation in RDII processes and improved prediction accuracy for peak flows and RDII volumes in storm events. HIGHLIGHTS Machine learning models, particularly the LSTM model, outperformed traditional methods in estimating RDII in sewer systems.; Feature engineering techniques allowed for the extraction of physically significant features in sewer flow modelling.; Machine learning models successfully simulated the temporal variation in RDII processes, resulting in improved accuracy for predicting peak flows and RDII volumes during storm events.;

Since its inception in 2009, femtosecond laser-assisted cataract surgery (FLACS) has become an alternative to conventional phacoemulsification cataract surgery (CPCS). Clinical studies were unable to demonstrate superior visual outcomes, but revealed reduced endothelial cell loss. More recently, the cost-effectiveness of FLACS over CPCS in routine cataract surgeries has been challenged. However, the unique abilities of FLACS to customize anterior capsulotomies precisely, soften and fragment the nucleus without capsular bag stress, and create corneal incisions may have special utility in complex cataract and less-common scenarios. In this article, we review the unique role of FLACS in complex cataract surgeries and how it could play a role to improve the safety and predictability of nonroutine cataract surgery.

Summary: Background: Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants. Findings: We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue. Interpretation: Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis. Funding: NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.

As an important component of the deep tunnel drainage system for dealing with urban waterlogging, the rotating stepped dropshaft has been proposed due to its small air entrainment. However, the hydraulic characteristics inside the shaft still need to be fully studied. In this study, the flow patterns, water velocity, and pressure in the rotating stepped dropshaft under different flow rates and geometric parameters were studied using a three-dimensional numerical model. The results show that increasing the central angle of the step and reducing the step height can both reduce the terminal velocity. A theoretical formula for predicting the terminal velocity was established and well validated. The connection between the shaft and the outlet pipe poses a severe threat to the structural safety due to alternating positive and negative pressures. Wall-attached swirling flow generates a circular high-pressure zone at the bottom of the dropshaft and the larger the flow rate, the greater the pressure gradient at the center of the bottom. By using the momentum theorem and considering the impact pressure range of the swirling flow, the shaft bottom pressure can be predicted reasonably well. HIGHLIGHTS The hydraulic characteristics of rotating stepped dropshafts are analyzed and the terminal velocity is evaluated theoretically and well validated.; The pressure distribution inside rotating stepped dropshafts and the impact effect of the wall-attached swirling flow on the shaft bottom are determined.; A simplified theoretical model is established to predict the impact pressure of the shaft.;

A 16-month monitoring program was conducted on a prototype sanitary system in a coastal city in China. The groundwater infiltration (GWI) on dry weather days and the rain-derived inflow and infiltration (RDII) on wet weather days were quantified and analyzed. The proportion of monthly averaged GWI to total flow can be as high as 70% during the observation period mainly due to the high groundwater level. The results also show that the ratio of RDII volume to total rainfall volume (defined as R-value) reaches a limited value of approximately 10% for the studied system when the total rainfall depth increases. A reference indicator Rlim for the limited R-value was proposed for assessing the conditions of sewer systems in terms of RDII. The Rlim value depends on local sewer conditions and in general, a lower Rlim value represents a better performance on RDII and vice versa. This study enriches the case studies on the performance of a specific sanitary sewer system on inflow and infiltration in a typical coastal city with exceptionally high groundwater levels, excess rainfall events in the monitoring season and possible typhoon events, which addresses the unique locational and hydrological properties of a representative coastal city. HIGHLIGHTS The time-period for the ‘minimum night flow method’ should be adjusted accordingly.; High infiltration due to high groundwater levels was observed specifically for the study site.; The ratio of RDII volume to total rainfall volume (R-value) tends to be limited as rainfall increases for all RDII events.; The limited R-value for high rainfall events was proposed for assessing the performance of sewer systems.;

This study investigated the hydraulic characteristics of stormwater sumps and their design optimization for sediment retention using physical experiments. Particle image velocimetry was utilized to measure the flow field, and the use of internal structures was investigated for improving solids retention. Results indicate that these internal structures can significantly improve the sediment removal efficiency of suspended solids with an average size of 125 μm, resulting in an efficiency improvement of 20–30%. Additionally, a modified Péclet number was proposed to more accurately evaluate the sediment removal efficiency of stormwater sumps, and recommendations were provided for further improving and optimizing sump design. This study provides insights into the hydraulic characteristics of stormwater sumps and has important implications for optimizing and designing particle removal systems for various industrial and environmental applications. HIGHLIGHTS The study demonstrates that incorporating enhancements leads to a substantial increase (20–30%) in the efficiency of removing suspended solids in stormwater sumps.; The study introduces a modified dimensionless number that provides a more precise evaluation of sediment removal efficiency in stormwater sumps.; The study highlights that scaling, with a ratio of up to 6, can reasonably predict particle removal efficiency.;

Substantial evidence suggests that all types of water, such as drinking water, wastewater, surface water, and groundwater, can be potential sources of Helicobacter pylori (H. pylori) infection. Thus, it is critical to thoroughly investigate all possible preconditioning methods to enhance the recovery of H. pylori, improve the reproducibility of subsequent detection, and optimize the suitability for various water types and different detection purposes. In this study, we proposed and evaluated five distinct preconditioning methods for treating water samples collected from multiple urban water environments, aiming to maximize the quantitative qPCR readouts and achieve effective selective cultivation. According to the experimental results, when using the qPCR technique to examine WWTP influent, effluent, septic tank, and wetland water samples, the significance of having a preliminary cleaning step becomes more evident as it can profoundly influence qPCR detection results. In contrast, the simple, straightforward membrane filtration method could perform best when isolating and culturing H. pylori from all water samples. Upon examining the cultivation and qPCR results obtained from groundwater samples, the presence of infectious H. pylori (potentially other pathogens) in aquifers must represent a pressing environmental emergency demanding immediate attention. Furthermore, we believe groundwater can be used as a medium to reflect the H. pylori prevalence in a highly populated community due to its straightforward analytical matrix, consistent detection performance, and minimal interferences from human activities, temperature, precipitation, and other environmental fluctuations.

Peptidoglycan (PG) and most surface glycopolymers and their modifications are built in the cytoplasm on the lipid carrier undecaprenyl phosphate (UndP). These lipid-linked precursors are then flipped across the membrane and polymerized or directly transferred to surface polymers, lipids, or proteins. Despite its essential role in envelope biogenesis, UndP is maintained at low levels in the cytoplasmic membrane. The mechanisms by which bacteria distribute this limited resource among competing pathways is currently unknown. Here, we report that the Bacillus subtilis transcription factor SigM and its membrane-anchored anti-sigma factor respond to UndP levels and prioritize its use for the synthesis of the only essential surface polymer, the cell wall. Antibiotics that target virtually every step in PG synthesis activate SigM-directed gene expression, confounding identification of the signal and the logic of this stress-response pathway. Through systematic analyses, we discovered 2 distinct responses to these antibiotics. Drugs that trap UndP, UndP-linked intermediates, or precursors trigger SigM release from the membrane in

Sediment accumulation in combined sewers can induce blockage and odor problems. Among various cleaning methods, using self-cleaning device-generated flushing waves has been thought to be an effective solution. In this study, a series of numerical tests were conducted using CFD software to investigate the cleaning efficiency of deposited sediment particles based on a simplified self-cleaning device. The CFD model was validated by the experimental and numerical results in the literature. The effects of several parameters including the flushing gate height, sediment bed thickness, sediment bed length, and sediment bed position on cleaning efficiency were discussed. A relative accumulative transport rate was defined to analyze the cleaning efficiency. Results showed that the lowest height of the flushing gate had the best effects on sediment removal. The flushing waves generated from the sudden opening of the flushing gate were capable of cleaning sediment deposits in the given initial sediment bed thickness, length, and position. The required time duration for cleaning the sediment deposit completely increased about 6, 3, and 3 times when the sediment bed thickness, sediment bed length, and distance between the flushing gate and sediment bed increased 10, 4, and 7 times, respectively. HIGHLIGHTS Both the flow hydrodynamics and sediment scour models were well validated with the experimental results.; The required time duration for cleaning the sediment deposit increased about 6, 3, and 3 times when the sediment bed thickness, sediment bed length, and distance between the flushing gate and sediment bed increased 10, 4, and 7 times, respectively.;

Abstract Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins’ preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions.

Context: Many parts of Tabernaemontana divaricata (T. divaricata) including its leaf is used for the analgesic and antibacterial purpose by Adivasis of Kerala. Aims: To evaluate the antibacterial potential of T. divaricata against common caries pathogens like S. mutans and L. acidophilus. Settings and Design: Research is done in Biogenix Research Lab, Thiruvananthapuram. Methods and Material: Ethyl alcoholic extract of T. divaricata leaves is tested for its antibacterial action against common caries pathogens at various levels. It includes assessing the leaves’ antibacterial activity, acid production of bacteria in the presence of the study sample, Minimum inhibitory concentration (MIC), minimum bacterial concentration (MBC) and colony forming units (CFU) levels in the presence of the leaf extract. Statistical Analysis Used: In descriptive statistics, mean and standard deviation is used. Mann–Whitney U test, Independent Students T-test, Student Paired T-test, and One-way ANOVA followed by Turkeys Post hoc analysis are the tests used in inferential statistics. Results: It is found that T. divaricata has substantial antibacterial action against S. mutans and L. acidophilus. Conclusions: Our indigenous plants have a lot of medicinal properties. T. divaricata is no exception to this, though it is commonly considered as a garden plant. In the current study, it has been proven that its leaves have antibacterial action against oral pathogens. So, the research has to be taken to a further level for its medicinal application.

The deliberate practice (DP) theory claims that expertise essentially reflects the accumulated amount of deliberate practice, and that with sufficient practice, genetic influences on expertise will be bypassed. Thus, a core prediction of the DP theory is that genetic effects on performance decrease as a function of practice. Here, we test this prediction using music as a model domain. Musical expertise (measured with a musical auditory discrimination test) and lifetime practice hours were determined in 6471 twins including 1302 complete twin pairs. We fitted a bivariate Cholesky decomposition with practice hours as a moderator to determine to what extent genetic and environmental influences on musical expertise are influenced by practice hours. On average, 50% of individual differences in musical expertise were due to genetic influences, whereas shared environmental and residual influences each explained about 25%. Importantly, music practice significantly moderated these estimates. Variation in musical expertise decreased with more practice hours due to decreased shared environmental and residual variance. In contrast, the overall genetic component was unaffected by the number of practice hours. Consequently, the relative genetic contribution (heritability) increased with more practice hours. These findings are in contrast with predictions from the DP theory and suggest that genetic predisposition remains important for musical expertise even after prolonged practice.

As power electronics continue to drive advancement in electronic devices by managing the system's energy flow, it is advantageous to examine all areas of energy transfer. Wireless power transfer is one section seeing increased adoption in consumer, industrial, and healthcare applications. This consequently increases the concern for safety, reliability, and efficiency. Power transmission to any unintended load is a primary safety issue in high-power wireless power transfer applications, such as unmanned aircraft systems. Foreign object detection is utilized to selectively transmit power to only the intended target to mitigate this issue. This paper seeks to demonstrate a novel alternative method of using machine learning and artificial intelligence techniques for performing foreign object detection solely on the transmitter portion of the system by only monitoring the TX coil current. This method is first evaluated in SPICE simulation software. Then by transitioning to a closed-loop hardware-based testbed designed to be deployed in unmanned aircraft systems. During the test process for the novel FOD method, the aggregate detection accuracy achieved was 83%, including worst-case misalignment conditions with the RX coil. When the outlying worst-case conditions are excluded, the detection accuracy improves to 97%. To measure the FOD effectiveness in preventing temperature rise in a metallic object, the metallic object was placed at the peak power draw location on the transmitter coil. When the metallic object is left at this location for extended periods, the novel FOD method lowers the maximum temperature reached by 86.8°C when compared to no FOD being active. The primary advantage to this novel method is the simplistic hardware additions, which only require minimal alterations to a WPTS without any FOD implemented. Along with this, implementing this foreign object detection method in the transmitter would mitigate the need for a direct communication link between the receiver and transmitter. As a result, the entire system complexity would decrease, thus increasing the UAS power density while maintaining a safe, effective, and reliable wireless power transmission method.

Photonic computing shows promise for transformative advancements in machine learning (ML) acceleration, offering ultrafast speed, massive parallelism, and high energy efficiency. However, current photonic tensor core (PTC) designs based on standard optical components hinder scalability and compute density due to their large spatial footprint. To address this, we propose an ultracompact PTC using customized programmable multi-operand multimode interference (MOMMI) devices, named M3ICRO. The programmable MOMMI leverages the intrinsic light propagation principle, providing a single-device programmable matrix unit beyond the conventional computing paradigm of one multiply-accumulate operation per device. To overcome the optimization difficulty of customized devices that often requires time-consuming simulation, we apply ML for optics to predict the device behavior and enable differentiable optimization flow. We thoroughly investigate the reconfigurability and matrix expressivity of our customized PTC and introduce a novel block unfolding method to fully exploit the computing capabilities of a complex-valued PTC for near-universal real-valued linear transformations. Extensive evaluations demonstrate that M3ICRO achieves a 3.5–8.9× smaller footprint, 1.6–4.4× higher speed, 9.9–38.5× higher compute density, 3.7–12× higher system throughput, and superior noise robustness compared to state-of-the-art coherent PTC designs. It also outperforms electronic digital A100 graphics processing unit by 34.8–403× higher throughput while maintaining close-to-digital task accuracy across various ML benchmarks.

Abstract Background Given the heterogeneity of stroke, it is important to determine the best course of motor therapy for each patient, i.e., to personalize rehabilitation based on predictions of long-term outcomes. Here, we propose a hierarchical Bayesian dynamic (i.e., state-space) model (HBDM) to forecast long-term changes in a motor outcome due to rehabilitation in the chronic phase post-stroke. Methods The model incorporates the effects of clinician-supervised training, self-training, and forgetting. In addition, to improve forecasting early in rehabilitation, when data are sparse or unavailable, we use the Bayesian hierarchical modeling technique to incorporate prior information from similar patients. We use HBDM to re-analyze the Motor Activity Log (MAL) data of participants with chronic stroke included in two clinical trials: (1) the DOSE trial, in which participants were assigned to a 0, 15, 30, or 60-h dose condition (data of 40 participants analyzed), and (2) the EXCITE trial, in which participants were assigned a 60-h dose, in either an immediate or a delayed condition (95 participants analyzed). Results For both datasets, HBDM accounts well for individual dynamics in the MAL during and outside of training: mean RMSE = 0.28 for all 40 DOSE participants (participant-level RMSE 0.26 ± 0.19—95% CI) and mean RMSE = 0.325 for all 95 EXCITE participants (participant-level RMSE 0.32 ± 0.31), which are small compared to the 0-5 range of the MAL. Bayesian leave-one-out cross-validation shows that the model has better predictive accuracy than static regression models and simpler dynamic models that do not account for the effect of supervised training, self-training, or forgetting. We then showcase model’s ability to forecast the MAL of “new” participants up to 8 months ahead. The mean RMSE at 6 months post-training was 1.36 using only the baseline MAL and then decreased to 0.91, 0.79, and 0.69 (respectively) with the MAL following the 1st, 2nd, and 3rd bouts of training. In addition, hierarchical modeling improves prediction for a patient early in training. Finally, we verify that this model, despite its simplicity, can reproduce previous findings of the DOSE trial on the efficiency, efficacy, and retention of motor therapy. Conclusions In future work, such forecasting models can be used to simulate different stages of recovery, dosages, and training schedules to optimize rehabilitation for each person. Trial registration This study contains a re-analysis of data from the DOSE clinical trial ID NCT01749358 and the EXCITE clinical trial ID NCT00057018

Wire-arc directed energy deposition has the potential to revolutionize the production process of large-size components with faster deposition speeds at a lower cost. As the cornerstone of modern materials, steels, especially high-performance steels with properties such as corrosion, wear, and heat resistance, have increasingly been applied in wire-arc directed energy deposition. This paper provides a review of recent advancements in wire-arc directed energy deposition of high-performance steels, covering the microstructure, properties, and defect formation mechanism. Aiming at the properties of high-performance steels deposited by wire-arc directed energy deposition, such as thermal history and cooling rate. The comprehensive review had been introduced for the perspective what the simulation, analysis, and their composition with results and pre/in-situ/post-process for improving the properties of wire-arc directed energy deposition processed high-performance steels are then summarized. Finally, a systematic framework for performance optimization of wire-arc directed energy deposition high-performance steels is proposed. This review contributes to a better scientific understanding of the wire-arc directed energy deposition of high-performance steels and puts forward guiding opinions for the future work on high-performance steels manufacturing.

Abstract Site investigation, deformation monitoring, laboratory test, and theoretical calculations were used to analyze the evolution details of a large expressway roadside landslide during the start-up sliding process. The monitoring results show that the initial deformation and failure occurred on the protective wall at the slope toe, then gradually developed to the upper part of the slope, and finally led to tensile cracks at the slope trailing edge. Accelerated deformation of the slope support structures, such as the protective wall at the slope toe, the anti-slide pile, and the anchor cable, were observed during the continuous extreme rainfall. The infiltrated rainwater can change the weight, the osmotic pressure, the anti-sliding force, the sliding force of the sliding mass, and further soften the fully weathered tuff soil and reduce its strength, resulting in the landslide occurrence. Block the slope surface runoff is an effective measure to reduce the landslide risk. The current analysis will be helpful to the prevention, control, and emergency disposal of similar landslides.

Abstract A growing number of studies have shown a connection between rhythmic processing and language skill. It has been proposed that domain-general rhythm abilities might help children to tap into the rhythm of speech (prosody), cueing them to prosodic markers of grammatical (syntactic) information during language acquisition, thus underlying the observed correlations between rhythm and language. Working memory processes common to task demands for musical rhythm discrimination and spoken language paradigms are another possible source of individual variance observed in musical rhythm and language abilities. To investigate the nature of the relationship between musical rhythm and expressive grammar skills, we adopted an individual differences approach in N = 132 elementary school-aged children ages 5–7, with typical language development, and investigated prosodic perception and working memory skills as possible mediators. Aligning with the literature, musical rhythm was correlated with expressive grammar performance (r = 0.41, p

Pan et al. determine the impact of the antiviral remdesivir (RDV) on biomarkers associated with clinical outcomes, within a randomized, double-blind, placebo-controlled phase 3 study (PINETREE). They demonstrate that RDV-treated patients have an accelerated reduction in soluble angiopoietin-2, D-dimer and neutrophil-to-lymphocyte ratios.

Prokaryotic communities play important roles in sewer sediment ecosystems, but the community composition, functional potential, and assembly mechanisms of sewer sediment prokaryotic communities are still poorly understood. Here, we studied the sediment prokaryotic communities in different urban functional areas (multifunctional, commercial, and residential areas) through 16S rRNA gene amplicon sequencing. Our results suggested that the compositions of prokaryotic communities varied significantly among functional areas. Desulfomicrobium, Desulfovibrio, and Desulfobacter involved in the sulfur cycle and some hydrolytic fermentation bacteria were enriched in multifunctional area, while Methanospirillum and Methanoregulaceae, which were related to methane metabolism were significantly discriminant taxa in the commercial area. Physicochemical properties were closely related to overall community changes (p < 0.001), especially the nutrient levels of sediments (i.e., total nitrogen and total phosphorus) and sediment pH. Network analysis revealed that the prokaryotic community network of the residential area sediment was more complex than the other functional areas, suggesting higher stability of the prokaryotic community in the residential area. Stochastic processes dominated the construction of the prokaryotic community. These results expand our understanding of the characteristics of prokaryotic communities in sewer sediment, providing a new perspective for studying sewer sediment prokaryotic community structure.

ABSTRACTThe peptidoglycan (PG) layer protects bacteria from osmotic lysis and defines their shape. The class A penicillin-binding proteins (aPBPs) are PG synthases that possess both glycan polymerization and crosslinking activities needed for PG biogenesis. In Gram-negative bacteria, aPBPs require activation by outer membrane lipoproteins, which are thought to stimulate their cognate synthase by inducing conformational changes that promote polymerase function. How aPBPs are controlled in Gram-positive bacteria is less clear. One of the few known regulators is MacP in Streptococcus pneumoniae (Sp). MacP is required for the activity of Sp PBP2a, but its mode of action has been obscure. We therefore selected for PBP2a variants capable of functioning in the absence of MacP. Amino acid substitutions that bypassed the MacP requirement for PBP2a function in vivo also activated its polymerase activity in vitro. Many of these changes mapped to the interface between the transmembrane (TM) helix and polymerase domain in a model PBP2a structure. This region is conformationally flexible in the experimentally determined structures of aPBPs and undergoes a structural transition upon binding the substrate-mimicking drug moenomycin. Our findings suggest that MacP promotes PG polymerization by altering the TM-polymerase domain interface in PBP2a and that this mechanism for aPBP activation may be broadly conserved. Furthermore, Sp cells expressing an activated PBP2a variant displayed heterogeneous shapes, highlighting the importance of proper aPBP regulation in cell morphogenesis.IMPORTANCEClass A penicillin-binding proteins (aPBPs) play critical roles in bacterial cell wall biogenesis. As the targets of penicillin, they are among the most important drug targets in history. Although the biochemical activities of these enzymes have been well studied, little is known about how they are regulated in cells to control when and where peptidoglycan is made. In this report, we isolate variants of the Streptococcus pneumoniae enzyme PBP2a that function in cells without MacP, a partner normally required for its activity. The amino acid substitutions activate the cell wall synthase activity of PBP2a, and their location in a model structure suggests an activation mechanism for this enzyme that is shared with aPBPs from distantly related organisms with distinct activators.

Background Guideline‐based hypertension management is integral to the prevention of stroke. We examine trends in antihypertensive medications prescribed after stroke and assess how well a prescriber's blood pressure (BP) medication choice adheres to clinical practice guidelines (BP‐guideline adherence). Methods and Results The FSR (Florida Stroke Registry) uses statewide data prospectively collected for all acute stroke admissions. Based on established guidelines, we defined optimal BP‐guideline adherence using the following hierarchy of rules: (1) use of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker as first‐line antihypertensive among diabetics; (2) use of thiazide‐type diuretics or calcium channel blockers among Black patients; (3) use of beta blockers among patients with compelling cardiac indication; (4) use of thiazide, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, or calcium channel blocker class as first line in all others; (5) beta blockers should be avoided as first line unless there is a compelling cardiac indication. A total of 372 254 cases from January 2010 to March 2020 are in the FSR with a diagnosis of acute ischemic stroke, hemorrhagic stroke, transient ischemic attack, or subarachnoid hemorrhage; 265 409 with complete data were included in the final analysis. Mean age was 70±14 years; 50% were women; and index stroke subtypes were 74% acute ischemic stroke, 11% intracerebral hemorrhage, 11% transient ischemic attack, and 4% subarachnoid hemorrhage. BP‐guideline adherence to each specific rule ranged from 48% to 74%, which is below quality standards of 80%, and was lower among Black patients (odds ratio, 0.7 [95% CI, 0.7–0.83]; P

Obesity perturbs central functions of human adipose tissue, centred on differentiation of preadipocytes to adipocytes, i.e., adipogenesis. The large environmental component of obesity makes it important to elucidate epigenetic regulatory factors impacting adipogenesis. Promoter Capture Hi-C (pCHi-C) has been used to identify chromosomal interactions between promoters and associated regulatory elements. However, long range interactions (LRIs) greater than 1 Mb are often filtered out of pCHi-C datasets, due to technical challenges and their low prevalence. To elucidate the unknown role of LRIs in adipogenesis, we investigated preadipocyte differentiation to adipocytes using pCHi-C and bulk and single nucleus RNA-seq data. We first show that LRIs are reproducible between biological replicates, and they increase >2-fold in frequency across adipogenesis. We further demonstrate that genomic loci containing LRIs are more epigenetically repressed than regions without LRIs, corresponding to lower gene expression in the LRI regions. Accordingly, as preadipocytes differentiate into adipocytes, LRI regions are more likely to contain repressed preadipocyte marker genes; whereas these same LRI regions are depleted of actively expressed adipocyte marker genes. Finally, we show that LRIs can be used to restrict multiple testing of the long-range cis-eQTL analysis to identify variants that regulate genes via LRIs. We exemplify this by identifying a putative long range cis regulatory mechanism at the LYPLAL1/TGFB2 obesity locus. In summary, we identify LRIs that mark repressed regions of the genome, and these interactions increase across adipogenesis, pinpointing developmental regions that need to be repressed in a cell-type specific way for adipogenesis to proceed.

Sumps are commonly used in urban stormwater systems, which can be considered as a simple pretreatment device for stormwater quality control. However, they may function as pollution sources due to sediment washout under high flow conditions. An experimental study was conducted to investigate the scour process of predeposited sediments from a sump and its influencing parameters. Under conditions with large inflows or high sediment deposit, the sediment particles could be resuspended, entrained and flushed out. The washout mass decreased exponentially with time if the sediment bed surface depth was larger than a threshold value; otherwise, the amount of washout would be much smaller. The same scour pattern was observed for all the testing cases, of which the largest scour depth always occurred below the outlet. The deposit below the inlet might increase under conditions with high flow rates and low levels of sediment bed. Dimension analysis was performed and principal non-dimensional parameters were found, including the Péclet number, the pipe Froude number, and the dimensionless particle diameter, which can be used to determine whether the washout would occur and its intensity in a stormwater sump under given conditions. HIGHLIGHTS Maximum scour depth always occurs at the downstream side of stormwater sumps.; Sediment bed surface depth, discharge and particle size affect the washout process.; Péclet number, pipe Froude number and dimensionless particle size are most important to assess sump washout.;

OBJECTIVES:. Temporal trends and factors associated with the withdrawal of life-sustaining therapy (WLST) after acute stroke are not well determined. DESIGN:. Observational study (2008–2021). SETTING:. Florida Stroke Registry (152 hospitals). PATIENTS:. Acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) patients. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Importance plots were performed to generate the most predictive factors of WLST. Area under the curve (AUC) for the receiver operating curve were generated for the performance of logistic regression (LR) and random forest (RF) models. Regression analysis was applied to evaluate temporal trends. Among 309,393 AIS patients, 47,485 ICH patients, and 16,694 SAH patients; 9%, 28%, and 19% subsequently had WLST. Patients who had WLST were older (77 vs 70 yr), more women (57% vs 49%), White (76% vs 67%), with greater stroke severity on the National Institutes of Health Stroke Scale greater than or equal to 5 (29% vs 19%), more likely hospitalized in comprehensive stroke centers (52% vs 44%), had Medicare insurance (53% vs 44%), and more likely to have impaired level of consciousness (38% vs 12%). Most predictors associated with the decision to WLST in AIS were age, stroke severity, region, insurance status, center type, race, and level of consciousness (RF AUC of 0.93 and LR AUC of 0.85). Predictors in ICH included age, impaired level of consciousness, region, race, insurance status, center type, and prestroke ambulation status (RF AUC of 0.76 and LR AUC of 0.71). Factors in SAH included age, impaired level of consciousness, region, insurance status, race, and stroke center type (RF AUC of 0.82 and LR AUC of 0.72). Despite a decrease in the rates of early WLST (< 2 d) and mortality, the overall rates of WLST remained stable. CONCLUSIONS:. In acute hospitalized stroke patients in Florida, factors other than brain injury alone contribute to the decision to WLST. Potential predictors not measured in this study include education, culture, faith and beliefs, and patient/family and physician preferences. The overall rates of WLST have not changed in the last 2 decades.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) reduced IsoLGs and AF susceptibility. We hypothesized that IsoLGs mediate detrimental pathophysiologic effects in atrial cardiomyocytes that promote the AF substrate. Using Seahorse XFp extracellular flux analysis and a luminescence assay, IsoLG exposure suppressed intracellular ATP production in atrial HL-1 cardiomyocytes. IsoLGs caused mitochondrial dysfunction, with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) with protein carbonylation, and mitochondrial DNA damage. Moreover, they generated cytosolic preamyloid oligomers previously shown to cause similar detrimental effects in atrial cells. In mouse atrial and HL-1 cells, patch clamp experiments demonstrated that IsoLGs rapidly altered action potentials (AP), implying a direct effect independent of oligomer formation by reducing the maximum Phase 0 upstroke slope and shortening AP duration due to ionic current modifications. IsoLG-mediated mitochondrial and electrophysiologic abnormalities were blunted or totally prevented by 2-HOBA. These findings identify IsoLGs as novel mediators of oxidative stress-dependent atrial pathophysiology and support the investigation of dicarbonyl scavengers as a novel therapeutic approach to prevent AF.

Summary: Background: Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver. Methods: To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals’ subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis. Findings: We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels. Interpretation: Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease. Funding: The work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005–2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research.

There has been a longstanding debate about the question: What amounts of what types of youth sport activities optimally facilitate later athletic excellence? This article provides a review of relevant research. We first evaluate popular conceptualizations of participation patterns—early specialization, deliberate practice, and deliberate play. Then, we review the available evidence on associations between performance and individual participation variables. The review reveals conceptual, definitional, and empirical flaws of the conceptions of early specialization, deliberate practice, and deliberate play. These approaches thus possess limited usefulness for empirical research. A review of studies considering individual, clearly defined participation variables provides a differentiated pattern of findings: Predictors of rapid junior performance and of long-term senior performance are opposite. Higher-performing juniors, compared to lower-performing peers, started playing their main sport, began involvement in talent promotion programs, and reached developmental performance milestones at younger ages, while accumulating larger amounts of coach-led main-sport practice, but less other-sports practice. In contrast, senior world-class athletes, compared to less-accomplished national-class peers, started playing their main sport, began involvement in talent promotion programs, and achieved performance milestones at older ages, while accumulating less coach-led main-sport practice, but more other-sports practice. We discuss implications for theory, practice, and future research.

Summary: Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months’ follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4–15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0–not evaluable) and 1.8 months (95% CI 1.8–2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Summary: Cochlear and vestibular hair cells are highly specialized sensory receptors for hearing and balance. Here, we report a serendipitous identification of a hair-cell-specific organelle in neonatal mouse inner ear, which we name “apicosome.” The apicosome is ∼500 nm in diameter and shows itinerant nature and transient appearance during development in cochlear hair cells. In contrast to cochlear hair cells, the apicosome persists in vestibular hair cells even in adult. The timing of apicosome translocation and disappearance in cochlear hair cells during development is correlated with kinocilium development and maintenance. The apicosome is not seen in supporting cells despite the fact that nascent supporting cells have microvilli and a primary cilium. Interestingly, transdifferentiated hair cells from supporting cells also contain apicosome, suggesting that it is unique to hair cells. Thus, our study identifies a previously undescribed organelle in hair cells and lays the foundation for further characterization of this specialized structure.

Joana Paixao,1,2 Maria Galangue,1 Celestina Gaston,1 Raísa Carralero,1 Celestina Lino,1 Gracieth Júlio,1 Zinga David,1 Moises Francisco,1 Cruz S Sebastião,1,3,4 Euclides NM Sacomboio,1,4 Joana Morais,1,5 Ngiambudulu M Francisco1 1Grupo de Investigação Microbiana e Imunológica, Instituto Nacional de Investigação em Saúde (National Institute for Health Research), Luanda, Angola; 2Unidade de Ensino e Investigação de Microbiologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal; 3Centro de Investigação em Saúde de Angola, Luanda, Angola; 4Instituto Superior de Ciências de Saúde, Universidade Agostinho Neto, Luanda, Angola; 5Faculdade de Medicina, Universidade Agostinho Neto, Luanda, AngolaCorrespondence: Ngiambudulu M Francisco, Grupo de Investigação Microbiana e Imunológica, Instituto Nacional de Investigação em Saúde (National Institute for Health Research), Rua: Amílcar Cabral, No. 96, por trás do Hospital Josina Machel, P.O. Box: 3635, Luanda, Angola, Tel +244 931 36 1717, Email franciscongiamb@yahoo.comBackground: The global emergence of coronavirus disease 2019 (COVID-19) has challenged healthcare and rapidly spread over the globe. Early detection of new infections is crucial in the control of emerging diseases. Evidence of early recorded COVID-19 cases outside China has been documented in various countries. In this study, we aimed to identify the time of SARS-CoV-2 infection circulation by retrospectively analyzing sera of measles patients, weeks before the reported first COVID-19 cases in Angola.Materials and Methods: We examined the humoral response against SARS-CoV-2 by using an enzyme-linked immunosorbent assay (ELISA)-based assay on a combined two-step sandwich enzyme immunoassay method. In total, we received 568 study patients with blood specimens collected from 23 September 2019 to 28 February 2020, 442 sera samples that met the criteria of the study were withdrawn and selected from the overall 568 received samples. In this study, we considered seropositives, patients who tested positive for SARS-CoV-2 immunoglobulin G (IgG) and M (IgM) antibodies with the index value > 1.Results: Of the 442 sera samples that met the criteria of the study, 204 were measles seropositive. Forty out of 204 were confirmed reactive to SARS-CoV-2 viral proteins using IgG and IgM more than 2 weeks before the first reported case in Angola. The humoral response analysis showed significant differences (p = 0.01) between the IgG and IgM indexes in the unvaccinated measles patients. Similarly, a significant difference (p = 0.001) was seen between the IgG and IgM indexes in the vaccinated measles patients.Conclusion: Here, using the humoral response analysis, we report the identification of early circulation SARS-CoV-2 infection weeks before the first recognized cases in the Republic of Angola.Keywords: infection, antibodies, pandemic, COVID-19, humoral response

In recent years, three simple tracers (conductivity, turbidity and temperature) have shown their advantages to many other tracers for tracing and assessment of extraneous water (or inflow and infiltration, I/I) into sewer systems due to low detection cost and high monitoring frequency. A better understanding of the error and uncertainty of the three simple tracers on the quantification of I/I will help to improve the reliability and reduce the cost of actual projects. A large-scale experimental model simulating a 36 m long sewer was constructed for conducting extraneous water flow tests including groundwater infiltration, wastewater inflow and hot water inflow under different I/I flow rates and concentrations. The accuracy and uncertainty of the three tracers were estimated, and their correlation with tracer concentration difference before and after extraneous inflow was also analyzed. Experimental results provide guidance for the practical applicability of the three tracers under different I/I conditions. HIGHLIGHTS Large-scale experimental tests were conducted to evaluate three simple tracers for I/I assessment.; The accuracy and uncertainty of three simple tracers were evaluated.; The suitable conditions for each of the three tracers were illustrated.;

As we look forward to the next generation of hyperspectral infrared (IR) atmospheric sounders, grating spectrometers hold promise for improved performance (e.g., horizontal and spectral resolutions) and more rapid revisit while reducing the size and complexity of the instrument. We briefly revisit the technology used in the Atmospheric Infrared Sounder (AIRS), recognizing that it was developed in the 1990’s and has matured key technologies in the areas of IR detectors, optical coatings, gratings, and cryocoolers. AIRS has been an unqualified success not only as a science and operational mission but also as a technology demonstration of the reliability and simplicity of grating spectrometer IR sounding instruments. Advancements in focal plane arrays (FPAs) have enabled a new class of grating spectrometer IR sounders that offer more spectral channels on a single FPA, mitigating some of the issues seen in AIRS that used linear arrays. These improvements have been manifested in the CubeSat Infrared Atmospheric Sounder (CIRAS) brassboard instrument, developed at the California Institute of Technology Jet Propulsion Laboratory with industry partner Ball Aerospace. Further enhancements beyond those used in CIRAS enable the development of a new class of instruments with a very long-wavelength infrared response and a very high spatial resolution (

Introduction The risk of hemorrhagic transformation (HT) in the early phase of acute ischemic stroke (AIS) remains unknown, leading to potential unnecessary delays in initiation of anticoagulation for secondary stroke prevention. We sought to assess the rate of HT associated withdirect oral anticoagulant (DOAC) initiation within and beyond 48 hours after AIS, using a pooled analysis of available published data. Methods A pooled analysis of 6 studies (4 prospective observational blinded outcome studies and2 randomized trials) of DOAC initiation within 14 days of AIS or transient ischemic attack (TIA) was conducted. The primary endpoint was incident radiographic HT on follow‐up imaging. Secondary endpoints included symptomatic HT, new parenchymal hemorrhage, recurrent ischemic events, extracranial hemorrhage, mortality within the study period, and follow‐up modified Rankin Scale score.The results were reported as odds ratio (OR) andhazard ratio (HR)with 95% confidence interval (CI). Results We evaluated 509 patients; median infarct volume was1.5 (0.1‐7.8) ml, andmedian National Institutes of Health Stroke Scale was2 (0‐3).Incident radiographic HT was seen on follow‐up scan in 34 (6.8%) patients.DOAC initiation within 48 hours from index event was not associated with incident HT (adjusted OR 0.67, [0.30 – 1.50]P = 0.32).No patients developed symptomatic HT.Conversely, 31 (6.1%) patients developedrecurrent ischemic events, 64% of which occurred within 14 days.Initiating a DOAC within 48 hours of onset was associated with a trend towards lower rates of recurrent ischemic events, but this was not statistically significant (HR 0.42, [0.17 – 1.008]P = 0.052). In contrast to HT,recurrent ischemic events were associated with poor functional outcomes (OR = 6.8, [2.84 – 16.24], p< 0.001). Conclusions Initiation of DOAC within 48 hours after stroke was not associated with decreased risk of recurrent ischemic events, or increasedincident risk of HT. Both recurrent ischemic events and incident HT occurred at similar rates.Unlike HT, however, recurrent ischemic events were associated with poor outcomes.

Purpose of review: Kidney disease is present in almost half of Canadian patients with type 2 diabetes (T2D), and it is also the most common first cardiorenal manifestation of T2D. Despite clear guidelines for testing, opportunities are being missed to identify kidney diseases, and many Canadians are therefore not receiving the best available treatments. This has become even more important given recent clinical trials demonstrating improvements in both kidney and cardiovascular (CV) endpoints with sodium-glucose cotransporter 2 (SGLT2) inhibitors and a nonsteroidal mineralocorticoid receptor antagonist, finerenone. The goal of this document is to provide a narrative review of the current evidence for the treatment of diabetic kidney disease (DKD) that supports this new standard of care and to provide practice points. Sources of information: An expert panel of Canadian clinicians was assembled, including 9 nephrologists, an endocrinologist, and a primary care practitioner. The information the authors used for this review consisted of published clinical trials and guidelines, selected by the authors based on their assessment of their relevance to the questions being answered. Methods: Panelists met virtually to discuss potential questions to be answered in the review and agreed on 10 key questions. Two panel members volunteered as co-leads to write the summaries and practice points for each of the identified questions. Summaries and practice points were distributed to the entire author list by email. Through 2 rounds of online voting, a second virtual meeting, and subsequent email correspondence, the authors reached consensus on the contents of the review, including all the practice points. Key findings: It is critical that DKD be identified as early as possible in the course of the disease to optimally prevent disease progression and associated complications. Patients with diabetes should be routinely screened for DKD with assessments of both urinary albumin and kidney function. Treatment decisions should be individualized based on the risks and benefits, patients’ needs and preferences, medication access and cost, and the degree of glucose lowering needed. Patients with DKD should be treated to achieve targets for A1C and blood pressure. Renin-angiotensin-aldosterone system blockade and treatment with SGLT2 inhibitors are also key components of the standard of care to reduce the risk of kidney and CV events for these patients. Finerenone should also be considered to further reduce the risk of CV events and chronic kidney disease progression. Education of patients with diabetes prescribed SGLT2 inhibitors and/or finerenone is an important component of treatment. Limitations: No formal guideline process was used. The practice points are not graded and are not intended to be viewed as having the weight of a clinical practice guideline or formal consensus statement. However, most practice points are well aligned with current clinical practice guidelines.

Scores on the Armed Services Vocational Aptitude Battery (ASVAB) predict military job (and training) performance better than any single variable so far identified. However, it remains unclear what factors explain this predictive relationship. Here, we investigated the contributions of fluid intelligence (Gf) and two executive functions—placekeeping ability and attention control—to the relationship between the Armed Forces Qualification Test (AFQT) score from the ASVAB and job-relevant multitasking performance. Psychometric network analyses revealed that Gf and placekeeping ability independently contributed to and largely explained the AFQT–multitasking performance relationship. The contribution of attention control to this relationship was negligible. However, attention control did relate positively and significantly to Gf and placekeeping ability, consistent with the hypothesis that it is a cognitive “primitive” underlying the individual differences in higher-level cognition. Finally, hierarchical regression analyses revealed stronger evidence for the incremental validity of Gf and placekeeping ability in the prediction of multitasking performance than for the incremental validity of attention control. The results shed light on factors that may underlie the predictive validity of global measures of cognitive ability and suggest how the ASVAB might be augmented to improve its predictive validity.