bluuebunny/crossref_metadata_2025 huggingface dataset:
Can We Use Eplets (or Molecular) Mismatch Load Analysis to Improve Organ Allocation? The Hope and the Hype
Authors: Tambur Anat R. , Das Rajdeep
Published: September 2022

In recent years, there have been calls for implementation of “epitope matching” in deceased-donor organ allocation policies (later changed to “eplet matching”). Emerging data indeed support the use of molecular mismatch load analysis in specific patient groups, with the objective of posttransplant stratification into different treatment arms. For this purpose, the expectation is to statistically categorize patients as low- or high-immune-risk. Importantly, these patients will continue to be monitored‚ and their risk category, as well as their management, can be adjusted according to on-going findings. However, when discussing deceased donor organ allocation and matching algorithms, where the decision is not modifiable and has lasting impact on outcomes, the situation is fundamentally different. The goal of changing allocation schemes is to achieve the best possible HLA compatibility between donor and recipient. Immunologically speaking, this is a very different objective. For this purpose, the specific interplay of immunogenicity between the donor and any potential recipient must be understood. In seeking compatibility, the aim is not to redefine matching but to identify those mismatches that are “permissible” or‚ in other words, less immunogenic. In our eagerness to improve transplant outcome, unfortunately, we have conflated the hype with the hope. Terminology is used improperly, and new terms are created in the process with no sufficient support. Here, we call for a cautious evaluation of baseline assumptions and a critical review of the evidence to minimize unintended consequences.
Ferroptosis involved in sevoflurane-aggravated young rats brain injury induced by liver transplantation
Authors: Yu Xi , Ma Xiaoyan , Lyu Jingshu , Jiang Ning , Lu Yuechun , Liao Yihao , Wang Keke , Yu Wenli
Published: September 2022

Liver transplantation is the only treatment available for pediatrics with end-stage liver disease. However, neurological damage is prone to occur after liver transplantation, especially in children. Accumulating evidence has shown that sevoflurane is closely linked to brain injury induced by liver transplantation. However, the study on the role of sevoflurane in brain injury induced by liver transplantation is rare and needs to be further investigated. The study is aiming to investigate the effects of sevoflurane on brain injury induced by liver transplantation and its underlying mechanisms. The brain injury rat model was built through 70% hepatic ischemia-reperfusion (HIR) of young rats. We detected the ferroptosis and brain injury after HIR by histological, transmission electron microscope analyses, western blot, and Enzyme-linked immunosorbent assays. And we detected the level of ferroptosis in brain by using sevoflurane during HIR compared with HIR without using sevoflurane. At the same time, we use iron inhibitor deferoxamine (DFO) to verify that the brain injury was caused by ferrotosis of brain. The results indicated that the pathological injury, ferroptosis indicators, and brain injury indicators were aggravated in the sevoflurane group compared with the HIR group, the decrease in the degree of brain injury and ferroptosis was observed in the group using DFO. Collectively, the results suggest that ferroptosis may mediate sevoflurane-aggravated young rats' brain injury induced by liver transplantation. Our findings provide a potential therapeutic target for brain injury after pediatric liver transplantation.
The Untrained Public’s Ability to Apply the Layperson Audiovisual Assist Tourniquet vs a Combat Application Tourniquet: A Randomized Controlled Trial
Authors: Goolsby Craig , Jonson Carl-Oscar , Goralnick Eric , Dacuyan-Faucher Nicole , Schuler Keke , Kothera Curt , Shah Amit , Cannon Jeremy , Prytz Erik
Published: September 2022

BACKGROUND:

Although the Stop the Bleed campaign’s impact is encouraging, gaps remain. These gaps include rapid skill decay, a lack of easy-to-use tourniquets for the untrained public, and training barriers that prevent scalability. A team of academic and industry partners developed the Layperson Audiovisual Assist Tourniquet (LAVA TQ)—the first audiovisual-enabled tourniquet for public use. LAVA TQ addresses known tourniquet application challenges and is novel in its design and technology.

STUDY DESIGN:

This study is a prospective, randomized, superiority trial comparing the ability of the untrained public to apply LAVA TQ to a simulated leg vs their ability to apply a Combat Application Tourniquet (CAT). The study team enrolled participants in Boston, MA; Frederick, MD; and Linköping, Sweden in 2022. The primary outcome was the proportion of successful applications of each tourniquet. Secondary outcomes included: mean time to application, placement position, reasons for failed application, and comfort with the devices.

RESULTS:

Participants applied the novel LAVA TQ successfully 93% (n = 66 of 71) of the time compared with 22% (n = 16 of 73) success applying CAT (relative risk 4.24 [95% CI 2.74 to 6.57]; p < 0.001). Participants applied LAVA TQ faster (74.1 seconds) than CAT (126 seconds ; p < 0.001) and experienced a greater gain in comfort using LAVA TQ than CAT.

CONCLUSIONS:

The untrained public is 4 times more likely to apply LAVA TQ correctly than CAT. The public also applies LAVA TQ faster than CAT and has more favorable opinions about its usability. LAVA TQ’s highly intuitive design and built-in audiovisual guidance solve known problems of layperson education and skill retention and could improve public bleeding control.
Permanent vs Absorbable Mesh for Ventral Hernia Repair in Contaminated Fields: A Multicenter Propensity Matched Analysis of One-Year Outcomes Using the Abdominal Core Health Quality Collaborative Database
Authors: Rodriguez-Quintero Jorge Humberto , Romero-Velez Gustavo , Lima Diego L , Huang Li-Ching , Sreeramoju Prashanth , Malcher Flavio
Published: September 2022

Background:

Traditionally, the use of absorbable mesh in contaminated fields aimed to reduce postoperative morbidity at the expense of increased hernia recurrence. This dogma has recently been challenged in randomized trials that demonstrate the advantages of permanent mesh in this setting. Although these studies are of high quality, their reproducibility across institutions is limited. We sought to compare the outcomes between permanent and absorbable mesh in a multicentric cohort from the Abdominal Core Health Quality Collaborative (ACHQC).

Study Design:

Patients who underwent elective ventral hernia repair in class II and III surgeries from January 2013 to December 2021 were identified within ACHQC. Outcomes were compared amongst permanent (P), absorbable synthetic (AS) and biologic (B) mesh at thirty days and one year using a propensity score matched analysis (PSM).

Results:

2484 patients were included; 73.4% P, 11.2% AS, and 15.4% B. 64% were clean-contaminated and 36% contaminated interventions. After PSM, there was no significant difference between groups regarding (SSO) (P 16%, AS 15%, B 21%, p=0.13), surgical site infection (SSI) (P 12%, AS 14%, B 12%, p=0.64), and surgical site occurrence requiring procedural intervention (SSOPI) at 30 days (P 12%, AS 15%, B 17%, p=0.1). At one-year, the recurrence rate was significantly lower amongst the permanent group (P 23%, AS 40%, B 32%, p=0.029).

Conclusions:

In this multi centric cohort, permanent mesh has equivalent 30-day outcomes and lower rates of hernia recurrence at one year after hernia repair in contaminated fields.
Endovascular Balloon Occlusion of the Inferior Vena Cava in Trauma: A Single-Center Case Series
Authors: Howell Erin C , Kulkarni Shreyus S , Walker Patrick F , Morrison Jonathan J , Kundi Rishi , Scalea Thomas M
Published: September 2022

Injury to the inferior vena cava (IVC) can produce bleeding that is difficult to control. Endovascular balloon occlusion provides rapid vascular control without extensive dissection and may be useful in large venous injuries, especially in the juxtarenal IVC. We describe the procedural steps, technical considerations, and clinical scenarios for using the Bridge occlusion balloon (Philips) in IVC trauma. We present a single center case series of five patients in which endovascular balloon occlusion of the IVC was employed for hemorrhage control. All five patients were men (median age 35, range 22 - 42 years). They all sustained penetrating injuries—four gunshot wounds and one stab wound. Median presenting Shock Index was 0.7 (range 0.5 – 1.5). Median initial lactate was 5.4 mmol/L (range 4.6 - 6.9 mmol/L). There were two suprarenal IVC injuries, two juxtarenal injuries, and three infrarenal injuries. Four patients underwent primary repair of their injury and one underwent IVC ligation. Four patients had intraoperative Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) for inflow control and afterload support. The median number of total blood products transfused during the initial operation was 37 units (range 16 - 77 units). Four patients underwent damage control operations, and one patient had a single definitive operation. Four of the five patients (80%) survived to discharge with the lone mortality being due to other injuries. Endovascular balloon occlusion serves as a valuable adjunct in the management of IVC injury and demonstrates the potential of hybrid open-endovascular operative techniques in abdominal vascular trauma.
Longitudinal changes in clozapine dose in patients with treatment-resistant schizophrenia: a 5-year retrospective cohort study
Authors: Tsukahara Masaru , So Ryuhei , Nakajima Shinichiro , Kitagawa Kohei , Kodama Masafumi , Takeuchi Hiroyoshi
Published: September 2022

This retrospective cohort study aimed to investigate the longitudinal changes in clozapine dose over a 5-year period in patients with treatment-resistant schizophrenia (TRS). Patients with TRS who were administered clozapine at a hospital between April 2012 and December 2016 and continued treatment with clozapine for at least 1 year were included. Clozapine doses were compared at the dose-fixation point, defined as when the same regimen of clozapine had been continued for 8 weeks or longer, and the post-dose-fixation phase, at 12, 36 and 60 months after clozapine initiation. We included 103 patients and found no significant differences in clozapine dose between the dose-fixation point and post-dose-fixation phase. Approximately half of the patients were categorized into an unchanged group at 12 months after clozapine initiation, whereas approximately 40% of patients were categorized into either the decreased or increased group at 60 months. Multivariable regression analysis revealed that the change in clozapine dose between the dose-fixation point and 60 months after clozapine initiation was negatively associated with clozapine dose at the dose-fixation point. On average, the clozapine dose was unchanged during long-term treatment in patients with TRS, although the dose was decreased or increased in approximately 40% of the patients.
Patterns of antipsychotic prescription and accelerometer-based physical activity levels in people with schizophrenia spectrum disorders: a multicenter, prospective study
Authors: Oliva Vincenzo , Fanelli Giuseppe , Zamparini Manuel , Zarbo Cristina , Rocchetti Matteo , Casiraghi Letizia , Starace Fabrizio , Martinelli Alessandra , Serretti Alessandro , de Girolamo Giovanni ,   the DiAPASon Consortium
Published: September 2022

Antipsychotic polypharmacy (APP) in patients with schizophrenia spectrum disorders (SSDs) is usually not recommended, though it is very common in clinical practice. Both APP and SSDs have been linked to worse health outcomes and decreased levels of physical activity, which in turn is an important risk factor for cardiovascular diseases and premature mortality. This real-world, observational study aimed to investigate antipsychotic prescribing patterns and physical activity in residential patients and outpatients with SSDs. A total of 620 patients and 114 healthy controls were recruited in 37 centers across Italy. Each participant underwent a comprehensive sociodemographic and clinical evaluation. Physical activity was monitored for seven consecutive days through accelerometer-based biosensors. High rates of APP were found in all patients, with residential patients receiving more APP than outpatients, probably because of greater psychopathological severity. Physical activity was lower in patients compared to controls. However, patients on APP showed trends of reduced sedentariness and higher levels of light physical activity than those in monopharmacy. Rehabilitation efforts in psychiatric residential treatment facilities were likely to result in improved physical activity performances in residential patients. Our findings may have important public health implications, as they indicate the importance of reducing APP and encouraging physical activity.
Aripiprazole: examining the clinical implications of D2 affinity
Authors: Anam Adiba , Lynch Sean , Mosharraf Nafiz , Soukas Chloe , Gekhman Dmitriy
Published: September 2022

Schizophrenia is a prevalent psychiatric illness, which causes significant financial and social burden on the population overall. The development of second generation antipsychotics, such as Aripiprazole, Risperidone, and Paliperidone, has changed treatment practice for many psychiatrists. Aripiprazole has extremely high binding affinity for the dopamine D2 receptor, which is the receptor thought to be responsible for the antipsychotic effect, although Aripiprazole is not the most potent of the second generation antipsychotics. In theory, Aripiprazole could displace or outcompete other, more potent antipsychotics, prompting decreased antipsychotic effect. We describe a proposed case of this phenomenon, Ms. A. We describe how Aripiprazole may have caused a worsening of psychiatric symptoms by blocking the antipsychotic effects of Paliperidone due to its strong binding affinity for the D2 receptor. Aripiprazole has a high affinity for the D2 receptor, but may have a lesser reduction of psychotic symptoms compared to other antipsychotics. Prescribers should be aware of this potential interaction and carefully consider initiating long-acting injectable forms of Aripiprazole to avoid this phenomenon.
Carbon dioxide and blood-feeding shift visual cue tracking during navigation in
Aedes aegypti
mosquitoes
Authors: Barredo Elina , Raji Joshua I. , Ramon Michael , DeGennaro Matthew , Theobald Jamie
Published: September 2022

Haematophagous mosquitoes need a blood meal to complete their reproductive cycle. To accomplish this, female mosquitoes seek vertebrate hosts, land on them and bite. As their eggs mature, they shift attention away from hosts and towards finding sites to lay eggs. We asked whether females were more tuned to visual cues when a host-related signal, carbon dioxide, was present, and further examined the effect of a blood meal, which shifts behaviour to ovipositing. Using a custom, tethered-flight arena that records wing stroke changes while displaying visual cues, we found the presence of carbon dioxide enhances visual attention towards discrete stimuli and improves contrast sensitivity for host-seeking
Aedes aegypti
mosquitoes. Conversely, intake of a blood meal reverses vertical bar tracking, a stimulus that non-fed females readily follow. This switch in behaviour suggests that having a blood meal modulates visual attention in mosquitoes, a phenomenon that has been described before in olfaction but not in visually driven behaviours.
Polymorphobacter megasporae sp. nov., isolated from an Antarctic lichen
Authors: Noh Hyun-Ju , Park Yerin , Yang Junwon , Jang Seonghan , Lee Hyoungseok , Lee Yung Mi
Published: September 2022

A Gram-stain-negative, aerobic, orange-coloured, rod-shaped and non-motile bacterial strain, PAMC 29362T, was isolated from an Antarctic lichen, Megaspora verrucosa. Phylogenetic and phylogenomic analyses indicated that strain PAMC 29362T belongs to the genus

Polymorphobacter

and was most closely related to

Polymorphobacter arshaanensis

(97.0% of 16S rRNA gene similarity),

Polymorphobacter fuscus

(96.3 %), Polymorphobacter multimanifer (95.3 %) and

Polymorphobacter glacialis

(95.2 %). Genomic relatedness analyses showed that strain PAMC 29362T is clearly distinguished from type strains of the genus

Polymorphobacter

based on values of average nucleotide identity (<74.3 %) and digital DNA–DNA hybridization (<20.4 %). The genomic DNA G+C content of PAMC 29362T was 65.5 %. The major fatty acids (>10 %) were summed feature 8 (C18:1
 ω7c; 38.5 %) and summed feature 3 (C16:1
 ω7c and/or C16:1
 ω6c; 31.5 %). The major respiratory quinone was Q-10. Based on the results of phylogenetic, genome-based relatedness and physiological analyses, strain PAMC 29362T is proposed to represent a novel species of the genus

Polymorphobacter

, with the name Polymorphobacter megasporae sp. nov. The type strain is PAMC 29362T (=KCTC 82 578T=JCM 34545T)
NetSHy: Network Summarization via a Hybrid Approach Leveraging Topological Properties
Authors: Vu Thao , Litkowski Elizabeth M. , Liu Weixuan , Pratte Katherine A. , Lange Leslie , Bowler Russell P. , Banaei-Kashani Farnoush , Kechris Katerina J.
Published: September 2022

Biological networks can provide a system level understanding of underlying processes. In many contexts, networks have a high degree of modularity, i.e., they consist of subsets of nodes, often known as subnetworks or modules, which are highly interconnected and may perform separate functions. In order to perform subsequent analyses to investigate the association between the identified module and a variable of interest, a module summarization, that best explains the module’s information and reduces dimensionality is often needed. Conventional approaches for obtaining network representation typically rely only on the profiles of the nodes within the network while disregarding the inherent network topological information. In this article, we propose NetSHy, a hybrid approach which is capable of reducing the dimension of a network while incorporating topological properties to aid the interpretation of the downstream analyses. In particular, NetSHy applies principal component analysis (PCA) on a combination of the node profiles and the well-known Laplacian matrix derived directly from the network similarity matrix to extract a summarization at a subject level. Simulation scenarios based on random and empirical networks at varying network sizes and sparsity levels show that NetSHy outperforms the conventional PCA approach applied directly on node profiles, in terms of recovering the true correlation with a pheno-type of interest and maintaining a higher amount of explained variation in the data when networks are relatively sparse. The robustness of NetSHy is also demonstrated by more consistent correlation with the observed phenotype as the sample size decreases. Lastly, a genome wide association study (GWAS) is performed as an application of a downstream analysis, where NetSHy summarization scores on the biological networks identify more significant single nucleotide polymorphisms (SNP) than the conventional network representation.
Can the application of machine learning to electronic health records guide antibiotic prescribing decisions for suspected urinary tract infection in the Emergency Department?
Authors: Rockenschaub Patrick , Gill Martin J. , McNulty David , Carroll Orlagh , Freemantle Nick , Shallcross Laura
Published: September 2022

Background

Urinary tract infections (UTIs) are a major cause of emergency hospital admissions, but it remains challenging to diagnose them reliably. Application of machine learning (ML) to routine patient data could support clinical decision-making. We developed a ML model for bacteriuria in the ED and evaluated its performance in key patient groups to determine scope for its future use in clinical practice.

Methods

We used retrospective electronic health records from a large UK hospital (2011-2019). Non-pregnant adults who attended the ED and had a urine sample cultured were eligible for inclusion. The primary outcome was predominant bacterial growth ≥104 cfu/mL in urine. Predictors included demography, medical history, ED diagnoses, blood tests, and urine flow cytometry. Linear and tree-based models were trained via repeated cross-validation, re-calibrated, and validated on data from 2018/19. Changes in performance were investigated by age, sex, ethnicity, and suspected ED diagnosis, and compared to clinical judgement.

Results

Among 12,680 included samples, 4,677 (36.9%) showed bacterial growth. Relying primarily on flow cytometry parameters, our best model achieved an area under the ROC curve (AUC) of 0.813 (95% CI 0.792-0.834) in the test data, and achieved both higher sensitivity and specificity compared to proxies of clinician’s judgement. Performance remained stable for white and non-white patients but was lower during a period of laboratory procedure change in 2015, in patients ≥65 years (AUC 0.783, 95% CI 0.752-0.815), in men (AUC 0.758, 95% CI 0.717-0.798). Performance was also slightly reduced in patients with recorded suspicion of UTI (AUC 0.797, 95% CI 0.765-0.828).

Conclusions

Our results suggest scope for use of ML in ED decision making for suspected UTI but performance varied with patient characteristics. Clinical utility of predictive models for UTI is therefore likely to differ for important patient subgroups including women <65 years, women ≥65 years, and men. Tailored models and decision thresholds may be required that account for differences in achievable performance, background incidence, and risks of infectious complications in these groups.
Central desks as an approach for health governance in conflict settings – case studies from northwest Syria
Authors: Aref Maher Al , Zoubi Zedoun Al , Khalil Munzer Al , Abdulla Orwa Al , Ekzayez Abdulkarim
Published: September 2022

Background

The conflict in Syria affected severely the health sector; health infrastructure was damaged, the Damascus ministry of health withdrew from opposition held areas, health workers fled the country, and there has been always a shortage of funding and medical supplies. To address these needs, Syrian NGOs, INGOs, donors, and UN Agencies have been providing health interventions through humanitarian channels. However, many of these interventions were short termed, and there was no governance framework to guide the newly introduced parallel system, leaving it subject to individual organizations’ strategies and approaches.

To counter these challenges, local communities and Syrian NGOs established new platforms to govern and coordinate certain aspects of the health sector. These platforms are called “central desks”, which are perceived to be independent and neutral structures and can coordinate services between all actors. Examples of these structures are Syrian Immunization Group (SIG), Health Information System (HIS), the Infection Protection and Control initiative (IPC), and the Referral System network.

Methods

The research was based on an institutional approach to governance as presented by (Abimbola et. Al, 2017) and (Baez-Carmago and Jacobs, 2011) of health governance. We have investigated the central desks across the main themes; governance inputs of these central desks, such as strategic vision and legitimacy; governance processes, such as accountability and transparency, and governance outcomes, such as effectiveness and efficiency. Further to intensive literature review, eight focus group discussion were conducted, average pf 12 participants. Key themes then were deducted and coded. The qualitative analysis was done using NVIVO 12 software.

Conclusion

Central desks, that are not part of national ministries of health, are new innovative approaches that can increase the efficiency of health interventions in conflict settings. The detailed features of such desks should be context specific and locally informed and led.
“E Pluribus Unum”: Prospective acceptability benchmarking from the Contouring Collaborative for Consensus in Radiation Oncology (C3RO) Crowdsourced Initiative for Multi-Observer Segmentation
Authors: Lin Diana , Wahid Kareem A. , Nelms Benjamin E. , He Renjie , Naser Mohammed A. , Duke Simon , Sherer Michael V. , Christodouleas John P. , Mohamed Abdallah S. R. , Cislo Michael , Murphy James D. , Fuller Clifton D. , Gillespie Erin F.
Published: September 2022

OBJECTIVE

Contouring Collaborative for Consensus in Radiation Oncology (C3RO) is a crowdsourced challenge engaging radiation oncologists across various expertise levels in segmentation. A challenge in artificial intelligence (AI) development is the paucity of multi-expert datasets; consequently, we sought to characterize whether aggregate segmentations generated from multiple non-experts could meet or exceed recognized expert agreement.

MATERIALS AND METHODS

Participants who contoured ≥1 region of interest (ROI) for the breast, sarcoma, head and neck (H&N), gynecologic (GYN), or gastrointestinal (GI) challenge were identified as a non-expert or recognized expert. Cohort-specific ROIs were combined into single simultaneous truth and performance level estimation (STAPLE) consensus segmentations. STAPLEnon-expert ROIs were evaluated against STAPLEexpert contours using Dice Similarity Coefficient (DSC). The expert interobserver DSC (IODSCexpert) was calculated as an acceptability threshold between STAPLEnon-expert and STAPLEexpert. To determine the number of non-experts required to match the IODSCexpert for each ROI, a single consensus contour was generated using variable numbers of non-experts and then compared to the IODSCexpert.

RESULTS

For all cases, the DSC for STAPLEnon-expert versus STAPLEexpert were higher than comparator expert IODSCexpert for most ROIs. The minimum number of non-expert segmentations needed for a consensus ROI to achieve IODSCexpert acceptability criteria ranged between 2-4 for breast, 3-5 for sarcoma, 3-5 for H&N, 3-5 for GYN ROIs, and 3 for GI ROIs.

DISCUSSION AND CONCLUSION

Multiple non-expert-generated consensus ROIs met or exceeded expert-derived acceptability thresholds. 5 non-experts could potentially generate consensus segmentations for most ROIs with performance approximating experts, suggesting non-expert segmentations as feasible cost-effective AI inputs.
Zymosan-induced leukocyte and cytokine changes in pigs: a new model for streamlined drug testing against severe COVID-19
Authors: Kökény Gábor , Bakos Tamás , Barta Bálint András , Nagy Georgina Viktória , Mészáros Tamás , Kozma Gergely T. , Szabó András , Szebeni János , Merkely Béla , Radovits Tamás
Published: September 2022

Injection of 0.1 mg/kg zymosan in pigs i.v. elicited transient hemodynamic disturbance within minutes, without major blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This change was followed by a transient granulopenia with a trough at 1 h, and then, up to about 6 h, a major granulocytosis, resulting in a 3-4-fold increase of neutrophil-to-lymphocyte ratio (NLR). In parallel with the changes in WBC differential, qRT-PCR and ELISA analyses showed increased transcription and/or release of inflammatory cytokines and chemokines into blood, including IL-6, TNF-α, CCL-2, CXCL-10, and IL-1RA. The expression of IL-6 peaked at already 1.5-2.5 h, and we observed significant correlation between lymphopenia and IL-6 gene expression. While these changes are consistent with zymosan’s known stimulatory effect on both the humoral and cellular arms of the innate immune system, what gives novel clinical relevance to the co-manifestation of above hemodynamic, hematological, and immune changes is that they represent independent bad prognostic indicators in terminal COVID-19 and other diseases involving cytokine storm. Thus, within a 6 h experiment, the model enables consecutive reproduction of a symptom triad that is characteristic of late-stage COVID-19. Given the limitations of modeling cytokine storm in animals and effectively treating severe COVID-19, the presented relatively simple large animal model may advance the R&D of drugs against these conditions. One of these disease markers (NLR), obtained from a routine laboratory endpoint (WBC differential), may also enable streamlining the model for high throughput drug screening against innate immune overstimulation.
A Complete Set of Equations for a Computational Model of Electrolyte and Water Transport along the Nephrons in a Mammalian Kidney
Authors: Layton Anita T.
Published: September 2022

To investigate kidney under different physiological and pharmacological conditions, we have developed and applied computational models of electrolyte and water transport along nephrons in a kidney. The models predict spredict luminal fluid flow, hydrostatic pressure, membrane potential, luminal and cytosolic solute concentrations, and transcellular and paracellular fluxes through transporters and channels. The complete set of model equations are presented here.
Stress and Coping Strategies among Medical Students in Dubai, United Arab Emirates, in 2020: A Cross-Sectional Study
Authors: Boushehri Yas Kaveh , Jeyaseelan Lakshmanan , Sultan Meshal A.
Published: September 2022

Studies across the world, have revealed elevated levels of stress among medical students. The rate of significant stress is 55% higher among healthcare professionals in comparison to the general population. This level of stress may lead to higher rates of burnout, depression, and functional impairment. This study aims to investigate the stress levels among medical students in Dubai and also to assess their coping strategies. The total number of participants in this study was 97. Rates of high stress levels as per the Perceived Stress Scale (PSS-10) was found to be higher among year 1 to year 3 medical students (43.6%), in comparison to year 4 and year 5 medical students (7.7%). The Brief-COPE inventory was used in this study and found that among medical students the mean score for a Problem Focused coping style was 22 out of 32 (medium to high range). Future research that evaluates a more comprehensive investigation into the psychological impact of stress and also exploration of effective strategies to enhance coping with stress is highly warranted.
Inferential Eye Movement Control while Following Dynamic Gaze
Authors: Han Nicole X. , Eckstein Miguel P.
Published: September 2022

Attending to other people’s gaze is evolutionary important to make inferences about intentions and actions. Gaze influences covert attention and triggers eye movements. However, we know little about how the brain controls the fine-grain dynamics of eye movements during gaze following. Observers followed people’s gaze shifts in videos during search and we related the observer eye movement dynamics to the timecourse of gazer head movements extracted by a deep neural network. We show that the observers’ brains use information in the visual periphery to execute predictive saccades that anticipate the information in the gazer’s head direction by 190-350 ms. The brain simultaneously monitors moment-to-moment changes in the gazer’s head velocity to dynamically alter eye movements and re-fixate the gazer (reverse saccades) when the head accelerates before the initiation of the first forward gaze-following saccade. Using saccade-contingent manipulations of the videos, we experimentally show that the reverse saccades are planned concurrently with the first forward gaze-following saccade and have a functional role in reducing subsequent errors fixating on the gaze goal. Together, our findings characterize the inferential and functional nature of the fine-grain eye movement dynamics of social attention.
clrDV: A differential variability test for RNA-Seq data based on the skew-normal distribution
Authors: Li Hongxiang , Khang Tsung Fei
Published: September 2022

Genes that show differential variability between conditions are important for complementing a systems biology understanding of the molecular players involved in a biological process. Under the dominant paradigm for modeling RNA-Seq gene counts using the negative binomial model, tests of differential variability are challenging to develop, owing to dependence of the variance on the mean. The limited availability of methods for detecting genes with differential variability means that researchers often omit differential variability as an analytical step in RNA-Seq data analysis. Here, we describe clrDV, a statistical method for detecting genes that show differential variability between two populations. clrDV is based on a compositional data analysis framework. We present the skew-normal distribution for modeling gene-wise null distribution of centered log-ratio transformation of compositional RNA-seq data. Simulation results show that clrDV has false discovery rate and Type II error that are on par with or superior to existing methodologies. In addition, its run time is faster than the closest competitor’s, and remains relatively constant for increasing sample size per group. Analysis of a large neurodegenerative disease RNA-Seq dataset using clrDV recovers multiple gene candidates that have been reported to be associated with Alzheimer’s disease. Additionally, we find that the majority of genes with differential variability have smaller relative gene expression variance in the Alzheimer’s disease population compared to the control population.
Mitf is a Schwann Cell Sensor of Axonal Integrity that Drives Nerve Repair
Authors: Daboussi Lydia , Costaguta Giancarlo , Gullo Miriam , Jasinski Nicole , Pessino Veronica , O’Leary Brendan , Lettieri Karen , Driscoll Shawn , Pfaff Samuel L.
Published: September 2022

Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular systems controlling repair cell formation and function are not well defined and consequently it is unclear whether this form of cellular plasticity has a role in peripheral neuropathies. Here we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism and dedifferentiation are misexpressed and nerve repair is disrupted. Taken together, our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf, which is critical for activating cellular plasticity and counteracting neural disease.

Highlights

Mitf-induced Schwann cell plasticity is triggered by peripheral neuropathy.

Nrg-ErbB signaling activates Mitf via cytoplasmic-to-nuclear translocation.

Mitf restores sensorimotor function following axonal breakdown.

Mitf regulates a core repair program across both injury and neurodegeneration.
Comparison of gene clustering criteria reveals intrinsic uncertainty in pangenome analyses
Authors: Manzano-Morales Saioa , Liu Yang , González-Bodí Sara , Huerta-Cepas Jaime , Iranzo Jaime
Published: September 2022

Background

A key step for comparative genomics is to group open reading frames into functionally and evolutionarily meaningful gene clusters. Gene clustering is complicated by intraspecific duplications and horizontal gene transfers, that are frequent in prokaryotes. In consequence, gene clustering methods must deal with a trade-off between identifying vertically transmitted representatives of multi-copy gene families (recognizable by synteny conservation) and retrieving complete sets of species-level orthologs. We studied the implications of adopting homology, orthology, or synteny conservation as formal criteria for gene clustering by performing comparative analyses of 125 prokaryotic pangenomes.

Results

Clustering criteria affect pangenome functional characterization, core genome inference, and reconstruction of ancestral gene content to different extents. Species-wise estimates of pangenome and core genome sizes change by the same factor when using different clustering criteria, which allows for robust cross-species comparisons regardless of the clustering criterion. However, cross-species comparisons of genome plasticity and functional profiles are substantially affected by inconsistencies among clustering criteria. Such inconsistencies are driven not only by mobile genetic elements, but also by genes involved in defense, secondary metabolism, and other accessory functions. In some pangenome features, the variability attributed to methodological inconsistencies can even exceed the effect sizes of ecological and phylogenetic variables.

Conclusions

Choosing an appropriate criterion for gene clustering is critical to conduct unbiased pangenome analyses. We provide practical guidelines to choose the right method depending on the research goals and the quality of genome assemblies, and a benchmarking dataset to assess the robustness and reproducibility of future comparative studies.
Coevolutionary maintenance of forked tails and song in hirundines (Aves: Hirundininae)
Authors: Hasegawa Masaru
Published: September 2022

Both conspicuous plumage ornamentation and song are well-known examples of sexually selected traits but their interrelationship is not well-known, perhaps in part because of confounding factors, including interspecific variation in ecology, habitat, morphology, and type of ornamentation. Here, using a phylogenetic comparative approach, we examined the evolutionary relationship between forked tails and the presence/absence of song in hirundines (Aves: Hirundininae). Hirundines have similar ecology (e.g., aerial insectivores, social monogamy, and biparental provisioning), morphology (e.g., syrinx with nearly complete bronchial rings), and plumage ornamentation (i.e., a sexually selected forked tail), which provides a unique opportunity to examine the evolutionary associations between plumage ornamentation and song. In particular, hirundines have repeatedly lost their ornamentation, forked tails, enabling us to test their association with the evolutionary gain/loss of their simple song. After controlling for phylogeny and covariates, we demonstrated that song was less likely to be found in species with forkless tails than in species with forked tails. Two correlates of tail shape, sexual dimorphism in the overall plumage characteristics as a well-known measure of sexual selection and incubation type as a measure of extrapair mating opportunity, had no detectable relationship with the presence/absence of song, indicating the importance of forked tails, rather than their correlates. Evolutionary pathway analysis further supported the correlated evolution of the two traits, in which forked tails and song are maintained together and less likely to be lost under the presence of each other. The current study provided macroevolutionary support for the integrated use of visual and acoustic courtship traits.
Human-like Modulation Sensitivity Emerging through Optimization to Natural Sound Recognition
Authors: Koumura Takuya , Terashima Hiroki , Furukawa Shigeto
Published: September 2022

Natural sounds contain rich patterns of amplitude modulation (AM), which is one of the essential sound dimensions for hearing perception. The sensitivity of human hearing to AM measured by psychophysics takes diverse forms, from low-pass to high-pass, depending on the experimental conditions. Here, we address with a single framework the questions of why such patterns of AM sensitivity have emerged in the human auditory system and how they are realized by our neural mechanisms. Assuming that optimization for natural sound recognition has taken place during human evolution and development, we examined its effect on the formation of AM sensitivity by optimizing a computational model, specifically, a multi-layer (or deep) neural network, for natural sound recognition and simulating psychophysical experiments in which the model’s AM sensitivity was measured. Relatively higher layers in the optimized model exhibited qualitatively and quantitatively similar AM sensitivity to that of humans, even though the model was not designed to reproduce human-like AM sensitivity. The similarity of the model’s AM sensitivity to humans’ correlated with its sound recognition accuracy. Optimization of the model to degraded sounds revealed the necessity of natural AM patterns for the emergence of human-like AM sensitivity. Consistent results were observed from optimizations to two different types of natural sound. Moreover, simulated neurophysiological experiments on the same model revealed a correspondence between the model layers and the auditory brain regions that is based on the similarity of their neural AM tunings. The layers in which human-like psychophysical AM sensitivity emerged exhibited substantial neurophysiological similarity with the auditory midbrain and higher regions. These results suggest that the behavioral AM sensitivity of human hearing has emerged as a result of optimization for natural-sound recognition in the course of our evolution and/or development and that it is based on a stimulus representation encoded in the neural firing rates in the auditory midbrain and higher regions.
Amyloid-beta biomarkers in Braak stages and their predictive relationships with cognitive impairment: Support vector machine and deep learning approaches
Authors: Taha Ahmed , Soni Bhavin , Thakuri Deepa S. , Ritter Erin , Bhattarai Puskar , Chand Ganesh B.
Published: September 2022

Amyloid-beta (Aβ) and tau tangles are hallmarks of Alzheimer’s disease. Aβ distributions in the tau-defined Braak staging regions and their multivariate predictive relationships with mild cognitive impairment (MCI) are not known. In this study, we used PiB PET data from 60 participants (33 with MCI and 27 healthy controls (HC)), quantified Aβ as distribution volume ratio (DVR) in Braak regions, and compared between MCI and controls to test the hypothesis that DVR alters with declining cognition. We found elevated DVR in participants with MCI, especially in the spatial distribution of Braak stages III-IV and V-VII, while an alteration in Braak stage I-II was near the statistical significance. DVR markers correlated with cognitive status, especially in Braak stages III-IV and VI-V. To evaluate whether these markers are predictive of cognitive dysfunction, we designed support vector machine and artificial neural network models. These methods showed predictive multivariate relationships between Aβ makers of Braak regions and cognitive impairment. Overall, these results highlight the importance of computer-aided research efforts for understanding AD pathophysiology.
The genetic basis for adaptation in giant sea anemones to their symbiosis with anemonefish and Symbiodiniaceae
Authors: Barua Agneesh , Kashimoto Rio , Khalturin Konstantin , Satoh Noriyuki , Laudet Vincent
Published: September 2022

Sea anemones in the order Anthozoa play an integral part in marine ecosystems by providing refuge and habitat for various organisms. Despite this, much of their molecular ecology remains elusive. Sea anemones can nurture numerous symbiotic relationships; the most iconic being the one between giant sea anemones and anemonefish. However, the genes and biological processes associated with this symbiosis in the sea anemones in unknown. Additionally, it is unclear how genes can mediate interactions between sea anemones, anemonefish, and symbionts from the algal family Symbiodiniaceae. Here we compared the gene expression profiles of tentacles from several cnidarians to uncover the genetic basis for adaptations in giant sea anemones to their symbiosis with anemonefish and Symbiodiniaceae. We found that tentacle transcriptomes of cnidarians are highly diverse, with closely related species having more similar expression patterns. However, despite an overall high correlation between gene expression and phylogeny, the giant sea anemones showed distinct expression patterns. The giant sea anemones had gene co-expression clusters enriched for processes involved in nutrient exchange and metabolism. These genes were not only differentially expressed, but also experienced evolutionary shifts in expression in giant sea anemones. Using a phylogenetic multilevel model, we found that Symbiodiniaceae and anemonefish significantly affect gene expression in giant sea anemone tentacles. By characterizing gene expression patterns, we identify genes and biological processes that provide evidence for the cross-talk between Symbiodiniaceae, anemonefish, and giant sea anemones. Our study demonstrates how integrated biological processes can lead to the evolution of a successful multi-organism interaction.
Chitinase-3-like 1 regulates TH2 cells, TFHcells and IgE following helminth infection
Authors: Curtiss Miranda L. , Rosenberg Alexander F. , Scharer Christopher D. , Mousseau Betty , Ballesteros Benavides Natalia A. , Bradley John E. , León Beatriz , Steele Chad , Randall Troy D. , Lund Frances E.
Published: September 2022

Data from patient cohorts and mouse models of atopic dermatitis, food allergy and asthma strongly support a role for the chitinase-like protein ChI3L1 in allergic disease. To address whether CHI3L1 also contributes to TH2 responses following nematode infection, we infectedChi3l1-/-mice withHeligmosomoides polygyrus(Hp) and analyzed T cell responses. Not surprisingly, we observed impaired TH2 responses inHp-infectedChi3l1-/-mice. However, we also found that T cell intrinsic expression ofChi3l1was required for ICOS upregulation following activation of naïve CD4 T cells and was necessary for the development of the IL-4+TFHsubset, which supports germinal center (GC) B cell reactions and IgE responses. The requirement forChi3l1in TFHand IgE responses was also seen following alum-adjuvanted vaccination. While Chi3l1 was critical for IgE humoral responses it was not required for vaccine or infection induced IgG1 responses. These results suggest thatChi3l1specifically modulates IgE responses that are highly dependent on help from IL-4-producing TFHcells.
Sinking diatom aggregates provide carbon to drive microscale denitrification in a bulk oxygenated ocean
Authors: Ciccarese Davide , Tantawi Omar , Zhang Irene , Plata Desiree , Babbin Andrew R.
Published: September 2022

Sinking marine particles drive the biological gravitational pump that naturally sequesters carbon dioxide from the atmosphere. Ubiquitous throughout the ocean, these particles are largely composed of phytoplankton that aggregate together or are repackaged by zooplankton into pellets that sink to the deep. Despite their small size, the compartmentalized nature of these particles promotes intense localized metabolic activity by the bacteria lucky enough to colonize them. Due to their sheer numbers, these microscale interactions can change the chemistry of the bulk ocean and impact global biogeochemical budgets. As soon as phytoplankton-derived particles are exported from the surface ocean, the fate of the carbon depends on the lability and availability of the carbon, the diffusive supply of oxidants from the bulk, and the development of microbial communities throughout the aggregate. Here we show with a model experimental system that aggregates composed of marine diatoms — important primary producers substantially contributing to global carbon export — can support active denitrification even among bulk oxygenated water ill-conducive to anaerobic metabolisms. We further show the primary nitrite maximum could be formed, in part, due to dissimilatory reduction of nitrate and nitrite occurring at anoxic microsites within such particles. Particle-based denitrification and other anaerobic metabolisms can change the global budget of elemental cycles important for life and climate across the oceans.