bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of Large Anterior Skull Base Defects After Resection of Sinonasal Tumors With Intracranial Extension by Using Pedicled Double Flap Techniques
Authors: Ngo Cong Van , Nguyen Hoang , Aklinski Joseph , Minh Le Huu Nhat , Le Hoang Huy , Nguyen Khang Ngoc , Tran Uyen Hanh , Le Nhat , Huynh Le Phuong , Tran Truong Minh
Published: August 2022

Introduction:

The use of surgical resection for large anterior skull base (ASB) tumors and sinonasal malignancies with intracranial extension will result in a large skull base defect. Reconstruction of large ASB defects using traditional techniques is high risk and may lead to postoperative cerebral spinal fluid (CSF) leakage, meningitis, and an increase in mortality rate. The use of a pedicled double flap technique to reconstruct the ASB defect may decrease complications. This study presents the clinical outcomes of patients who underwent double flap reconstruction techniques after resection of their sinonasal malignancies with significant intracranial extension at Cho Ray hospital in Vietnam.

Methods:

The case series study was conducted at Cho Ray hospital from September 2010 to September 2020. All patients with large sinonasal malignancies that invaded intracranially underwent transnasal endoscopic surgery and subfrontal craniotomy. Reconstruction of large skull base defects (>2 cm) were followed up by using the pedicled double flaps technique. This study was performed in line with the principles of the Declaration of Helsinki. Approval of the study was granted by the Independent Ethics Committee of Cho Ray Hospital (Date: March 3, 2014/No: 11/BVCRHĐĐĐ).

Results:

During September 2010 to September 2020, there were 75 patients who underwent a modified multilayer, double flap reconstruction technique after the resection of their ASB tumor. Skull base defects were commonly seen along the horizontal plate of the ethmoid bone and the ethmoid roof (98.6%). Large skull base defects (>2 cm) accounted for 81.3% of cases. Overall, the risk of postoperative CSF leakage and meningitis after double flap repair was considerably low. Of all participants, only 1 experienced postoperative CSF leakage and 1 experienced postoperative meningitis. Despite the complications, these patients improved significantly and remained stable.

Conclusion:

The use of double vascularized pedicled flaps may decrease the incidence of postoperative CSF leakage and meningitis. This technique is an effective method for the reconstruction of ASB tumors with large defects.
Clinical and Endoscopic Consequences of Delay in Stent Exchange Procedures With ERCP During the Covid-19 Pandemic
Authors: Keskin Onur , Kav Taylan , Vahabov Cevansir , Usta Burcu , Sivri Bülent , Parlak Erkan
Published: August 2022

Introduction:

During the COVID-19 pandemic, elective endoscopic retrograde cholangiopancreatography (ERCP) procedures have been postponed as recommended by international guidelines. In this study, the results of biliary and pancreatic ERCP procedures that had to be postponed during the pandemic process were investigated.

Materials and Methods:

Forty-seven patients whose stent exchange procedures with ERCP were postponed between March 2020 and June 2020 due to the COVID-19 pandemic were included in the study. Patients were evaluated in 2 groups as delayed biliary procedures (n: 32) and delayed pancreatic procedures (n: 15). Clinical problems (biliary or pancreatic pain, itching, cholangitis, etc.) and technical problems encountered during the procedure (stent migration, abundant stone sludge in the bile ducts, etc.) were compared with 46 patients who could be treated without delay (39 interventions for the biliary system and seven interventions for the pancreas).

Findings:

Considering the procedures for the biliary system, there was no difference in age and sex between the groups. Although clinical problems in biliary procedures were more common in the group with delay than in those without delay, this difference was not significant (34% vs. 20%; P: 0.14). The technical problems encountered during the procedures in the group with delay were significantly higher than those without delay (21% vs. 2.5%; P: 0.019), with stent migration being the most common problem (n: 5). Age and sex did not differ in the patients who had pancreatic interventions with and without delay. The clinical problems that developed in the patients did not differ between the groups with and without delay (26% vs. 28%; P: 0.8). Although technical problems were encountered in 1 out of 15 patients in the group with delay, no technical problem was experienced in the group without delay (P: 0.68).

Conclusion:

Postponing elective ERCP procedures for the biliary system not for the pancreatic system during the COVID-19 pandemic brings technical problems.
Excess Mortality Among Solid Organ Transplant Recipients in the United States During the COVID-19 Pandemic
Authors: Clarke Jacob A. , Wiemken Timothy L. , Korenblat Kevin M.
Published: August 2022

Background.

The COVID-19 pandemic is the first sustained respiratory disease pandemic to arise since the start of solid organ transplantation (SOT). Prior studies have demonstrated that SOT recipients are at greater risk for severe complications of infection and are less likely to respond to vaccination.

Methods.

The Scientific Registry of Transplant Recipients Standard Analysis Files was used to assess the cumulative excess mortality in SOT recipients during the first 20 mo of the pandemic.

Results.

Compared with excess mortality rates in the US population (25.9 deaths/10 000; confidence interval [CI], 10.9-41.1), the excess mortality per 10 000 was higher in all SOT groups: kidney (188.5; CI, 150.7-225.6), lung (173.6; CI, 17-334.7), heart (123.7; CI, 56-191.4), and liver (105.1; CI, 64.6-146). The higher rates persisted even with attempts to control for population age structure and renal allograft failure. Excess mortality was also higher in Black (236.8; CI, 186.1-287) and Hispanic (256.9; CI, 208.1-305.2) organ recipients compared with other racial and ethnic groups in the Scientific Registry of Transplant Recipients and compared with the Black and Hispanic populations in the United States.

Conclusions.

Studies of excess mortality provide insight into the health and survival of specialized populations like SOT recipients during major health events like the COVID-19 pandemic.
Nutraceuticals in mood disorders: current knowledge and future directions
Authors: Travica Nikolaj , Teasdale Scott , Marx Wolfgang
Published: August 2022

Purpose of review

There is a large evidence base of clinical trials that have investigated the efficacy of a range of nutraceuticals on mood disorders. The aim of the current review is to provide an update regarding the efficacy and safety of nutraceutical agents in mood disorders and to highlight considerations for future research.

Recent findings

Nutraceuticals such as omega-3, probiotics, zinc, saffron and curcumin have been recommended as adjunctive interventions to standard treatments for people with depression, while St John's wort has been recommended as a monotherapy. In contrast, less research has been devoted to investigating the effect of nutraceuticals in bipolar disorder, with omega-3 being weakly recommended as an adjunctive to standard treatments. Although the safety profile of most nutraceuticals appears acceptable, more insight into the long-term effects within a range of cohorts is recommended.

There are a number of nutraceuticals that have clinical trial support for their use as either adjunctive interventions for depression; however, there is mostly limited support for their use in bipolar disorder. Further randomized controlled trials that take into consideration a number of emerging mechanisms, potential nutraceutical combinations and factors that may predict treatment response are required to inform clinical use.
Palaeoclimatic changes resulted in range expansion and subsequent divergence in brown fur seals,Arctocephalus pusillus
Authors: Malan A. , von der Heyden S. , Herron S. , Arnould J. P. Y. , Kirkwood R. , Matthee C. A.
Published: August 2022

Past climatic change as a driving force of marine diversification is still largely unclear, particularly for Southern Hemisphere species. Here, we present a case using the brown fur seal,Arctocephalus pusillus,assessing the geographical structure and demographic history using mitochondrial and nuclear data. Results show the two previously defined subspecies (one from Australia and the other from southern Africa) are phylogeographically distinct. Migration analyses based on nuclear data suggest the absence of migrants among the two genetically close assemblages. The demographic history ofA. pusillusis characterized by a glacial population expansion (approx. 18 kya) in the southern African lineage, which coincides with time estimates of population expansion of prey species of seals. Approximate Bayesian calculations support an eastward dispersal event during the Last Glacial Maximum when sea levels were lower, followed by a postglacial divergence event, approximately 13 kya. The demographic history of the brown fur seal in the Southern Oceans provides support that recent palaeoclimatic changes could have facilitated expansions in some marine species and that postglacial sea-level rise may have acted as a dispersal barrier for species mostly confined to continental shelves.
Active anemosensing hypothesis: how flying insects could estimate ambient wind direction through sensory integration and active movement
Authors: van Breugel Floris , Jewell Renan , Houle Jaleesa
Published: August 2022

Estimating the direction of ambient fluid flow is a crucial step during chemical plume tracking for flying and swimming animals. How animals accomplish this remains an open area of investigation. Recent calcium imaging with tethered flying
Drosophila
has shown that flies encode the angular direction of multiple sensory modalities in their central complex: orientation, apparent wind (or airspeed) direction and direction of motion. Here, we describe a general framework for how these three sensory modalities can be integrated over time to provide a continuous estimate of ambient wind direction. After validating our framework using a flying drone, we use simulations to show that ambient wind direction can be most accurately estimated with trajectories characterized by frequent, large magnitude turns. Furthermore, sensory measurements and estimates of their derivatives must be integrated over a period of time that incorporates at least one of these turns. Finally, we discuss approaches that insects might use to simplify the required computations, and present a list of testable predictions. Together, our results suggest that ambient flow estimation may be an important driver underlying the zigzagging manoeuvres characteristic of plume tracking animals’ trajectories.
An assessment of transmission dynamics via time-varying reproduction number of the second wave of the COVID-19 epidemic in Fiji
Authors: Lal Rajnesh , Huang Weidong , Li Zhenquan , Prasad Swastika
Published: August 2022

This study involves the estimation of a key epidemiological parameter for evaluating and monitoring the transmissibility of a disease. The time-varying reproduction number is the index for quantifying the transmissibility of infectious diseases. Accurate and timely estimation of the time-varying reproduction number is essential for optimizing non-pharmacological interventions and movement control orders during epidemics. The time-varying reproduction number for the second wave of the pandemic in Fiji is estimated using the popular
EpiEstim R
package and the publicly available COVID-19 data from 19 April 2021 to 1 December 2021. Our findings show that the non-pharmacological interventions and movement control orders introduced and enforced by the Fijian Government had a significant impact in preventing the spread of COVID-19. Moreover, the results show that many restrictions were either relaxed or eased when the time-varying reproduction number was below the threshold value of 1. The results have provided some information on the second wave of the COVID-19 pandemic that could be used in the future as a guide for public health policymakers in Fiji. Estimation of time-varying reproduction numbers would be helpful for continuous monitoring of the effectiveness of the current public health policies that are being implemented in Fiji.
Morality in the flesh: on the link between bodily self-consciousness, moral identity and (dis)honest behaviour
Authors: Scattolin Marina , Panasiti Maria Serena , Aglioti Salvatore Maria
Published: August 2022

The sense of owning a body (ownership) and controlling its actions (agency) are two main pillars of bodily self-consciousness (BSC). Although studies suggest that BSC signals and morality may be associated, whether such association has a positive or negative direction remains unclear. To investigate this issue, we conducted two pre-registered, online studies, in which a total of 1309 participants completed BSC- and morality-related questionnaires and undertook a task where they could cheat for monetary gain. We found that participants with high sense of ownership displayed high moral identity, which supports the notion that ownership is used to associate the self with positive characteristics. Moreover, high agency was associated with increased moral identity when sense of power is high. Results regarding deception are less clear, and might relate to the impact of COVID-19. Our results concerning moral identity may inspire policies that rely on changes of corporeal awareness to contrast immorality.
Substance Use and other Correlates of HIV infection among transwomen and men who have sex with men in Perú: Implications for Targeted HIV Prevention Strategies for Transwomen
Authors: Cyrus Elena , Lama Javier R. , Sanchez Jorge , Leon Segundo , Villaran Manuel V. , Vagenas Panagiotis , Sullivan Daniell S. , Vu David , Coudray Makella , Altice Frederick L.
Published: August 2022

Introduction

Characterization of HIV risk factors among transwomen and men who have sex with men (MSM) should be assessed separately and independently. However, due to several constraints, these populations continue to be conflated in clinical research and data. There are limited datasets globally powered to make such comparisons. The study aimed to use one of the largest surveys of transwomen and MSM in Latin America to determine differences in HIV risk and related correlates between the two populations.

Methods

Secondary data analysis was completed using a cross-sectional biobehavioral survey of 4413 MSM and 714 transwomen living in Perú. Chi Square analysis of selected HIV correlates was conducted to examine differences between transwomen and MSM. Additionally, stratified binary logistic regression was used to split data for further comparative analyses of correlates associated with transwomen and MSM separately.

Results

HIV prevalence among transwomen was two-fold greater than among MSM (14.9% vs. 7.0%, p<0.001). Transwomen had a higher prevalence of most HIV risk factors assessed, including presence of alcohol dependence (16.4% vs. 19.0%; p<.001) and drug use in the past 3 months (17.0% vs. 14.9%). MSM were more likely to use marijuana (68.0% vs. 50.0%, p<.001), and transwomen were more likely to engage in inhaled cocaine use (70.0% vs. 51.1%, p<.001). The regression exposed differences in correlates driving sub-epidemics in transwomen vs. MSM, with a trend of substance use increasing HIV risk for transwomen only.

Conclusions

Transwomen were more likely to be HIV-infected and had different risk factors from MSM. Targeted prevention strategies are needed for transwomen that are at highest risk. Additionally, further research is needed to determine if these observations in Perú regarding substance use patterns and the role of substance use in HIV risk relate to other trans populations globally.
Detecting rapid pan-cortical voltage dynamics in vivo with a brighter and faster voltage indicator
Authors: Lu Xiaoyu , Wang Yunmiao , Liu Zhuohe , Gou Yueyang , Jaeger Dieter , St-Pierre François
Published: August 2022

Widefield imaging with genetically encoded voltage indicators (GEVIs) is a promising approach for understanding the role of large cortical networks in the neural coding of behavior. However, the slow kinetics of current GEVIs limit their deployment for single-trial imaging of rapid neuronal voltage dynamics. Here, we developed a high-throughput platform to screen for GEVIs that combine fast kinetics with high brightness, sensitivity, and photostability under widefield one-photon illumination. Rounds of directed evolution produced JEDI-1P, a green-emitting fluorescent indicator whose performance is improved for all metrics. Next, we optimized a neonatal intracerebroventricular delivery method to achieve cost-effective and wide-spread JEDI-1P expression in mice. We also developed an approach to effectively correct optical measurements from hemodynamic and motion artifacts. Finally, we achieved stable brain-wide voltage imaging and successfully tracked gamma-frequency whisker and visual stimulations in awake mice in single trials, opening the door to investigating the role of high-frequency signals in brain computations.
Unusual Morphological Changes of Rugositalea oryzae, A Novel Wrinkled Bacterium Isolated from The Rice Rhizosphere, Under Nutrient Stress
Authors: Chung Young Ryun , Lee Jung Eun , Aslam Zubair , Chung Eu Jin , Lee Kwang Hee , Kang Byung Ho , Khan Ajmal , Niraula Sarbjeet , Chang Woo-Suk
Published: August 2022

Bacterial cell morphology might result from natural selection to gain a competitive advantage under environmentally stressful conditions such as nutrient limitation. A bacterial strain YC6860T isolated from the rhizosphere of rice (Oryza sativa L.) showed pleomorphic behavior with smooth cell morphology and wrinkled surface rods depending upon nutritional conditions. Based on scanning and transmission electron microscopy studies, we hypothesized that the surface-to-volume ratio of cells increases with decreasing nutrient concentrations. The transition from smooth to wrinkled cell surface morphology could be one of the adaptation strategies by which YC6860T maximizes its ability to access available nutrients. To characterize the properties of the wrinkled strain, we performed taxonomic and phylogenetic analyses. 16S rRNA gene sequencing results showed that the strain represented a novel, deep-rooting lineage within the order Rhizobiales with the highest similarity of 94.2% to Pseudorhodoplanes sinuspersici RIPI 110T. Whole genome sequencing was also performed to characterize its genetic features. The strain YC6860T might belong to a new genus, named Rugositalea, and a new species, named Rugositalea oryzae, In addition, taxonomic analysis showed that YC6860T is Gram-negative, aerobic, and rod-shaped with large regular wrinkles resembling a delicate twist of fusilli, measuring 0.5-0.6 µm in width and 1.5-1.6 µm in length under nutrient-limiting conditions. This unique cell structure with regular rugosity could be the first finding that has not been reported in the existing bacterial morphology.
Regional and LTP-Dependent Variation of Synaptic Information Storage Capacity in Rat Hippocampus
Authors: Samavat Mohammad , Bartol Thomas M. , Bromer Cailey , Bowden Jared B. , Hubbard Dusten D. , Hanka Dakota C. , Kuwajima Masaaki , Mendenhall John M. , Parker Patrick H. , Abraham Wickliffe C. , Harris Kristen M. , Sejnowski Terrence J.
Published: August 2022

Connectomics is generating an ever-increasing deluge of data, which challenges us to develop new methods for analyzing and extracting insights from these data. We introduce here a powerful method for analyzing three-dimensional reconstruction from serial section electron microscopy (3DEM) to measure synaptic information storage capacity (SISC) and apply it to data followingin vivolong-term potentiation (LTP). Connectomic researchers have focused on the pattern of connectivity between neurons. The strengths of synapses have also been studied by quantifying the sizes of synapses. Importantly, synapses from the same axon onto the same dendrite have a common history of coactivation, making them a candidate for measuring the precision of synaptic plasticity based on the similarity of their dimensions. Quantifying precision is fundamental to understanding information storage and retrieval in neural circuits. We quantify this precision with Shannon information theory, which is a more reliable estimate than prior analyses based on signal detection theory because there is no overlap between states, and outliers do not artificially bias the outcome. Spine head volumes are well correlated with other measures of synaptic weight, thus SISC can be determined by identifying the non-overlapping clusters of dendritic spine head volumes to determine the number of distinguishable synaptic weights. SISC analysis of spine head volumes in the stratum radiatum of hippocampal area CA1 revealed 24 distinguishable states (4.1 bits). In contrast, spine head volumes in the middle molecular layer of control dentate gyrus occupied only 5 distinguishable states (2 bits). Thus, synapses in different hippocampal regions had significantly different SISCs. Moreover, these were not fixed properties but increased by 30 min following induction of LTP in the dentate gyrus to occupy 10 distinguishable states (3 bits), and this increase lasted for at least 2 hours. We also observed a broader and nearly uniform distribution of spine head volumes across the increased number of states, suggesting the distribution evolved towards the theoretical upper bound of SISC following LTP. For dentate granule cells these findings show that the spine size range was broadened by the interplay among synaptic plasticity mechanisms. SISC provides a new analytical measure to probe these mechanisms in normal and diseased brains.
Efficient coding, channel capacity and the emergence of retinal mosaics
Authors: Jun Na Young , Field Greg D. , Pearson John M.
Published: August 2022

Among the most striking features of retinal organization is the grouping of its output neurons, the retinal ganglion cells (RGCs), into a diversity of functional types. Each of these types exhibits a mosaic-like organization of receptive fields (RFs) that tiles the retina and visual space. Previous work has shown that many features of RGC organization, including the existence of ON and OFF cell types, the structure of spatial RFs, and their relative arrangement, can be predicted on the basis of efficient coding theory. This theory posits that the nervous system is organized to maximize information in its encoding of stimuli while minimizing metabolic costs. Here, we use efficient coding theory to present a comprehensive account of mosaic organization in the case of natural videos as the retinal channel capacity—the number of simulated RGCs available for encoding—is varied. We show that mosaic density increases with channel capacity up to a series of critical points at which, surprisingly, new cell types emerge. Each successive cell type focuses on increasingly high temporal frequencies and integrates signals over large spatial areas. In addition, we show theoretically and in simulation that a transition from mosaic alignment to anti-alignment across pairs of cell types is observed with increasing output noise and decreasing input noise. Together, these results offer a unified perspective on the relationship between retinal mosaics, efficient coding, and channel capacity that can help to explain the stunning functional diversity of retinal cell types.
Contrast and luminance gain control in the macaque’s lateral geniculate nucleus
Authors: Raghavan R.T. , Kelly Jenna G. , Hasse J. Michael , Levy Paul G. , Hawken Michael J. , Movshon J. Anthony
Published: August 2022

In natural scenes, there is substantial variation in the mean and fluctuation of light levels (luminance and contrast). Retinal ganglion cells maintain their sensitivity despite this variation and their limited signaling bandwidth using two adaptive mechanisms, which control luminance and contrast gain. However, the signature of each mechanism and their interactions further downstream of the retina are unknown. We recorded neurons in the magnocellular and parvocellular layers of the lateral geniculate nucleus (LGN) in anesthetized adult male macaques and characterized how they adapt to changes in contrast and luminance. As contrast increases, neurons in the magnocellular layers maintain sensitivity to high temporal frequency stimuli but attenuate sensitivity to low temporal-frequency stimuli. Neurons in the parvocellular layers do not adapt to changes in contrast. As luminance increases, magnocellular and parvocellular cells increase their sensitivity to high temporal frequency stimuli. Adaptation to luminance is independent of adaptation to contrast, as previously reported for LGN neurons in the cat. Our results are similar to those previously reported for macaque retinal ganglion cells, suggesting that adaptation to luminance and contrast result from two independent mechanisms that are retinal in origin.
Rejection of inappropriate synaptic partners mediated by transcellular FLRT2-UNC5 signaling
Authors: Prigge Cameron L. , Sharma Arsha , Dembla Mayur , El-Quessny Malak , Kozlowski Christopher , Paisley Caitlin E. , Johnson Tyler , Santina Luca Della , Feller Marla B. , Kay Jeremy N.
Published: August 2022

During nervous system development, neurons choose synaptic partners with remarkable specificity; however, the cell-cell recognition mechanisms governing rejection of inappropriate partners remain enigmatic. Here we show that mouse retinal neurons avoid inappropriate partners using the FLRT2-UNC5 receptor-ligand system. Within the inner plexiform layer (IPL), FLRT2 is expressed by direction-selective (DS) circuit neurons, whereas UNC5C/D are expressed by non-DS neurons projecting to adjacent IPL sublayers. In vivo gain- and loss-of-function experiments demonstrate that FLRT2-UNC5 binding eliminates growing DS dendrites that have strayed from the DS circuit IPL sublayers. Abrogation of FLRT2-UNC5 binding allows mistargeted arbors to persist, elaborate, and acquire synapses from inappropriate partners. Conversely, UNC5C misexpression within DS circuit sublayers inhibits dendrite growth and drives arbors into adjacent sublayers. Mechanistically, UNC5s promote dendrite elimination by interfering with FLRT2-mediated adhesion. Based on their broad expression, FLRT-UNC5 recognition is poised to exert widespread effects upon synaptic partner choices across the nervous system.
Evaluating Progress in Automatic Chest X-Ray Radiology Report Generation
Authors: Yu Feiyang , Endo Mark , Krishnan Rayan , Pan Ian , Tsai Andy , Reis Eduardo Pontes , Fonseca Eduardo Kaiser Ururahy Nunes , Ho Lee Henrique Min , Abad Zahra Shakeri Hossein , Ng Andrew Y. , Langlotz Curtis P. , Venugopal Vasantha Kumar , Rajpurkar Pranav
Published: August 2022

The application of AI to medical image interpretation tasks has largely been limited to the identification of a handful of individual pathologies. In contrast, the generation of complete narrative radiology reports more closely matches how radiologists communicate diagnostic information in clinical workflows. Recent progress in artificial intelligence (AI) on vision-language tasks has enabled the possibility of generating high-quality radiology reports from medical images. Automated metrics to evaluate the quality of generated reports attempt to capture overlap in the language or clinical entities between a machine-generated report and a radiologist-generated report. In this study, we quantitatively examine the correlation between automated metrics and the scoring of reports by radiologists. We analyze failure modes of the metrics, namely the types of information the metrics do not capture, to understand when to choose particular metrics and how to interpret metric scores. We propose a composite metric, called RadCliQ, that we find is able to rank the quality of reports similarly to radiologists and better than existing metrics. Lastly, we measure the performance of state-of-the-art report generation approaches using the investigated metrics. We expect that our work can guide both the evaluation and the development of report generation systems that can generate reports from medical images approaching the level of radiologists.
Development and validation of a dynamic prediction model for unplanned ICU admission and mortality in hospitalized patients
Authors: Placido Davide , Thorsen-Meyer Hans-Christian , Kaas-Hansen Benjamin Skov , Reguant Roc , Brunak Søren
Published: August 2022

Frequent assessment of the severity of illness for hospitalized patients is essential in clinical settings to prevent outcomes such as in-hospital mortality and unplanned ICU admission. Classical severity scores have been developed typically using relatively few patient features, especially for intensive care. Recently, deep learning-based models demonstrated better individualized risk assessments compared to classic risk scores such as SOFA and NEWS, thanks to the use of aggregated and more heterogeneous data sources for dynamic risk prediction. We investigated to what extent deep learning methods can capture patterns of longitudinal change in health status using time-stamped data from electronic health records. We used medical history data, biochemical measurements, and the clinical notes from all patients admitted to non-intensive care units in 12 hospitals in Denmark’s Capital Region and Region Zealand during 2011-2016. Data from a total of 852,620 patients and 2,241,849 admissions were used to predict the composite outcome of unplanned ICU transfer and in-hospital death at different time points after admission to general departments. We subsequently examined feature interpretations of the models. The best model used all data modalities with an assessment rate of 6 hours and a prediction window of 14 days, with an AUPRC of 0.287 and AUROC of 0.898. These performances are comparable to the current state of the art and make the model suitable for further prospective validation as a risk assessment tool in a clinical setting.
Consumption of processed meat and its interactions with alcohol drinking and polygentic risk scores on breast cancer risk: a cohort study in the UK biobank
Authors: Zhu Pingxiu , Zhang Yanyu , Zou Shuqing , Yu Xingxing , Song Mengjie , Lin Moufeng , Yang Haomin
Published: August 2022

Background

Processed meat and alcohol have been consistently associated with breast cancer risk, but evidence for their effects in women with different genetic susceptibility of breast cancer is scarce, and little is known about their interactions.

Methods

We analyzed data from 260,779 female participants in the UK Biobank. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between processed meat and breast cancer risk. We further assessed its interaction with alcohol intake and polygenic risk score (PRS) for breast cancer.

Results

Processed meat intake more than once a week was positively associated with risk of breast cancer, especially in women took alcohol ≥1/d (HR=1.50, 95% CI=1.17-1.93), and in women who usually took alcohol together with meals (HR=1.70, 95% CI=1.21-2.39, P for interaction=0.048). The association between processed meat and breast cancer did not differ by menopausal status. When further stratified by PRS, processed meat more than once a week intake was associated with risk of breast cancer (HR=1.17, 95% CI=1.02-1.35) in women with the highest quantile of PRS, and additive interaction was found between them.

Conclusions

Processed meat was associated with risk of breast cancer in women, and the effect was stronger in those who took alcohol together with the meal and with high PRS of breast cancer, suggesting the focus of future preventive measures on these women.

Funding

This work was supported by the Natural Science Foundation of Fujian Province [grant no: 2021J01721], the Startup Fund for High-level Talents of Fujian Medical University [grant no: XRCZX2020007], Startup Fund for Scientific Research, Fujian Medical University [grant no: 2019QH1002] and Laboratory Construction Program of Fujian Medical University [grant no: 1100160208].
Automated severe aortic stenosis detection on single-view echocardiography: A multi-center deep learning study
Authors: Holste Gregory , Oikonomou Evangelos K. , Mortazavi Bobak J. , Coppi Andreas , Faridi Kamil F. , Miller Edward J. , Forrest John K. , McNamara Robert L. , Ohno-Machado Lucila , Yuan Neal , Gupta Aakriti , Ouyang David , Krumholz Harlan M. , Wang Zhangyang , Khera Rohan
Published: August 2022

Background and Aims

Early diagnosis of aortic stenosis (AS) is critical to prevent morbidity and mortality but requires skilled examination with Doppler imaging. This study reports the development and validation of a novel deep learning model that relies on 2-dimensional parasternal long axis (PLAX) videos from transthoracic echocardiography (TTE) without Doppler imaging to identify severe AS, suitable for point-of-care ultrasonography.

Methods

In a training set of 5,257 studies (17,570 videos) from 2016-2020 (Yale-New Haven Hospital [YNHH], Connecticut), an ensemble of 3-dimensional convolutional neural networks was developed to detect severe AS, leveraging self-supervised contrastive pretraining for label-efficient model development. This deep learning model was validated in a temporally distinct set of 2,040 consecutive studies from 2021 from YNHH as well as two geographically distinct cohorts of 5,572 and 865 studies, from California and other hospitals in New England, respectively.

Results

The deep learning model achieved an AUROC of 0.978 (95% CI: 0.966, 0.988) for detecting severe AS with 95.4% specificity and 90% sensitivity in the temporally distinct test set, maintaining its diagnostic performance in both geographically distinct cohorts (AUROC 0.972 [95% CI: 0.969, 0.975] in California and 0.915 [95% CI: 0.896, 0.933] in New England, respectively). The model was interpretable with saliency maps identifying the aortic valve as the predictive region. Among non-severe AS cases, predicted probabilities were associated with worse quantitative metrics of AS suggesting association with various stages of AS severity.

Conclusions

This study developed and externally validated an automated approach for severe AS detection using single-view 2D echocardiography, with implications for point-of-care screening.

STRUCTURED GRAPHICAL ABSTRACT

Key Question

Is it feasible to automatically screen for the presence of severe aortic stenosis (AS) using single-view echocardiographic videos without the use of Doppler imaging?

Key Finding

Using self-supervised pretraining and ensemble learning, we trained a deep learning model to detect severe AS using single-view echocardiography without Doppler imaging. The model maintained its high performance in multiple geographically and temporally distinct cohorts.

Take-home Message

We present an automated method to detect severe AS using single-view TTE videos, with implications for point-of-care ultrasound screening as part of routine clinic visits and in limited resource settings by individuals with minimal training.

An automated deep learning approach for severe aortic stenosis detection from single-view echocardiography evaluated across geographically and temporally distinct cohorts.
On multistability and constitutive relations of motion of MDA-MB-231 cells on Fibronectin lanes
Authors: Amiri Behnam , Heyn Johannes C.J. , Schreiber Christoph , Rädler Joachim O. , Falcke Martin
Published: August 2022

Cell motility on flat substrates exhibits multistability between steady and oscillatory morphodynamics, spread and moving states, the biphasic adhesion-velocity relation, and the universal correlation between speed and persistence (UCSP) as simultaneously observed phenomena. Their universality and concurrency suggest a unifying mechanism to exist causing all of them. We search for that mechanism by investigating trajectories of MDA-MB-231 cells on Fibronectin lanes. We also find multistability caused by the clutch mechanism of retrograde flow. Control of the clutch parameters by integrin signalling causes the biphasic adhesion-velocity relation. Protrusion competition based on the clutch causes direction reversal events, the statistics of which explains the UCSP. We suggest that F-actin polymerisation, clutch mechanism of retrograde flow, protrusion competition via membrane tension and drag forces cause the multistability and dynamic cell states, state transition statistics causes the UCSP and the control of this dynamic system by integrin signalling entails the adhesion-velocity relation.
Automated assembly of molecular mechanisms at scale from text mining and curated databases
Authors: Bachman John A. , Gyori Benjamin M. , Sorger Peter K.
Published: August 2022

The analysis of ‘omic data depends heavily on machine-readable information about protein interactions, modifications, and activities. Key resources include protein interaction networks, databases of post-translational modifications, and curated models of gene and protein function. Software systems that read primary literature can potentially extend and update such resources while reducing the burden on human curators, but machine-reading software systems have a high error rate. Here we describe an approach to precisely assemble molecular mechanisms at scale using natural language processing systems and the Integrated Network and Dynamical Reasoning Assembler (INDRA). INDRA identifies overlaps and redundancies in information extracted from published papers and pathway databases and uses probability models to reduce machine reading errors. INDRA enables the automated creation of high-quality, non-redundant corpora for use in data analysis and causal modeling. We demonstrate the use of INDRA in extending protein-protein interaction databases and explaining co-dependencies in the Cancer Dependency Map.
The Solvation of the E. coli CheY Phosphorylation Site Mapped by XFMS
Authors: Hamid Maham , Khalid Muhammad Farhan , Chaudhary Safee Ullah , Khan Shahid
Published: August 2022

The Escherichia coli CheY protein belongs to a large bacterial response regulator superfamily. X-ray hydroxy radical foot-printing with mass spectroscopy (XFMS) has shown that allosteric activation of CheY by its motor target triggers a concerted internalization of aromatic sidechains. We reanalyzed the XFMS data to compare polar versus non-polar CheY residue positions. The polar residues around and including the 57D phosphorylated site had an elevated hydroxy radical reactivity. Bioinformatic measures revealed that a water-mediated hydrogen bond network connected this ring of residues with the central 57D. These residues solvated 57D to energetically stabilize the apo-CheY fold. The abundance of these reactive residues was reduced upon activation. This result was supported by the bioinformatics and consistent with the previously reported activation-induced increase in core hydrophobicity. It further illustrated XFMS detection of structural waters. Direct contacts between the ring residues and the phosphorylation site would stabilize the aspartyl phosphate. In addition, we report that the ring residue, 18R, is a constant central node in the 57D solvation network and that 18R non-polar substitutions determine CheY diversity as assessed by its evolutionary trace in bacteria with well-studied chemotaxis. These results showcase the importance of structured water dynamics for phosphorylation-mediated signal transduction.
Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I
Authors: Leddy Owen , White Forest M. , Bryson Bryan D.
Published: August 2022

CD8+ T cell recognition of Mycobacterium tuberculosis (Mtb)-specific peptides presented on major histocompatibility complex class I (MHC-I) contributes to immunity to tuberculosis (TB), but the principles that govern presentation of Mtb antigens on MHC-I are incompletely understood. In this study, mass spectrometry (MS) analysis of the MHC-I repertoire of Mtb-infected primary human macrophages reveals that substrates of Mtb’s type VII secretion systems (T7SS) are overrepresented among Mtb-derived peptides presented on MHC-I. Quantitative, targeted MS shows that ESX-1 activity contributes to presentation of Mtb antigens on MHC-I, consistent with a model in which Mtb T7SS substrates access a cytosolic antigen processing pathway via ESX-1-mediated phagosome permeabilization.

Chemical inhibition of proteasome activity, lysosomal acidification, or cysteine cathepsin activity did not block presentation of Mtb antigens on MHC-I, suggesting involvement of other proteolytic pathways or redundancy among multiple pathways. Our study identifies Mtb antigens presented on MHC-I that could serve as targets for TB vaccines, and reveals an important role for T7SS activity in presentation of Mtb antigens on MHC-I.
BindingSiteAugmentedDTA: Enabling A Next-Generation Pipeline for Interpretable Prediction Models in Drug-Repurposing
Authors: Yousefi Niloofar , Yazdani-Jahromi Mehdi , Tayebi Aida , Kolanthai Elayaraja , Neal Craig J. , Banerjee Tanumoy , Gosai Agnivo , Balasubramanian Ganesh , Seal Sudipta , Garibay Ozlem Ozmen
Published: August 2022

While research into Drug-Target Interaction (DTI) prediction is fairly mature, generalizability and interpretability are not always addressed in the existing works in this field. In this paper, we propose a deep learning-based framework, called BindingSite-AugmentedDTA, which improves Drug-Target Affinity (DTA) predictions by reducing the search space of potential binding sites of the protein, thus making the binding affinity prediction more efficient and accurate. Our BindingSite-AugmentedDTA is highly generalizable as it can be integrated with any DL-based regression model, while it significantly improves their prediction performance. Also, unlike many existing models, our model is highly interpretable due to its architecture and self-attention mechanism, which can provide a deeper understanding of its underlying prediction mechanism by mapping attention weights back to protein binding sites. The computational results confirm that our framework can enhance the prediction performance of seven state-of-the-art DTA prediction algorithms in terms of 4 widely used evaluation metrics, including Concordance Index (CI), Mean Squared Error (MSE), modified squared correlation coefficient , and the Area Under the Precision Curve (AUPC). We also contribute to the two most commonly used DTA benchmark datasets, namely Kiba and Davis, by including additional information on 3D structure of all proteins contained in these two datasets. We manually extracted this information from Protein Data Bank (PDB) files of proteins available at https://www.uniprot.org/. Furthermore, we experimentally validate the practical potential of our proposed framework through in-lab experiments. We measure the binding interaction between several drug candidate compounds for the inhibition of binding between (SARS-CoV-2 S-protein RBD) Spike and ACE-2 (host cell binding target) proteins. We then compare the computationally-predicted results against the ones experimentally-observed in the laboratory. The relatively high agreement between computationally-predicted and experimentally-observed binding interactions supports the potential of our framework as the next-generation pipeline for prediction models in drug repurposing.
Uracil-DNA glycosylase efficiency is modulated by substrate rigidity
Authors: Orndorff Paul B. , Poddar Souvik , Owens Aerial M. , Kumari Nikita , Ugaz Bryan T. , Amin Samrat , Van Horn Wade D. , van der Vaart Arjan , Levitus Marcia
Published: August 2022

Uracil DNA-glycosylase (UNG) is a base excision repair enzyme that removes the highly mutagenic uracil lesion from DNA by a base flipping mechanism. UNG excision efficiency depends on DNA sequence, yet the underlying principles that dictate UNG substrate specificity have remained elusive. Here, we show that UNG efficiency is dictated by the intrinsic local deformability of the substrate sequence around the uracil. UNG specificity constants (kcat/KM) and DNA flexibilities were measured for an engineered set of DNA substrates containing AUT, TUA, AUA, and TUA motifs. Time-resolved fluorescence spectroscopy, NMR imino proton exchange measurements, and molecular dynamics simulations of the bare DNA indicated significant differences in substrate flexibilities. A strong correlation between UNG efficiency and substrate flexibility was observed, with higher kcat/KM values measured for more flexible strands. DNA bending and base flipping were observed in simulations, with more frequent uracil flipping observed for the more bendable sequences. Experiments show that bases immediately adjacent to the uracil are allosterically coupled and have the greatest impact on substrate flexibility and resultant UNG activity. The finding that substrate flexibility controls UNG efficiency has implications in diverse fields, including the genesis of mutation hotspots, molecular evolution, and understanding sequence preferences of emerging base editors.
Myo1f has an essential role in γδT intraepithelial lymphocyte adhesion and migration
Authors: Martínez-Vargas Irving Ulises , Sánchez-Bello Maria Elena , Miguel-Rodríguez Carlos Emilio , Hernández-Cázares Felipe , Santos-Argumedo Leopoldo , Talamás Rohana Patricia
Published: August 2022

γδT intraepithelial lymphocyte represents up to 60% of the small intestine intraepithelial compartment. They are highly migrating cells and constantly interact with the epithelial cell layer and lamina propria cells. This migratory phenotype is related to the homeostasis of the small intestine, the control of bacterial and parasitic infections, and the epithelial shedding induced by LPS. Here, we demonstrate that Myo1f participates in the adhesion and migration of intraepithelial lymphocytes. Using long-tailed class I myosins KO mice, we identified the requirement of Myo1f for their migration to the small intestine intraepithelial compartment. The absence of Myo1f affects intraepithelial lymphocytes’ homing due to reduced CCR9 and a4b7 expression.In vitro, we confirm that adhesion to integrin ligands and CCL25-dependent and independent migration of intraepithelial lymphocytes are Myo1f-dependent. Mechanistically, Myo1f deficiency prevents correct chemokine receptor and integrin polarization, leading to reduced tyrosine phosphorylation and having consequences in cell signaling. Overall, we demonstrate that Myo1f has an essential role in the adhesion and migration in γδT intraepithelial lymphocytes.

SUMMARY STATEMENT

The adhesion and migration of γδT intraepithelial lymphocytes are regulated by the motor protein Myosin 1f through controlling the expression of integrins and the chemokine receptor CCR9.