bluuebunny/crossref_metadata_2025 huggingface dataset:
Task-Induced Mental Fatigue and Motivation Influence Listening Effort as Measured by the Pupil Dilation in a Speech-in-Noise Task
Authors: Menase Defne Alfandari , Richter Michael , Wendt Dorothea , Fiedler Lorenz , Naylor Graham
Published: January 2022

Objectives

Listening effort and fatigue are common complaints among individuals with hearing impairment (HI); however, the underlying mechanisms, and relationships between listening effort and fatigue are not well understood. Recent quantitative research suggests that the peak pupil dilation (PPD), which is commonly measured concurrent to the performance of a speech-in-noise task as an index of listening effort, may be informative of daily-life fatigue, but it remains unknown whether the same is true for task-induce fatigue. As fatigue effects are known to manifest differently depending on motivation, the main aim of the present study was to experimentally investigate the interactive effects of task-induced fatigue and motivation on the PPD.

Design

In a pre-/post-fatigue within-subject design, 18 participants with normal hearing (NH) engaged in a 98-trial-long speech-in-noise task (the ‘load sequence’, approximately 40 min. long), which either excluded or included additional memory demands (light vs. heavy load sequence). Before and after the load sequence, baseline pupil diameter (BPD) and PPD were measured during shorter ‘probe’ blocks of speech-in-noise tasks. In these probe blocks, if participants correctly repeated more than 60% of the keywords, they could win vouchers of either 20 or 160 Danish krones worth (low incentive vs. high incentive). After each probe block, participants reported their invested effort, tendency for quitting, and perceived performance.

Results

The BPD in anticipation of listening declined from pre-to post-load sequence, suggesting an overall decrease in arousal, but the decline did not scale with the magnitude of the load sequence, nor with the amount of monetary incentive. Overall, there was larger pre-to post-load sequence decline in PPD when the load sequence was heavy and when the monetary incentives were low. Post-hoc analyses showed that the decline in PPD was only significant in the heavy-load sequence-low reward condition. The speech-in-noise task performance, self-reported effort, and self-reported tendency to quit listening did not change with the experimental conditions.

Conclusions

This is the first study to investigate the influence of task-induced fatigue on BPD and PPD. Whereas BPD was not sensitive to the magnitude of previous load sequence and monetary incentives, the decline in PPD from pre-to post-load sequence was significant after the heavy load sequence when the offered monetary incentives were low. This result supports the understanding that fatigue and motivation interactively influence listening effort.
Radiological follow-up of adults hospitalised with pneumonia and SARS-CoV-2 infection, in Bristol UK, during the COVID19 pandemic
Authors: Ruffino Gabriella , Williams Rachel L , Barratt Shaney , Hyams Catherine
Published: January 2022

Introduction

Radiological change which may be attributed to infection can also be attributable to lung cancer. Patients with SARS-CoV-2 infection can develop groundglass lung opacification which may result in chronic lung changes. Current British Thoracic Society (BTS) guidelines recommend patients with pneumonia and COVID19 undergo repeat chest radiography.

Methods

A single-centre audit of patients hospitalised with community-acquired pneumonia or COVID19 over three time periods during the COVID19 pandemic (Aug-Dec 2020, Jun-Aug 2021, Dec-Jan 2022). We assessed whether patients were eligible for radiological follow-up and if repeat radiological investigation occurred.

Results

1040 adults were hospitalised with infective radiological change (pneumonia=596, COVID19=444). 831/1040 patients (80%) required radiological follow-up under BTS guideline criteria: there was minimal difference between the first two time periods studied. Patients hospitalised with CAP were less likely to have radiological follow-up planned than those admitted with COVID19 disease (49% versus 59% respectively). Following a change in hospital policy, follow-up rates increased to 69% and 71% for pneumonia and COVID19. Overall, only 47% eligible patients received follow-up in line with current guidelines.

Conclusion

BTS guideline adherence is important to avoid delay in diagnosing underlying malignancy or chronic lung disease. Radiological follow-up following CAP and COVID19 may be suboptimal, with a paucity of data. Follow-up arranged under the hospital team was more likely to occur than when the GP was responsible for instigating repeat radiological imaging. Further investigation into rates of radiological follow-up should be undertaken, including reasons for non-adherence, to ensure patients receive appropriate treatment following respiratory infection.
Cell-mediated and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients
Authors: Yang Lu M. , Costales Cristina , Ramanathan Muthukumar , Bulterys Philip L. , Murugesan Kanagavel , Schroers-Martin Joseph , Alizadeh Ash A. , Boyd Scott D. , Brown Janice M. , Nadeau Kari C. , Nadimpalli Sruti S. , Wang Aileen X. , Busque Stephan , Pinsky Benjamin A. , Banaei Niaz
Published: January 2022

Importance

Data on the humoral and cellular immune response to primary and booster SARS-CoV-2 vaccination in immunosuppressed patients is limited.

Objective

To determine humoral and cellular response to primary and booster vaccination in immunosuppressed patients and identify variables associated with poor response.

Design

Retrospective observational cohort study.

Setting

Large healthcare system in Northern California.

Participants

This study included patients fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) who underwent clinical testing for anti-SARS-SoV-2 S1 IgG ELISA (anti-S1 IgG) and SARS-CoV-2 interferon gamma release assay (IGRA) from January 1, 2021 through November 15, 2021. A cohort of 18 immunocompetent volunteer healthcare workers were included as reference. No participants had a prior diagnosis of SARS-CoV-2 infection.

Exposure(s)

Immunosuppressive diseases and therapies.

Main Outcome(s) and Measure(s)

Humoral and cellular SARS-CoV-2 vaccine response as measured by anti-S1 IgG and SARS-CoV-2 IGRA, respectively, after primary and booster vaccination.

Results

496 patients (54% female; median age 50 years) were included in this study. Among immunosuppressed patients after primary vaccination, 62% (261/419) had positive anti-S1 IgG and 71% (277/389) had positive IGRA. After booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Immunosuppressive factors associated with low rates of humoral response after primary vaccination included anti-CD20 monoclonal antibodies (P<.001), sphingosine 1-phsophate (S1P) receptor modulators (P<.001), mycophenolate (P=.002), and B cell lymphoma (P=.004); those associated with low rates of cellular response included S1P receptor modulators (P<.001) and mycophenolate (P<.001). Of patients who responded poorly to primary vaccination, 16% (4/25) with hematologic malignancy or primary immunodeficiency developed a significantly increased humoral response after the booster dose, while 52% (14/27) with solid malignancy, solid organ transplantation, or autoimmune disease developed an increased response (P=.009). Only 5% (2/42) of immunosuppressed patients developed a significantly increased cellular response following the booster dose.

Conclusions and Relevance

Cellular vaccine response rates were higher than humoral response rates in immunosuppressed individuals after primary vaccination, particularly among those undergoing B cell targeting therapies. However, humoral response can be increased with booster vaccination, even in patients on B cell targeting therapies.
Cortical and STN spectral changes during limb movements in PD patients with and without dystonia
Authors: Olson Joseph W. , Nakhmani Arie , Irwin Zachary T. , Edwards Lloyd J. , Gonzalez Christopher L. , Wade Melissa H. , Black Sarah D. , Awad Mohammad Z. , Kuhman Daniel J. , Hurt Christopher P. , Guthrie Bart L. , Walker Harrison C.
Published: January 2022

Background

Dystonia is an under-studied motor feature of Parkinson disease (PD). Although considerable efforts have focused on brain oscillations related to the cardinal symptoms of PD, whether dystonia is associated with specific electrophysiological features is unclear.

Objectives

To investigate subcortical and cortical field potentials at rest and during contralateral hand and foot movements in PD patients with and without dystonia.

Methods

We examined the prevalence and distribution of dystonia in PD patients undergoing deep brain stimulation surgery and recorded intracranial electrophysiology from motor cortex and directional electrodes in subthalamic nucleus (STN) both at rest and during self-paced repetitive contralateral hand and foot movements. Wavelet transforms and mixed models characterized changes in spectral content in patients with and without dystonia.

Results

Dystonia was highly prevalent at enrollment (61%) and occurred most commonly in the foot. Regardless of dystonia status, cortical recordings display beta (13-30 Hz) desynchronization during movements versus rest, while STN signals show increased power in low frequencies (6.0±3.3 and 4.2±2.9 Hz peak frequencies for hand and foot movements respectively). PD patients with dystonia during DBS surgery displayed greater M1 beta power at rest and STN low frequency power during movements versus those without dystonia.

Conclusions

Spectral power in motor cortex and STN field potentials differs markedly during repetitive limb movements, with cortical beta desynchronization and subcortical low frequency synchronization, especially in PD patients with dystonia. Greater knowledge on field potential dynamics in human motor circuits can inform dystonia pathophysiology in PD and guide novel approaches to therapy.
Multimodal repertoire analysis unveils B cell biology in immune-mediated diseases
Authors: Ota Mineto , Nakano Masahiro , Nagafuchi Yasuo , Kobayashi Satomi , Hatano Hiroaki , Yoshida Ryochi , Akutsu Yuko , Itamiya Takahiro , Ban Nobuhiro , Tsuchida Yumi , Shoda Hirofumi , Yamamoto Kazuhiko , Ishigaki Kazuyoshi , Okamura Tomohisa , Fujio Keishi
Published: January 2022

Objectives

Despite the involvement of B cells in the pathogenesis of immune-mediated diseases, biological mechanisms underlying their function are scarcely understood. To overcome this gap, here we constructed and investigated a large-scale repertoire catalog of five B cell subsets of immune-mediated disease patients.

Methods

We mapped B cell receptor regions from RNA sequencing data of sorted B cell subsets. Our dataset consisted of 595 donors under immune-mediated diseases and health. We characterized the repertoire features from various aspects, including their association with immune cell transcriptomes and clinical features and their response to belimumab treatment.

Results

Heavy-chain complementarity-determining region 3 (CDR-H3) length among naïve B cells was shortened among autoimmune diseases. Strong negative correlation between interferon signature strength and CDR-H3 length was observed only in naïve B cells and suggested the role for interferon in pre-mature B cell development. VDJ gene usage was skewed especially in plasmablasts and unswitched-memory B cells of systemic lupus erythematosus (SLE) patients. We developed a scoring system for this skewing, and it positively correlated with peripheral helper T cell transcriptomic signatures and negatively correlated with the amount of somatic hyper mutations in plasmablasts, suggesting the association of extra-follicular pathway. Further, this skewing led to high usage of IGHV4-34 gene in unswitched-memory B cells, whose usage showed prominent positive correlation with disease activity in SLE. Gene usage skewing in unswitched-memory B cells was ameliorated after belimumab treatment.

Conclusions

Our multimodal repertoire analysis enabled us the system-level understanding of B cell abnormality in diseases.
Detection of fecal coliforms and SARS-CoV-2 RNA in sewage and recreational waters in the Ecuadorian Coast: a call for improving water quality regulation
Authors: Cárdenas-Calle Maritza , Patiño Leandro , Pernia Beatríz , Erazo Roberto , Muñoz Carlos , Valencia-Avellan Magaly , Lozada Mariana , Regato-Arrata Mary , Barrera Miguel , Aquino Segundo , Moyano Stalyn , Fuentes Stefania , Duque Javier , Velazquez-Araque Luis , Carpio Bertha , Méndez-Roman Carlos , Calle Carlos , Cárdenas Guillermo , Guizado-Herrera David , Lucía Tello Clara , Bravo-Basantes Veronica , Zambranod Josué , Francis Jhannelle , Uyaguari Miguel
Published: January 2022

Wastewater surveillance represents an alternative approach for the diagnosis and early detection of infectious agents of public health importance. This study aimed to evaluate SARS-CoV-2 and other quality markers in oxidation lagoons, estuarine areas and seawater at Guayas and Santa Elena in Ecuador. Sample collections were conducted twice at 42 coastal sites and 2 oxidation lagoons during dry and rainy seasons (2020-2021). Physico-chemical and microbiological parameters were evaluated to determine organic pollution. Quantitative reverse transcription PCR was conducted to detect SARS-CoV-2. Results showed high levels of Escherichia coli and low dissolved oxygen concentrations. SARS-CoV-2 was detected in sea-waters and estuaries with salinity levels between 34.2-36.4 PSU and 28.8 °C-31.3 °C. High amounts of fecal coliforms were detected and correlated with the SARS-CoV-2 shedding. We recommend to decentralized autonomous governments in developing countries such as Ecuador to implement corrective actions and establish medium-term mechanisms to minimize a potential contamination route.

HIGHLIGHTS

SARS-CoV-2 RNA was detected in estuaries, bays and the wastewater treatment systems in Playas and Santa Elena.

High levels of fecal coliforms were detected along shorelines.

Water quality parameters revealed a negative impact on the beaches studied associated with human activities.
Development of the one-step qualitative RT-PCR assay to detect SARS-CoV-2 Omicron (B.1.1.529) variant in respiratory specimens
Authors: Phan Tung , Boes Stephanie , McCullough Melissa , Gribschaw Jamie , Wells Alan
Published: January 2022

A new SARS-CoV-2 Omicron (B.1.1.529) Variant of Concern has been emerging worldwide. We are seeing an unprecedented surge in patients due to Omicron in this COVID-19 pandemic. A rapid and accurate molecular test that effectively differentiates Omicron from other SARS-CoV-2 variants would be important for both epidemiologic value and for directing variant-specific therapies such as monoclonal antibody infusions. In this study, we developed a real-time RT-PCR assay for the qualitative detection of Omicron from routine clinical specimens sampling the upper respiratory tract. The limit of detection of the SARS-CoV-2 Omicron variant RT-PCR assay was 2 copies/μl. Notably, the assay did not show any cross-reactivity with other SARS-CoV-2 variants including Delta (B.1.617.2). This SARS-CoV-2 Omicron variant RT-PCR laboratory-developed assay is sensitive and specific to detect Omicron in nasopharyngeal and nasal swab specimens.
Waning Effectiveness of the BNT162b2 Vaccine Against Infection in Adolescents
Authors: Prunas Ottavia , Weinberger Daniel M. , Pitzer Virginia E. , Gazit Sivan , Patalon Tal
Published: January 2022

Background

The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 vaccine for adolescents has been demonstrated. However, little is known about the long-term effectiveness in this age group. It is known, though, that waning of vaccine-induced immunity against infection in adult populations is evident within a few months.

Methods

Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we conducted a matched case-control design for evaluating the association between time since vaccination and the incidence of infections, where two outcomes were evaluated separately: a documented SARS-CoV-2 infection (regardless of symptoms) and a symptomatic infection (COVID-19). Cases were defined as individuals aged 12 to 16 with a positive PCR test occurring between June 15 and December 8, 2021, when the Delta variant was dominant in Israel. Controls were adolescents who had not tested positive previously.

Results

We estimated a peak vaccine effectiveness between 2 weeks and 3 months following receipt of the second dose, with 85% and 90% effectiveness against SARS-CoV-2 infection and COVID-19, respectively. However, in line with previous findings for adults, waning of vaccine effectiveness was evident in adolescents as well. Long-term protection conferred by the vaccine was reduced to 75-78% against infection and symptomatic infection, respectively, 3 to 5 months after the second dose, and waned to 58% against infection and 65% against COVID-19 after 5 months.

Conclusions

Like adults, vaccine-induced protection against both SARS-CoV-2 infection and COVID-19 wanes with time, starting three months after inoculation and continuing for more than five months.
HMGN5 escorts oncogenic STAT3 signaling by regulating chromatin landscape in tumorigenesis of breast cancer
Authors: Mou Jiahui , Huang Meijun , Wang Feifei , Xu Xiaoding , Xie Hanqi , Lu Henglei , Li Mingyang , Li Yu , Kong Weiwen , Chen Jing , Xiao Ying , Chen Yiding , Wang Chaochen , Ren Jin
Published: January 2022

Epigenetic alterations are widely linked with carcinogenesis, therefore becoming emerging therapeutic targets in the treatment of cancers, including breast cancer. HMGNs are nucleosome binding proteins, which regulate chromatin structures in a cell type- and disease-specific manner. However, the roles of HMGNs in the tumorigenesis of breast cancer are less known. In this study, we report that HMGNs are highly expressed in 3D-cultured breast cancer cells. HMGN5, a member of HMGNs, controls the proliferation, invasion and metastasis of breast cancer cells in vitro and in vivo. Clinically, HMGN5 is an unfavorable prognostic marker in patients. Mechanistically, HMGN5 is governed by active STAT3 transcriptionally and further escorts STAT3 to shape oncogenic chromatin landscape and transcriptional program. Lastly, we provide evidence that interference of HMGN5 by nanoparticle-packaged siRNA is potentially an effective approach in breast cancer treatment. Taken together, our findings reveal a novel feed-forward circuit between HMGN5 and STAT3 in promoting breast cancer tumorigenesis and suggest HMGN5 as a novel epigenetic therapeutic-target in STAT3- hyperactive breast cancer.
Evaluation of a predictive method for the H&E-based molecular profiling of breast cancer with deep learning
Authors: Arslan Salim , Li Xiusi , Schmidt Julian , Hense Julius , Geraldes Andre , Bass Cher , Brown Keelan , Marcia Angelica , Dewhirst Tim , Pandya Pahini , Singhal Shikha , Mehrotra Debapriya , Raharja-Liu Pandu
Published: January 2022

We present a public validation of PANProfiler (ER, PR, HER2), an in-vitro medical device (IVD) that predicts the qualitative status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) by analysing the hematoxylin and eosin (H&E)-stained tissue scan. In public validation on 648 (ER), 648 (PR) and 560 (HER2) unseen cases with known biomarker status, the device achieves an accuracy of 87% (ER), 83% (PR) and 87% (HER2). The validation offers early evidence of the ability to predict clinically relevant breast biomarkers from an H&E slide in a relevant clinical setting.
Red blood cells protein profile is modified in breast cancer patients
Authors: Pereira-Veiga Thais , Bravo Susana , Gómez-Tato Antonio , Yáñez-Gómez Celso , Abuín Carmen , Varela Vanesa , Cueva Juan , Palacios Patricia , Dávila-Ibáñez Ana B. , Piñeiro Roberto , Vilar Ana , Chantada-Vázquez María del Pilar , López-López Rafael , Costa Clotilde
Published: January 2022

Metastasis is the primary cause of death for most breast cancer patients who succumb to the disease. During the haematogenous dissemination, circulating tumor cells interact with different blood components. Thus, there are micro-environmental and systemic processes contributing to cancer regulation. We have published that Red Blood Cells (RBCs) that accompany circulating tumor cells have prognostic value in metastatic breast cancer patients. Although the principal known role of RBCs is gas transport, it has been recently assigned additional functions as regulatory cells on circulation. Hence, to explore their potential contribution to tumor progression, we characterized the proteomic composition of RBCs from 53 breast cancer patients, compared with 33 healthy donors. RBCs from breast cancer patients showed a different proteomic profile compared to healthy donors. The differential proteins were mainly related to extracellular components, proteasome, and metabolism. Besides, LAMP2 emerge as a new RBCs marker with diagnostic and prognostic potential for metastatic patients. Seemingly, RBCs are acquiring modifications in their proteomic composition that probably represents the systemic cancer disease, conditioned by the tumor microenvironment.
Drosophila Mechanical Nociceptors Preferentially Sense Localized Poking
Authors: Liu Zhen , Wang Qi-Xuan , Wu Meng-Hua , Lin Shao-Zhen , Feng Xi-Qiao , Li Bo , Liang Xin
Published: January 2022

Mechanical nociception is an evolutionarily conserved sensory process required for the survival of living organisms. Previous studies have revealed much about the neural circuits and key sensory molecules in mechanical nociception, but the cellular mechanisms adopted by nociceptors in force detection remain elusive. To address this issue, we study the mechanosensation of a fly larval nociceptor (class IV da neurons, c4da) using a customized mechanical device. We find that c4da are sensitive to mN-scale forces and make uniform responses to the forces applied at different dendritic regions. Moreover, c4da showed a greater sensitivity to more localized forces, consistent with them being able to sense the poking of sharp objects, such as wasp ovipositor. Further analysis reveals that high morphological complexity, mechanosensitivity to lateral tension and active signal propagation in the dendrites altogether facilitate the mechanosensitivity and sensory features of c4da. In particular, we discover that Piezo and Ppk1/Ppk26, two key mechanosensory molecules, make differential but additive contributions to the mechanosensation of c4da. In all, our results provide updates into understanding how c4da process mechanical signals at the cellular level and reveal the contributions of key molecules.
Front propagation and arrival times in networks with application to neurodegenerative diseases
Authors: Putra Prama , Oliveri Hadrien , Thompson Travis , Goriely Alain
Published: January 2022

Many physical, epidemiological, or physiological dynamical processes on networks support front-like propagation, where an initial localized perturbation grows and systematically invades all nodes in the network. A key question is then to extract estimates for the dynamics. In particular, if a single node is seeded at a small concentration, when will other nodes reach the same initial concentration? Here, motivated by the study of toxic protein propagation in neurodegenerative diseases, we present and compare three different estimates for the arrival time in order of increasing analytical complexity: the linear arrival time, obtained by linearizing the underlying system; the Lambert time, obtained by considering the interaction of two nodes; and the nonlinear arrival time, obtained by asymptotic techniques. We use the classic Fisher-Kolmogorov-Petrovsky-Piskunov equation as a paradigm for the dynamics and show that each method provides different insight and time estimates. Further, we show that the nonlinear asymptotic method also gives an approximate solution valid in the entire domain and the correct ordering of arrival regions over large regions of parameters and initial conditions.
The Metaxin Mitochondrial Import Proteins: Multiple Metaxin-like Proteins in Fungi
Authors: Adolph Kenneth W.
Published: January 2022

Multiple metaxin-like proteins are shown to exist in fungi, as also found for the metaxin proteins of vertebrates and invertebrates. In vertebrates, metaxins 1 and 2 are mitochondrial membrane proteins that function in the import of proteins into mitochondria. Fungal metaxin-like proteins were identified by criteria including their homology with human metaxins and the presence of characteristic GST_N_Metaxin, GST_C_Metaxin, and Tom37 protein domains. Fungi in different taxonomic divisions (phyla) were found to possess multiple metaxin-like proteins. These include the Ascomycota, Basidiomycota, Blastocladiomycota, Chytridiomycota, Mucoromycota, Neocallimastigomycota, and Zoopagomycota divisions. Most fungi with multiple metaxin-like proteins contain two proteins, designated MTXa and MTXb. Amino acid sequence alignments show a high degree of homology among MTXa proteins, with over 60% amino acid identities, and also among MTXb proteins of fungi in the same division. But very little homology is observed in aligning MTXa with MTXb proteins of the same or different fungi. Both the MTXa proteins and MTXb proteins have the protein domains that characterize the metaxins and metaxin-like proteins: GST_N_Metaxin, GST_C_Metaxin, and Tom37. The metaxins and metaxin-like proteins of vertebrates, invertebrates, plants, protists, and bacteria all possess these domains. The secondary structures of MTXa and MTXb proteins are both dominated by similar patterns of α-helical segments, but extensive β-strand segments are absent. Nine highly conserved α-helical segments are present, the same as other metaxins and metaxin-like proteins. Phylogenetic analysis reveals that MTXa and MTXb proteins of fungi form two separate and distinct groups. These groups are also separate from the groups of vertebrate metaxins, metaxin-related Sam37 proteins of yeasts, and metaxin-like FAXC proteins.
Opposite-sex associations are linked with annual fitness, but sociality is stable over lifetime
Authors: Dunning Jamie , Burke Terry , Chan Alex Hoi Hang , Chik Heung Ying Janet , Evans Tim , Schroeder Julia
Published: January 2022

Animal sociality, an individual’s propensity to associate with others, has fitness consequences through mate choice, for example, directly, by increasing the pool of prospective partners, and indirectly through increased survival, and individuals benefit from both. Annually, fitness consequences are realised through increased mating success and subsequent fecundity. However, it remains unknown whether these consequences translate to life-time fitness. Here, we quantified social associations and their link to fitness annually and over lifetime, using a multi-generational, genetic pedigree. We used social network analysis to calculate variables representing different aspects of an individual’s sociality. Sociality showed high within-individual repeatability. We found that birds with more opposite-sex associates had higher annual fitness than those with fewer, but this did not translate to lifetime fitness. Instead, for lifetime fitness, we found evidence for stabilizing selection on opposite-sex sociality, and sociality in general, suggesting that reported benefits are only short-lived in a wild population, and that selection favours an average sociality.
A unique class of Zn2+-binding PBPs underlies cephalosporin resistance and sporogenesis of Clostridioides difficile
Authors: Sacco Michael D. , Wang Shaohui , Adapa Swamy R. , Zhang Xiujun , Gongora Maura V. , Gatdula Jean R. , Lewandowski Eric M. , Hammond Lauren R. , Townsend Julia A. , Marty Michael T. , Wang Jun , Eswara Prahathees J. , Jiang Rays H.Y. , Sun Xingmin , Chen Yu
Published: January 2022

β-Lactam antibiotics, particularly cephalosporins, are major risk factors for C. difficile infection (CDI), the most common hospital acquired infection. These broad-spectrum antibiotics irreversibly inhibit penicillin-binding proteins (PBPs), essential enzymes that assemble the bacterial cell wall. Little is known about the C. difficile PBPs, yet they play central roles in the growth, infection, and transmission of this pathogen. In this study we discover that PBP2, essential for vegetative growth, is the primary bactericidal target for β-lactams in C. difficile. We further demonstrate PBP2 is insensitive to cephalosporin inhibition, revealing a key cause of the well-documented, but poorly understood, cephalosporin resistance in C. difficile. For the first time, we determine the crystal structures of C. difficile PBP2, which bears several highly unique features, including significant ligand-induced conformational changes and an active site Zn2+-binding motif that influences β-lactam binding and protein stability. Remarkably, this motif is shared in two other C. difficile PBPs essential for sporulation, PBP3 and SpoVD. While these PBPs are present in a wide range of bacterial taxa, including species in extreme environments and the human gut, they are mostly found in anaerobes, typically Firmicutes. The widespread presence of this convergently evolved thiol-containing motif and its cognate Zn2+ suggests it may function as a redox-sensor to regulate cell wall synthesis for survival in adverse environments. Collectively, our findings address important etiological questions surrounding C. difficile, characterize new elements of PBP structure and function, and lay the groundwork for antibiotic development targeting both C. difficile growth and sporulation.
Mapping functional regions of essential bacterial proteins with dominant-negative protein fragments
Authors: Savinov Andrew , Fernandez Andres , Fields Stanley
Published: January 2022

Massively-parallel measurements of dominant negative inhibition by protein fragments have been used to map protein interaction sites and discover peptide inhibitors. However, the underlying principles governing fragment-based inhibition have thus far remained unclear. Here, we adapt a high-throughput inhibitory fragment assay for use inEscherichia coli, applying it to a set of ten essential proteins. This approach yielded single amino acid-resolution maps of inhibitory activity, with peaks localized to functionally important interaction sites, including oligomerization interfaces and folding contacts. Leveraging these data, we perform a systematic analysis to uncover principles of fragment-based inhibition. We determine a robust negative correlation between susceptibility to inhibition and cellular protein concentration, demonstrating that inhibitory fragments likely act primarily by titrating native protein interactions. We also characterize a series of trade-offs related to fragment length, showing that shorter peptides allow higher-resolution mapping but suffer from lower inhibitory activity. We employ an unsupervised statistical analysis to show that the inhibitory activities of protein fragments are largely driven not by generic properties such as charge, hydrophobicity, and secondary structure, but by the more specific characteristics of their bespoke macromolecular interactions. AlphaFold computational modeling of peptide complexes with one protein shows that the inhibitory activity of peptides is associated with their predicted ability to form native-like interactions. Overall, this work demonstrates fundamental characteristics of inhibitory protein fragment function and provides a foundation for understanding and controlling protein interactionsin vivo.

Significance Statement

Peptide fragments derived from protein sequences can inhibit interactions of their parental proteins, providing a promising avenue for drug development. Here we employ a massively-parallel assay to measurein vivoinhibition by fragments that tile the full sequences of ten essential bacterial proteins. We leverage these data to decipher principles of fragment-based inhibition, showing how parental protein concentration drives activity and how protein fragment length interplays with activity and specificity. We employ statistical analysis to parse the roles of biophysical properties in fragment-to-fragment variation, and AlphaFold modeling to determine the relationship between measured inhibitory activity and predicted native-like binding. These results provide a path towards rational design of peptide inhibitors and broader principles of protein-protein interactions in living cells.
Isolated Grauer’s gorilla populations differ in diet and gut microbiome
Authors: Michel Alice , Minocher Riana , Niehoff Peter-Philip , Li Yuhong , Nota Kevin , Gadhvi Maya A. , Su Jiancheng , Iyer Neetha , Porter Amy , Ngobobo-As-Ibungu Urbain , Binyinyi Escobar , Pekeyake Radar Nishuli , Parducci Laura , Caillaud Damien , Guschanski Katerina
Published: January 2022

The animal gut microbiome has been implicated in a number of key biological processes, ranging from digestion to behavior, and has also been suggested to facilitate local adaptation. However, studies in wild animals rarely compare multiple populations that differ ecologically, which is the level at which local adaptation may occur. Further, few studies simultaneously characterize diet and the gut microbiome from the same sample, despite the likely presence of co-dependencies. Here, we investigate the interplay between diet and gut microbiome in three geographically isolated populations of the critically endangered Grauer’s gorilla, which we show to be genetically differentiated. We find population- and social group-specific dietary and gut microbial profiles and co-variation between diet and gut microbiome, despite the presence of core microbial taxa. There was no detectable effect of age, sex, or genetic relatedness on the microbiome. Diet differed considerably across populations, with the high-altitude population consuming a lower diversity of plants compared to low-altitude populations, consistent with food plant availability constraining diet. The observed pattern of covariation between diet and gut microbiome is likely a result of long-term social and ecological factors. Our study suggests that the gut microbiome is sufficiently plastic to support flexible food selection and hence contribute to local adaptation.
Metabolic rescue ameliorates mitochondrial encephalo-cardiomyopathy in murine and human iPSC models of Leigh syndrome
Authors: Yoon Jin-Young , Daneshgar Nastaran , Chu Yi , Chen Biyi , Hefti Marco , Irani Kaikobad , Song Long-Sheng , Brenner Charles , Abel E. Dale , London Barry , Dai Dao-Fu
Published: January 2022

Mice with deletion of complex I subunit Ndufs4 develop mitochondrial encephalomyopathy resembling Leigh syndrome (LS). We report that LS mice also develop severe cardiac bradyarrhythmia and diastolic dysfunction. Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) with Ndufs4 deletion recapitulate LS cardiomyopathy. Mechanistically, we demonstrate a direct link between complex I deficiency, decreased intracellular NAD+/ NADH and bradyarrhythmia, mediated by hyperacetylation of the cardiac sodium channel NaV1.5, particularly at K1479 site. Neuronal apoptosis in the cerebellar and midbrain regions in LS mice was associated with hyperacetylation of p53 and activation of microglia. Targeted metabolomics revealed increases in several amino acids and citric acid cycle intermediates, likely due to impairment of NAD+-dependent dehydrogenases, and a substantial decrease in reduced Glutathione (GSH). Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+/ NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+-dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes, concomitant with improvement of NaV1.5 current and SERCA2a function measured by Ca2+- transients. NR also attenuated neuronal apoptosis and microglial activation in the LS brain and human iPS-derived neurons with Ndufs4 deletion. Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human iPSC models of LS.
Towards Predicting 30-Day Readmission among Oncology Patients: Identifying Timely and Actionable Risk Factors
Authors: Hwang Sy , Urbanowicz Ryan , Lynch Selah , Vernon Tawnya , Bresz Kellie , Giraldo Carolina , Kennedy Erin , Leabhart Max , Bleacher Troy , Ripchinski Michael R. , Mowery Danielle L. , Oyer Randall A.
Published: January 2022

1

Purpose

Predicting 30-day readmission risk is paramount to improving the quality of patient care. Previous studies have examined clinical risk factors associated with hospital readmissions. In this study, we compare sets of patient, provider, and community-level variables that are available at two different points of a patient’s inpatient encounter (first 48 hours and the full encounter) to train readmission prediction models in order to identify and target appropriate actionable interventions that can potentially reduce avoidable readmissions.

Methods

Using EHR data from a retrospective cohort of 2460 oncology patients, two sets of binary classification models predicting 30-day readmission were developed; one trained on variables that are available within the first 48 hours of admission and another trained on data from the entire hospital encounter. A comprehensive machine learning analysis pipeline was leveraged including preprocessing and feature transformation, feature importance and selection, machine learning modeling, and post-analysis.

Results

Leveraging all features, the LGB (Light Gradient Boosting Machine) model produced higher, but comparable performance: (AUROC: 0.711 and APS: 0.225) compared to Epic (AUROC: 0.697 and APS: 0.221). Given features in the first 48-hours, the RF (Random Forest) model produces higher AUROC (0.684), but lower AUPRC (0.18) and APS (0.184) than the Epic model (AUROC: 0.676). In terms of the characteristics of patients flagged by these models, both the full (LGB) and 48-hour (RF) feature models were highly sensitive in flagging more patients than the Epic models. Both models flagged patients with a similar distribution of race and sex; however, our LGB and random forest models more inclusive flagging more patients among younger age groups. The Epic models were more sensitive to identifying patients with an average lower zip income. Our 48-hour models were powered by novel features at various levels: patient (weight change over 365 days, depression symptoms, laboratory values, cancer type), provider (winter discharge, hospital admission type), community (zip income, marital status of partner).

Conclusion

We demonstrated that we could develop and validate models comparable to existing Epic 30-day readmission models, but provide several actionable insights that could create service interventions deployed by the case management or discharge planning teams that may decrease readmission rates over time.
Exploring the impact of shielding advice on the health and wellbeing of individuals identified as extremely vulnerable and advised to shield in Southwest England amid the COVID-19 pandemic: A mixed-methods evaluation
Authors: Lasseter Gemma , Compston Polly , Robin Charlotte , Lambert Helen , Hickman Matthew , Denford Sarah , Reynolds Rosy , Zhang Juan , Cai Shenghan , Zhang Tingting , Smith Louise E. , Rubin James , Yardley Lucy , Amlot Richard , Oliver Isabel
Published: January 2022

Objective: Explore the impact and responses to public health advice on the health and wellbeing of individuals identified as clinically extremely vulnerable (CEV) and advised to shield (not leave home for 12 weeks at start of the pandemic) in Southwest England during the first COVID-19 lockdown.
Design: Mixed-methods study; structured survey and follow-up semi-structured interviews.
Setting: Communities served by Bristol, North Somerset & South Gloucestershire Clinical Commissioning Group.
Participants: 204 people (57% female, 54% >69 years, 94% White British, 64% retired) in Southwest England identified as CEV and were advised to shield completed the survey. Thirteen survey respondents participated in follow-up interviews (53% female, 40% >69years, 100% White British, 61% retired).
Results: Receipt of official communication from NHS England or General Practitioner (GP) was considered by participants as the legitimate start of shielding. 80% of survey responders felt they received all relevant advice needed to shield, yet interviewees criticised the timing of advice and often sought supplementary information. Shielding behaviours were nuanced, adapted to suit personal circumstances, and waned over time. Few interviewees received community support, although food boxes and informal social support were obtained by some. Worrying about COVID-19 was common for survey responders (90%). Since shielding had begun, physical and mental health reportedly worsened for 35% and 42% of survey responders respectively. 21% of survey responders scored 10 or more on the PHQ-9 questionnaire indicating possible depression and 15% scored 10 or more on the GAD-7 questionnaire indicating possible anxiety.
Conclusions: This research highlights the difficulties in providing generic messaging that is applicable and appropriate given the diversity of individuals identified as CEV and the importance of sharing tailored and timely advice to inform shielding decisions. Providing messages that reinforce self-determined action and assistance from support services could reduce the negative impact of shielding on mental health and feelings of social isolation.
Hypothesis-free detection of gene-interaction effects on biomarker concentration in UK Biobank using variance prioritisation
Authors: Lyon Matthew S. , Millard Louise A. C. , Smith George Davey , Gaunt Tom R. , Tilling Kate
Published: January 2022

Blood biomarkers include disease intervention targets that may interact with genetic and environmental factors resulting in subgroups of individuals who respond differently to treatment. Such interactions may be observed in genetic effects on trait variance. Variance prioritisation is an approach to identify genetic loci with interaction effects by estimating their association with trait variance, even where the modifier is unknown or unmeasured. Here, we develop and evaluate a regression-based Brown-Forsythe test and variance effect estimate to detect such interactions. We provide scalable open-source software (varGWAS) for genome-wide association analysis of SNP-variance effects (https://github.com/MRCIEU/varGWAS) and apply our software to 30 blood biomarkers in UK Biobank. We find 468 variance quantitative trait loci across 24 biomarkers and follow up findings to detect 82 gene-environment and six gene-gene interactions independent of strong scale or phantom effects. Our results replicate existing findings and identify novel epistatic effects ofTREHrs12225548 xFUT2rs281379 andTREHrs12225548 xABOrs635634 on alkaline phosphatase andZNF827rs4835265 xNEDD4Lrs4503880 on gamma glutamyltransferase. These data could be used to discover possible subgroup effects for a given biomarker during preclinical drug development.
Phylogeography of hepatitis B: The role of Portugal in the early dissemination of HBV worldwide
Authors: Marcelino Rute , Ezeonwumelu Ifeanyi Jude , Janeiro André , Mimoso Paula , Matos Sónia , Briz Veronica , Pimentel Victor , Pingarilho Marta , Marinho Rui Tato , Marcelino José Maria , Taveira Nuno , Abecasis Ana
Published: January 2022

In 2015, 257 million people lived with chronic hepatitis B infection. In Portugal 1.4% of the population is chronically infected with hepatitis B virus. Limited information is available regarding the genetic diversity, origin of HBV in Portugal and its role in the dissemination of HBV worldwide. In this study, we aimed to investigate the epidemic history and transmission dynamics of HBV genotypes that are endemic in Portugal. HBV pol gene was sequenced from 130 patients followed in Lisbon. HBV genotype A (HBV/A) was the most prevalent genotype (n=54, 41.5%), followed by D [HBV/D; (n=44, 33.8%)], and E [HBV/E; (n=32, 24.6%)]. Spatio-temporal evolutionary dynamics were reconstructed using a Bayesian Markov Chain Monte Carlo method, as implemented in BEAST v1.10.4, with a GTR nucleotide substitution model, an uncorrelated lognormal relaxed molecular clock model under a Bayesian skyline plot and a continuous diffusion model. Our results indicate that HBV/D4 was the first subgenotype to be introduced in Portugal by the end of the XIX century, around 1857 (HPD 95% 1699 - 1931) followed by subgenotypes D3 and A2 a few decades later. Genotype E and subgenotype A1 were introduced in Portugal later, almost simultaneously. Our results also indicate a very important role of Portugal in the exportation of HBV subgenotypes D4 and A2 to Brazil and Cape Verde, respectively, in the beginning of the XX century. This work clarifies the epidemiological history of HBV in Portugal and show that Portugal had an important role in the global spread of this virus.
Comparison of Mammography Artificial Intelligence Algorithms for 5-year Breast Cancer Risk Prediction
Authors: Arasu Vignesh A. , Habel Laurel A. , Achacoso Ninah S. , Buist Diana S.M. , Cord Jason B. , Esserman Laura J. , Hylton Nola. M. , Glymour M. Maria , Kornak John , Kushi Lawrence H. , Lewis Don A. , Liu Vincent X. , Miglioretti Diana L. , Navarro Daniel A. , Sieh Weiva , Shen Li , Sofrygin Oleg , Yoon Hyo-Chun , Lee Catherine
Published: January 2022

PURPOSE

To examine the ability of 5 artificial intelligence (AI)-based computer vision algorithms, most trained to detect visible breast cancer on mammograms, to predict future risk relative to the Breast Cancer Surveillance Consortium clinical risk prediction model (BCSC v2).

PATIENTS AND METHODS

In this case-cohort study, women who had a screening mammogram in 2016 at Kaiser Permanente Northern California with no evidence of cancer on final imaging assessment were followed through September 2021. Women with prior breast cancer or a known highly penetrant gene mutation were excluded. From the 329,814 total eligible women, a random subcohort of 13,881 women (4.2%) were selected, of whom 197 had incident cancer. All 4,475 additional incident cancers were also included. Continuous AI-predicted scores were generated from the index 2016 mammogram. Risk estimates were generated with the Kaplan-Meier method and time-varying area under the curve [AUC(t)].

RESULTS

For incident cancers at 0-1 year (interval cancer risk), BCSC demonstrated an AUC(t) of 0.62 (95% CI, 0.58-0.66), and the AI algorithms had AUC(t)s ranging from 0.66-0.71, all significantly higher than BCSC (P< .05). For incident cancers at 1 to 5 years (5-year future cancer risk), BCSC demonstrated an AUC(t) of 0.61 (95% CI, 0.60-0.62), and the AI algorithms had AUC(t)s ranging from 0.63 to 0.67, all significantly higher than BCSC. Combined BCSC and AI models demonstrated AUC(t)s for interval cancer risk of 0.67-0.73 and for 5-year future cancer risk of 0.66-0.68.

CONCLUSION

The AI mammography algorithms we evaluated had significantly higher discrimination than the BCSC clinical risk model for interval and 5-year future cancer risk. Combined AI and BCSC models had slightly higher discrimination than AI alone.