bluuebunny/crossref_metadata_2025 huggingface dataset:
ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans
Authors: Yu Xiaobing , Ton Amy N. , Niu Zejun , Morales Blanca M. , Chen Jiadong , Braz Joao , Lai Michael H. , Barruet Emilie , Liu Hongju , Cheung Kin , Ali Syed , Chan Tea , Bigay Katherine , Ho Jennifer , Nikolli Ina , Hansberry Steven , Wentworth Kelly , Kriegstein Arnold , Basbaum Allan , Hsiao Edward C.
Published: April 2022

Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1R206H), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.
Long‐Term Functional Outcomes of an Anorectal Malformation French National Cohort
Authors: Schmitt Françoise , Scalabre Aurélien , Mure Pierre Yves , Borrione Claude , Lemelle Jean Louis , Sharma Dyuti , De Napoli Stéphan , Irtan Sabine , Levard Guillaume , Becmeur François , Buisson Philippe , Fourcade Laurent , Arnaud Alexis , De Vries Philine , Branchereau Sophie , Garignon Cynthia , Sauvat Frédérique , Kalfa Nicolas , Lardy Hubert , Jochault‐Ritz Sandy , Sapin Emmanuel , Coridon Hélène , Margaryan Marc , Pouzac Myriam , Carfagna Luana , Polimerol Marie Laurence , Varlet François , Sarnacki Sabine , Cretolle Célia , Podevin Guillaume
Published: April 2022

Objectives:

The present study aimed to assess long‐term functional outcomes of children with anorectal malformations (ARMs) across a network of expert centers in France.

Methods:

Retrospective cross‐sectional study of patients ages 6–30 years that had been surgically treated for ARM. Patient and ARM characteristics (eg, level, surgical approach) and functional outcomes were assessed in the different age groups.

Results:

Among 367 patients, there were 155 females (42.2%) and 212 males (57.8%), 188 (51.2%) cases with, and 179 (48.8%) higher forms without, perineal fistula. Univariate and multivariate statistical analyses with logistic regression showed correlation between the level of the rectal blind pouch and voluntary bowel movements (odds ratio [OR] = 1.84 [1.31–2.57], P < 0.001), or soiling (OR = 1.72 [1.31–2.25], P < 0.001), which was also associated with the inability to discriminate between stool and gas (OR = 2.45 [1.28–4.67], P = 0.007) and the presence of constipation (OR = 2.97 [1.74–5.08], P < 0.001). Risk factors for constipation were sacral abnormalities [OR = 2.26 [1.23–4.25], P = 0.01) and surgical procedures without an abdominal approach (OR = 2.98 [1.29–6.87], P = 0.01). Only the holding of voluntary bowel movements and soiling rates improved with age.

Conclusion:

This cross‐sectional study confirms a strong association between anatomical status and functional outcomes in patients surgically treated for ARM. It specifically highlights the need for long‐term follow‐up of all patients to help them with supportive care.
Long‐Term Sebelipase Alfa Treatment in Children and Adults With Lysosomal Acid Lipase Deficiency
Authors: Burton Barbara K. , Sanchez Alejandra Consuelo , Kostyleva Maria , Martins Ana Maria , Marulkar Sachin , Abel Florian , Barić Ivo
Published: April 2022

Objectives:

Sebelipase alfa is approved for treatment of lysosomal acid lipase deficiency (LAL‐D). This single‐arm, open‐label study (NCT02112994) evaluated sebelipase alfa efficacy and safety in patients with LAL‐D.

Methods:

Patients >8 months of age diagnosed with LAL‐D received sebelipase alfa 1.0 mg/kg by intravenous infusion every other week (qow) for up to 144 weeks. Dose escalation to 3.0 mg/kg qow and subsequently to 3.0 mg/kg weekly was permitted, per protocol; dose reductions for tolerability were permitted to 0.35 mg/kg qow. Descriptive statistical analyses were conducted.

Results:

Thirty‐one patients were enrolled and treated. Baseline median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were 63.5 and 65.5 U/L, respectively. Twenty‐eight patients completed 96 weeks of treatment, and 25 continued into the extended treatment period; 19 completed 144 weeks. From baseline to week 144, median ALT and AST levels changed by −42.0 and −22.0 U/L, respectively, median liver and spleen volumes changed from 1.4 to 1.3 and from 2.6 to 2.3 multiples of normal, respectively, median low‐density lipoprotein cholesterol levels decreased by 52.6 mg/dL, and median high‐density lipoprotein cholesterol increased by 9.8 mg/dL. Liver biopsies showed mostly improved or stable histopathology at 48 and 96 weeks versus baseline. Infusion‐associated reactions were mild (n = 1) or moderate (n = 2). One patient (a candidate for liver transplant at baseline) discontinued treatment because of liver transplant (unrelated to treatment). Two patients tested positive for nonneutralizing, anti‐drug antibodies on 1 occasion each.

Conclusion:

Sebelipase alfa was well tolerated and resulted in sustained improvements in liver and lipid parameters.
Comprehensive Clinical, Histopathologic, and Molecular Analysis and Long-term Follow-up of Patients With Nodal Blue Nevi
Authors: Colebatch Andrew J. , Adhikari Chandra , Diefenbach Russell J. , Rawson Robert V. , Ferguson Peter M. , Rizos Helen , Long Georgina V. , McCarthy Stanley W. , Thompson John F. , Wilmott James S. , Scolyer Richard A.
Published: April 2022

Blue nevi are benign, melanocytic neoplasms that show a range of clinical and morphologic patterns and include common/dendritic, cellular, and atypical cellular subtypes. Like other nevi, they most commonly occur in skin but can occasionally involve lymph nodes where they may be misinterpreted as representing metastatic melanoma. Moreover, whether benign blue nevi can metastasize to lymph nodes and their natural history and prognostic significance has been the subject of great controversy. To date, few cases of nodal blue nevi have been reported in the literature, and those reports have had limited clinical follow-up and supporting molecular data. This study sought to determine the clinical, pathologic, and molecular features of blue nevi involving lymph nodes, clarify their clinical significance, provide evidence for understanding their pathogenesis, and highlight potential pitfalls in the interpretation of lymph nodes with an ultimate aim of improving patient care. Thirteen cases of blue nevi involving lymph nodes were identified in the archives of Royal Prince Alfred Hospital, Sydney, Australia (1984-2018). A detailed assessment of the clinical and pathologic features of each case was performed, including an evaluation of all available immunohistochemical stains. Extended clinical follow-up was available for 9 patients. Droplet digital polymerase chain reaction for GNAQ Q209L, Q209P and GNA11 Q209L mutations was performed on 7 cases of blue nevi within lymph nodes together with matching cutaneous (presumed primary) blue nevi in 2 cases. All cases showed typical histologic features of blue nevi. BAP1 was retained in all cases (n=7). There were no recurrence or metastasis of blue nevus in any case on long-term clinical follow-up (n=9, median follow-up, 12 y). The majority of cases (n=5 of 7 evaluated) had GNAQ and GNA11 driver mutations. The 2 patients with a matched primary cutaneous blue nevus and regionally associated nodal blue nevus had the same GNAQ Q209L mutation in both sites in each patient. We conclude that blue nevi can involve lymph nodes and are associated with benign clinical behavior, and probably represent so-called “benign” metastasis. Awareness of these lesions is important when evaluating lymph nodes to avoid misdiagnosis as metastatic melanoma.
Perfusate Metabolomics Content and Expression of Tubular Transporters During Human Kidney Graft Preservation by Hypothermic Machine Perfusion
Authors: Faucher Quentin , Alarcan Hugo , Sauvage François-Ludovic , Forestier Lionel , Miquelestorena-Standley Elodie , Nadal-Desbarats Lydie , Arnion Hélène , Venhard Jean-Christophe , Brichart Nicolas , Bruyère Franck , Marquet Pierre , Barin-Le Guellec Chantal
Published: April 2022

Background.

Ischemia-related injury during the preimplantation period impacts kidney graft outcome. Evaluating these lesions by a noninvasive approach before transplantation could help us to understand graft injury mechanisms and identify potential biomarkers predictive of graft outcomes. This study aims to determine the metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in metabolomics variations.

Methods.

Kidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n = 35) using liquid chromatography coupled with tandem mass spectrometry and studied the transcriptional expression of tubular transporters on preimplantation biopsies (n = 26), both collected at the end of graft perfusion. We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome.

Results.

Seventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with a longer perfusion time and a decrease of 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R2 = 76%, Q2 = 54%, accuracy = 41%, and permutation test significant). Perfusion time did not affect the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics content nor transporter expression was predictive of graft outcome.

Conclusions.

Our results call for further studies, focusing on both intra- and extratissue metabolome, to investigate whether transporter alterations can explain the variations observed in the preimplantation period.
Dichotomous feedback: a signal sequestration-based feedback mechanism for biocontroller design
Authors: Sootla Aivar , Delalez Nicolas , Alexis Emmanouil , Norman Arthur , Steel Harrison , Wadhams George H. , Papachristodoulou Antonis
Published: April 2022

We introduce a new design framework for implementing negative feedback regulation in synthetic biology, which we term ‘dichotomous feedback’. Our approach is different from current methods, in that it sequesters existing fluxes in the process to be controlled, and in this way takes advantage of the process’s architecture to design the control law. This signal sequestration mechanism appears in many natural biological systems and can potentially be easier to realize than ‘molecular sequestration’ and other comparison motifs that are nowadays common in biomolecular feedback control design. The loop is closed by linking the strength of signal sequestration to the process output. Our feedback regulation mechanism is motivated by two-component signalling systems, where a second response regulator could be competing with the natural response regulator thus sequestering kinase activity. Here, dichotomous feedback is established by increasing the concentration of the second response regulator as the level of the output of the natural process increases. Extensive analysis demonstrates how this type of feedback shapes the signal response, attenuates intrinsic noise while increasing robustness and reducing crosstalk.
Stochastic modelling of bird flocks: accounting for the cohesiveness of collective motion
Authors: Reynolds Andy M. , McIvor Guillam E. , Thornton Alex , Yang Patricia , Ouellette Nicholas T.
Published: April 2022

Collective behaviour can be difficult to discern because it is not limited to animal aggregations such as flocks of birds and schools of fish wherein individuals spontaneously move in the same way despite the absence of leadership. Insect swarms are, for example, a form of collective behaviour, albeit one lacking the global order seen in bird flocks and fish schools. Their collective behaviour is evident in their emergent macroscopic properties. These properties are predicted by close relatives of Okubo's 1986 [
Adv. Biophys.
22
, 1–94. (
doi:10.1016/0065-227X(86)90003-1
)] stochastic model. Here, we argue that Okubo's stochastic model also encapsulates the cohesiveness mechanism at play in bird flocks, namely the fact that birds within a flock behave on average as if they are trapped in an elastic potential well. That is, each bird effectively behaves as if it is bound to the flock by a force that on average increases linearly as the distance from the flock centre increases. We uncover this key, but until now overlooked, feature of flocking in empirical data. This gives us a means of identifying what makes a given system collective. We show how the model can be extended to account for intrinsic velocity correlations and differentiated social relationships.
Dynamical robustness of complex networks subject to long-range connectivity
Authors: Majhi Soumen
Published: April 2022

In spite of a few attempts in understanding the dynamical robustness of complex networks, this extremely important subject of research is still in its dawn as compared to the other dynamical processes on networks. We hereby consider the concept of long-range interactions among the dynamical units of complex networks and demonstrate
for the first time
that such a characteristic can have noteworthy impacts on the dynamical robustness of networked systems, regardless of the underlying network topology. We present a comprehensive analysis of this phenomenon on top of diverse network architectures. Such dynamical damages being able to substantially affect the network performance, determining mechanisms that boost the robustness of networks becomes a fundamental question. In this work, we put forward a prescription based upon self-feedback that can efficiently resurrect global rhythmicity of complex networks composed of active and inactive dynamical units, and thus can enhance the network robustness. We have been able to delineate the whole proposition analytically while dealing with all

d

-path adjacency matrices, having an excellent agreement with the numerical results. For the numerical computations, we examine scale-free networks, Watts–Strogatz small-world model and also Erdös–Rényi random network, along with Landau–Stuart oscillators for casting the local dynamics.
Tracking scientific discovery of avian phylogenetic diversity over 250 years
Authors: Lum Deon , Rheindt Frank E. , Chisholm Ryan A.
Published: April 2022

Estimating the total number of species on Earth has been a longstanding pursuit. Models project anywhere between 2 and 10 million species, and discovery of new species continues to the present day. Despite this, we hypothesized that our current knowledge of phylogenetic diversity (PD) may be almost complete because new discoveries may be less phylogenetically distinct than past discoveries. Focusing on birds, which are well studied, we generated a robust phylogenetic tree for most extant species by combining existing published trees and calculated each discovery's marginal contribution to known PD since the first formal species descriptions in 1758. We found that PD contributions began to plateau in the early 1900s, about half a century earlier than species richness. Relative contributions of each phylogenetic order to known PD shifted over the first 150 years, with a growing contribution of the hyper-diverse perching birds (Passeriformes) in particular, but after the early 1900s this has remained relatively stable. Altogether, this suggests that our knowledge of the evolutionary history of extant birds is mostly complete, with few discoveries of high evolutionary novelty left to be made, and that conclusions of studies using avian phylogenies are likely to be robust to future species discoveries.
Why were Twitter Users Obsessed with Vitamin D during the first year of the pandemic?
Authors: Mavroeidi Alexandra , Innes Ryan , Miyake Esperanza , Pennington Diane
Published: April 2022

The aim of this study was to explore how the relationship between vitamin D and COVID-19 has been represented on the social media site Twitter. NCapture was used to collect textual Tweets on a weekly basis for three months during the pandemic. In total, 21,140 Tweets containing the keywords “vitamin D” and “COVID” were collected and imported to NVivo12. An inductive thematic analysis was carried out on the Tweets collected on the first (12/2/2021) and last week (21/5/2021) of the recording period to identify themes and subthemes. Quality control of the coding was conducted on a sample of the dataset (20%). Data were also compared to the “ground truth” to explore the accuracy of media outputs. The four main themes identified were “association of vitamin D with COVID-19”, “politically informed views”, “vitamin D deficiency” and “vitamin D sources”. When compared to the ground truth, the majority of information relating to the key findings was ‘incorrect’ for all of the findings. This study contributes to the area of research by highlighting the extent of the issue social media sites face with health-related misinformation. In the context of COVID-19, it is important that sites such as Twitter improve their existing misinformation policies, as misinformation can be detrimental in disease prevention.
How did the COVID-19 Pandemic impact self-reported cancer screening rates in 12 Midwestern states?
Authors: Semprini Jason
Published: April 2022

Objective

In the early months of the COVID-19 pandemic, the U.S. healthcare system reallocated resources to emergency response and mitigation. This reallocation impacted essential healthcare services, including cancer screenings.

Methods

To examine how the pandemic impacted cancer screenings at the population-level, this study analyzes 2018 and 2020 Behavioral Risk Factor Surveillance System (BRFSS) data to estimate the change in the proportion of eligible adults reporting a recent cancer screen (mammogram, pap smear, colon/sigmoidoscopy, blood stool test). All analyses accounted for response rates and sampling weights, and explored differences by gender and region across 12 Midwestern states.

Results

We found that the proportion of adult women completing a mammogram declined across all states (−0.9% to -18.1%). The change in colon/sigmoidoscopies, pap smears, and blood stool tests were mixed, ranging from a 9.7% decline in pap smears to a 7.1% increase in blood stool tests. Declines varied considerably between states and within states by gender or metro/urban/rural status.

Conclusions

The COVID-19 pandemic led to delayed breast, cervical, and colorectal cancer detection services. Policymakers should aim to advance cancer control efforts by implementing targeted screening initiatives.
Functional Magnetic Resonance Imaging of the amygdala and subregions at 3 Tesla: A scoping review protocol
Authors: Foster Sheryl L. , Breukelaar Isabella A. , Ekanayake Kanchana , Lewis Sarah , Korgaonkar Mayuresh S.
Published: April 2022

Background

Functional Magnetic Resonance Imaging (fMRI) is a widely accepted and utilised method of investigating neural activation within the brain. There has been increasing awareness and understanding in the field of neuropsychology over the last 10-15 years that the amygdala plays an important role in many mental health conditions. Functional connectivity (FC) of the amygdala with other parts of the brain is well-documented in the literature; however the role of the amygdala and its reported connections is still not well understood and this can be attributed, in part, to its very small size. It is challenging to achieve adequate spatial resolution to visualise amygdala activation using 3T MRI systems that are in widespread use for this type of clinical research. Optimisation of protocols for improved data accuracy and reproducibility may potentially lead to standardisation and subsequent advancements in overall image quality in this field.

Methods

The protocol for this scoping review was developed in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and registered with the Open Science Framework (OSF). A literature search of five databases (Medline, Embase, Web of Science, Google Scholar and Scopus) will be undertaken using a refined search strategy; peer-reviewed publications identified as being relevant will then be imported into Covidence software for abstract screening and data extraction by two reviewers working independently. The quantitative findings will be tabulated to provide an overview of the current methodologies for comparison. This will be accompanied by a narrative report summarising the extracted data in relation to the stated research questions.

Discussion

The objective of this scoping review is to identify and map the range of existing protocols used in fMRI for imaging the activation and FC patterns of the amygdala at 3 Tesla. This will be achieved by collating and presenting quantitative data relating to protocol parameter choices as well as other qualitative aspects of the data acquisition process.

Registration

Open Science Framework (OSF) – Registration type: OSF Pre-registration

Registration: https://osf.io/e3c28, DOI: 10.17605/OSF.IO/KW58P
Comprehensive analyses reveal the impacts of vaccination status and physiological variables in early infection on viral persistence in COVID-19 patients: a retrospective single-center cohort study
Authors: Tian Xiangxiang , Zhang Yifan , Wang Wanhai , Fang Fang , Zhang Wenhong , Wan Yanmin , Zhu Zhaoqin
Published: April 2022

BACKGROUND

Viral persistence is a crucial factor that influences the communicability of SARS-CoV-2 infection. However, the impacts of vaccination status and physiological variables on viral RNA shedding have not been adequately clarified.

METHODS

In this study, we retrospectively collected the clinical records of 377 hospitalized COVID-19 patients, which contained unvaccinated patients and patients received two doses of an inactivated vaccine or an mRNA vaccine. Firstly, we analyzed the impacts of vaccination on disease severity and viral RNA persistence. Next, to clarify the impacts of physiological variables on viral RNA shedding in COVID-19 patients, we retrieved 49 laboratory variables and analyzed their correlations with the duration of viral RNA shedding. Finally, we established a multivariate regression model to predict the duration of viral RNA shedding.

RESULTS

Our results showed that both inactivated and mRNA vaccines significantly reduced the rate of moderate cases, while the vaccine related shortening of viral RNA shedding were only observed in moderate patients. Correlation analysis showed that 10 significant laboratory variables were shared by the unvaccinated mild patients and mild patients inoculated with an inactivated vaccine, but not by the mild patients inoculated with an mRNA vaccine. Moreover, we demonstrated that a multivariate regression model established based on the variables correlating with viral persistence in unvaccinated mild patients could predict the duration of viral shedding for all groups of patients.

CONCLUSIONS

Vaccination contributed limitedly to the clearance viral RNA in COVID-19 patients. While, laboratory variables in early infection could predict the persistence of viral RNA.
The Cerebellum Plays More Than One Role in the Dysregulation of Appetite: Review of Structural Evidence from Typical and Eating Disorder Populations
Authors: Sader Michelle , Waiter Gordon D. , Williams Justin H. G.
Published: April 2022

Objective

Dysregulated appetite control is characteristic of anorexia nervosa (AN), bulimia nervosa (BN) and obesity (OB). Studies using a broad range of methods suggest the cerebellum plays an important role in aspects of weight and appetite control, and is implicated in both AN and OB by reports of aberrant grey matter volume (GMV) compared to non-clinical populations. As functions of the cerebellum are anatomically segregated, specific localization of aberrant anatomy may indicate the mechanisms of its relationship with weight and appetite in different states. We sought to determine if there were consistencies in regions of cerebellar GMV changes in AN/BN and OB, as well as across normative variation.

Method

Systematic review and meta-analysis using GingerALE.

Results

Twenty-six publications were identified as either case-control studies (nOB=277; nAN/BN=510) or regressed weight from normative (NOR) data against brain volume (total n=3,830). AN/BN and OB analyses both showed consistently decreased GMV within Crus I and Lobule VI, but volume reduction was bilateral for AN/BN and unilateral for OB. Analysis of the normative dataset identified a cluster in right posterior lobe which overlapped with AN/BN cerebellar reduction. Sensitivity analyses indicated robust repeatability for NOR and AN/BN cohorts, but found OB-specific heterogeneity.

Discussion

Findings suggest that more than one area of the cerebellum is involved in control of eating behaviour and is differentially affected in normal variation and pathological conditions. Specifically, we hypothesise an association with sensorimotor and emotional learning via Lobule VI in AN/BN, and executive function via Crus I in OB.
Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada: Test-Negative Design Study
Authors: Grewal Ramandip , Kitchen Sophie A , Nguyen Lena , Buchan Sarah A , Wilson Sarah E , Costa Andrew P , Kwong Jeffrey C
Published: April 2022

Background

As of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine ≥84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant.

Methods

We used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged ≥60 years who were tested for SARS-CoV-2 between December 30, 2021 and April 27, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death).

Results

We included 13,654 Omicron cases and 205,862 test-negative controls. The marginal effectiveness of a fourth dose (with 95% of fourth dose vaccine recipients receiving mRNA-1273) ≥7 days after vaccination versus a third dose received ≥84 days prior was 19% (95% Confidence Interval [CI], 12-26%) against infection, 31% (95%CI, 20-41%) against symptomatic infection, and 40% (95%CI, 24-52%) against severe outcomes. VE (compared to an unvaccinated group) increased with each additional dose, and for a fourth dose was 49% (95%CI, 43-54%), 69% (95%CI, 61-76%), and 86% (95%CI, 81-90%), against infection, symptomatic infection, and severe outcomes, respectively.

Conclusions

Our findings suggest that compared to a third dose received ≥84 days ago, a fourth dose improved protection against infection, symptomatic infection, and severe outcomes caused by Omicron among long-term care residents. Compared to unvaccinated individuals, fourth doses provide strong protection against severe outcomes, but the duration of protection remains unknown.
Urinary tract infections in children: building a causal model-based decision support tool for diagnosis with domain knowledge and prospective data
Authors: Ramsay Jessica A. , Mascaro Steven , Campbell Anita J. , Foley David , Mace Ariel O. , Ingram Paul , Borland Meredith L. , Blyth Christopher , Larkins Nicholas G. , Robertson Tim , Williams Phoebe , Snelling Tom , Wu Yue
Published: April 2022

Background

Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support.

Methods

We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods.

Results

We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting E.coli culture results, with a mean AUROC of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios.

Conclusion

Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.
Clonal diversity determines persistence of SARS-CoV-2 epitope-specific T cell response
Authors: Zornikova Ksenia V. , Khmelevskaya Alexandra , Sheetikov Savely A. , Kiryukhin Dmitry O. , Shcherbakova Olga V. , Titov Aleksei , Zvyagin Ivan V. , Efimov Grigory A.
Published: April 2022

T cells play a pivotal role in reducing disease severity during SARS-CoV-2 infection and formation of long-term immune memory. We studied 50 COVID-19 convalescent patients and found that T cell response was induced more frequently and persisted longer than circulating antibodies. To identify epitopes that give rise to long-lived T cell memory, we performed ex vivo T cell expansion, MHC-tetramer cell-sorting, and high-throughput sequencing. We identified 756 clonotypes specific to nine known CD8+ T cell receptor (TCR) epitopes. Some epitopes were recognized by highly similar public clonotypes with restricted variable and joining segment usage. Receptors for other epitopes were extremely diverse, suggesting alternative modes of recognition. We also tracked persistence of epitope-specific response and individual clonotypes for a median of eight months after infection. The number of recognized epitopes per patient and quantity of epitope-specific clonotypes decreased over time, but the studied epitopes were characterized by uneven decline in the number of specific T cells. Epitopes with more clonally diverse TCR repertoires induced more pronounced and durable responses. In contrast, the abundance of specific clonotypes in peripheral circulation had no influence on their persistence. Our study demonstrates the durability of SARS-CoV-2-specific CD8+ memory, and offers important implications for vaccine design.
A comparative analysis of pediatric mental health-related emergency department utilization in Montréal, Canada before and during the COVID-19 pandemic
Authors: Beaudry Gabrielle , Drouin Olivier , Gravel Jocelyn , Smyrnova Anna , Bender Andreas , Orri Massimiliano , Geoffroy Marie-Claude , Chadi Nicholas
Published: April 2022

Background

Reports on longitudinal trends in mental health–related (MHR) emergency department (ED) utilization spanning the pre- and post-pandemic periods are lacking, along with evidence comparing healthcare services utilization by sociodemographic subgroups. The aim of this study was to evaluate COVID-19–associated changes in MHR ED utilization among youth overall and by age, sex, and socioeconomic status (SES).

Methods

This retrospective cross-sectional study analyzed MHR ED utilization before and during the COVID-19 pandemic at a large urban pediatric tertiary care hospital in Montréal, Canada. All ED visits for children (5–11 years) and adolescents (12–17 years) between April 1, 2016 and November 30, 2021 were included. The main outcome was the monthly count of MHR ED visits. Pre-pandemic and pandemic periods were compared using an interrupted time series design. The effect of seasonality (in months), age (in years), sex (male or female), and SES (low, average, high) were compared using a generalized additive model.

Results

There were a total of 437,147 ED visits (204,215 unique patients) during the five-year study period of which 9,748 (5.8%) were MHR visits (7,686 unique patients). We observed an increase of 69% (95% CI, +53% to +85%; p = .001) in the mean monthly count of MHR ED visits during the pandemic period, which remained significant after adjusting for seasonality (44% increase, 95% CI, +38% to +51%; p = .001). The chance of presenting for a MHR ED visit increased non-linearly with age. There were increased odds of presenting for a MHR ED visit among girls between the pre-pandemic and pandemic periods (OR 1.42, 95% CI 1.29–1.56). No difference by SES group during and before the COVID-19 pandemic was found (OR 1.01, 95% CI 0.89–1.15 [low]; OR 1.09, 95% CI 0.96–1.25 [high]).

Conclusions

Our study shows important increases in MHR ED utilization among youth, and especially among girls, during the first 20 months of the COVID-19 pandemic, highlighting the need for sustained, targeted and scalable mental health resources to support youth mental health during the current and future crises.
Highly parallelized laboratory evolution of wine yeasts for enhanced metabolic phenotypes
Authors: Ghiaci Payam , Jouhten Paula , Martyushenko Nikolay , Roca-Mesa Helena , Vázquez Jennifer , Konstantinidis Dimitrios , Stenberg Simon , Andrejev Sergej , Grkovska Kristina , Mas Albert , Beltran Gemma , Almaas Eivind , Patil Kiran R. , Warringer Jonas
Published: April 2022

Adaptive Laboratory Evolution (ALE) of microbes can improve the efficiency of sustainable industrial processes important to the global economy, but chance and genetic background effects often lead to suboptimal outcomes. Here we report an ALE platform to circumvent these flaws through parallelized clonal evolution at an unprecedented scale. Using this platform, we clonally evolved 10^4 yeast populations in parallel from many strains for eight desired wine production traits. Expansions of both ALE replicates and lineage numbers broadened the evolutionary search spectrum and increased the chances of evolving improved wine yeasts unencumbered by unwanted side effects. ALE gains often coincided with distinct aneuploidies and the emergence of semi-predictable side effects that were characteristic of each selection niche. Many high performing ALE strains retained their desired traits upon transfer to industrial conditions and produced high quality wine. Overall, our ALE platform brings evolutionary engineering into the realm of high throughput science and opens opportunities for rapidly optimizing microbes for use in many industrial sectors which otherwise could take many years to accomplish.
US-align: Universal Structure Alignments of Proteins, Nucleic Acids, and Macromolecular Complexes
Authors: Zhang Chengxin , Shine Morgan , Pyle Anna Marie , Zhang Yang
Published: April 2022

Structure comparison and alignment are of fundamental importance in structural biology studies. We developed the first universal platform, US-align, to uniformly align monomer and complex structures of different macromolecules (proteins, RNAs, and DNAs). The pipeline is built on a uniform TM-score objective function coupled with a heuristic alignment searching algorithm. Large-scale benchmarks demonstrated significant advantages of US-align over state-of-the-art methods in pairwise and multiple structure alignments of different molecules. Detailed analyses showed that the major advantage of US-align lies in the extensive optimization of the unified objective function powered by efficient heuristic search iterations, which significantly improve the accuracy and speed of the structural alignment process. Meanwhile, the universal protocol fusing different molecular and structural types helps facilitate the heterogeneous oligomer structure comparison and template-based protein-protein and protein-RNA/DNA docking.
Roles of Clamp Closing and Allosteric Effects of Discriminator and Upstream Interactions on Downstream Elements in Stabilizing an E. coli RNA Polymerase-Promoter Open Complex
Authors: Wang Hao-Che , Stronek Krysta , Record M. Thomas
Published: April 2022

E. coli RNA polymerase (α2ββ’ωσ70) forms stable open complexes (OC) at λPR and T7A1 promoters at 37 °C at similar rates but with very different lifetimes. To probe the origins of these differences, we determine OC lifetimes for full-length (FL) and downstream-truncated (DT) λPR and T7A1 promoter variants with eight combinations of discriminators and upstream elements. We find the discriminator is the major determinant of OC lifetime, while upstream elements modulate the discriminator effect. The very different lifetimes of these stable OC arise primarily from differences in , the free energy change for converting I2 (the initial open intermediate) to stable OC. is twice as favorable for λPR-discriminator variants as for T7A1-discriminator variants. Truncation at +6 (DT+6) eliminates most differences in , destabilizing λPR-discriminator variants without affecting T7A1-discriminator variants. All DT+6 OC are much more stable and longer-lived than I2. Urea greatly destabilizes OC, primarily affecting RNAP interactions with +6 and upstream DNA. From these findings we deduce that stabilization of I2 involves closing the β’-clamp with extensive coupled folding to contact the region of promoter DNA from the transcription start-site to +6. Lifetime differences between DT+6, DT+12 and FL promoters allow dissection of contributions to OC stability from interactions of regions of the downstream duplex with downstream mobile elements (DME; β-lobe, β’–clamp, β’-jaw). We propose an allosteric network by which differences in discriminator and −10 sequence are sensed by σ1.2 and β-gate loop and transmitted to σ1.1 and β-lobe to affect DME-duplex interactions that determine OC lifetime.
Green Lacewing Chrysoperla rufilabris (Neuroptera: Chrysopidae) is a potential biological agent for controlling crapemyrtle bark scale (Hemiptera: Eriococcidae)
Authors: Wu Bin , Xie Runshi , Gu Mengmeng , Qin Hongmin
Published: April 2022

Crapemyrtle bark scale (CMBS; Acanthococcus lagerstroemiae), an invasive sap-sucking hemipteran, has spread across 16 U.S. states. Infestation of CMBS negatively impacts the flowering of crapemyrtles and reduces the aesthetic quality of ornamental plants. The widespread use of soil-applied neonicotinoid insecticides to repress the CMBS infestation could threaten important beneficial insects; therefore, using natural enemies to control CMBS is greatly needed. This study evaluated larval green lacewing (Chrysoperla rufilabris) as a biocontrol agent of CMBS. Predatory behavior of the larval C. rufilabris upon CMBS was documented under a stereomicroscope using infested crapemyrtle samples collected from different locations in College Station. Predation potential of C. rufilabris upon CMBS eggs and foraging performance using Y-maze assay were both investigated in laboratory conditions. Results confirmed that larval C. rufilabris preyed on CMBS nymphs, eggs, and adult females. The evaluation of predation potential results showed that the number of CMBS eggs consumed in 24 hours by 3rd instar C. rufilabris (176.4 ±6.9) was significantly higher than by 2nd instar (151.5±6.6) and by 1st instar (11.8±1.3). The foraging performance results showed that larval C. rufilabris could target CMBS under dark, indicating that some cues associated with olfactory response were likely involved when preying on CMBS. This study is the first report that validated C. rufilabris as a natural predator of CMBS and its potential as a biological agent to control CMBS. Future investigation about the olfactory response of larval C. rufilabris to CMBS would benefit the development of environmental-friendly strategies to control CMBS spread.
The field of protein function prediction as viewed by different domain scientists
Authors: Ramola Rashika , Friedberg Iddo , Radivojac Predrag
Published: April 2022

Experimental biologists, biocurators, and computational biologists all play a role in characterizing a protein’s function. The discovery of protein function in the laboratory by experimental scientists is the foundation of our knowledge about proteins. Experimental findings are compiled in knowledge-bases by biocurators to provide standardized, readily accessible, and computationally amenable information. Computational biologists train their methods using these data to predict protein function and guide subsequent experiments. To understand the state of affairs in this ecosystem, centered here around protein function prediction, we surveyed scientists from these three constituent communities. Our objective was to understand their views on this research area, including the importance of the problem, the usefulness of the methods, the bottlenecks in the field, and the level of interaction between the communities. We show that the three core communities have common but also idiosyncratic perspectives on the field. Most strikingly, experimentalists rarely use modern prediction software, but when presented with predictions, report many to be surprising and useful. Ontologies appear to be highly valued by biocurators, less so by experimentalists and computational biologists, yet controlled vocabularies bridge the communities and simplify the prediction task. Additionally, many software tools are not readily accessible and the predictions presented to the users can be broad and uninformative. To meet both the social and technical challenges in the field, a more productive and meaningful interaction between members of the core communities is necessary.
Localization, induction, and cellular effects of tau-phospho-threonine 217
Authors: Rajbanshi Binita , Mandell James W. , Bloom George S.
Published: April 2022

Introduction

Tau phosphorylation at T217 is a promising AD biomarker, but its functional consequences were unknown.

Methods

Human brain and cultured mouse neurons were analyzed by immunoblotting and immunofluorescence for total tau, taupT217, taupT181, taupT231 and taupS396/pS404. dSTORM super resolution microscopy was used to localize taupT217 in cultured neurons. EGFP-tau was expressed in fibroblasts as wild type and T217E pseudo-phosphorylated tau, and fluorescence recovery after photobleaching (FRAP) reported tau turnover rates on microtubules.

Results

In brain, taupT217 appears in neurons at Braak stages I-II, becomes more prevalent later and co-localizes partially with other phospho-tau epitopes. In cultured neurons taupT217, is increased by extracellular tau oligomers (xcTauOs), and is associated with developing post-synaptic sites. FRAP recovery was fastest for EGFP-tauT217E.

Conclusion

TaupT217 increases in brain as AD progresses and is induced by xcTauOs. Post-synaptic taupT217 suggests a role for T217 phosphorylation in synapse impairment. T217 phosphorylation reduces tau’s affinity for microtubules.
Sequence characterization of the complete chloroplast genome of Eupatorium fortunei
Authors: Yan Kan , Ran Juan , Bao Songming , Zhang Nai , Zhao Wei , Ma Yanni , Ishimwe Marie Angela
Published: April 2022

Eupatorium fortunei has been utilized as herbal medicine to cure various diseases in various regions of the world especially China, Korea, and other Asian countries. The available literature shows Eupatorium fortunei contain anti-metastatic, anti-angiogenic, anti-bacterial, and anti-oxidant, along with compounds to cure human cancer. In present study, Eupatorium fortunei was used as an experimental material, and its genome was sequenced based on high-throughput sequencing technology. We assembled the complete chloroplast genome of Eupatorium fortunei and obtained NCBI accession number (OK545755). We analyzed chloroplast genome structure of Eupatorium fortunei and systematic analysis was conducted, including the size of the entire genome sequence, genome volume, large single-copy (LSC), small single-copy (SSC), inverted repeat region (IR)-LSC/SSC boundaries, etc. The obtained results showed that chloroplast genome of Eupatorium fortunei is a typical tetrad structure with a total length of 152,401 bp and a sum of 133 annotated genes, including eight ribosomal RNA (rRNA)-encoding genes, 37 transfer RNA (tRNA)-encoding genes, 87 protein-encoding genes, and one pseudo-gene. A sum of 29 Single Sequence Repeats (SSR)s were identified for mono-nucleotide, di-nucleotide and tri-nucleotide microsatellites with mono-nucleotides in majority. The phylogenetic analysis revealed that Eupatorium fortunei is more closely related to Litothamnus nitidus and belongs to the same branch. The genome assembly and analysis of the chloroplast genome of Eupatorium fortunei provides more accurate evidence for further taxonomic identification and localization of Asteraceae/Compositae plant.