bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution and genomic basis of the plant-penetrating ovipositor: a key morphological trait in herbivorous Drosophilidae
Authors: Peláez Julianne N. , Gloss Andrew D. , Ray Julianne F. , Chaturvedi Samridhi , Haji Diler , Charboneau Joseph L. M. , Verster Kirsten I. , Whiteman Noah K.
Published: November 2022

Herbivorous insects are extraordinarily diverse, yet are found in only one-third of insect orders. This skew may result from barriers to plant colonization, coupled with phylogenetic constraint on plant-colonizing adaptations. The plant-penetrating ovipositor, however, is one trait that surmounts host plant physical defences and may be evolutionarily labile. Ovipositors densely lined with hard bristles have evolved repeatedly in herbivorous lineages, including within the Drosophilidae. However, the evolution and genetic basis of this innovation has not been well studied. Here, we focused on the evolution of this trait inScaptomyza, a genus sister to HawaiianDrosophila, that contains a herbivorous clade. Our phylogenetic approach revealed that ovipositor bristle number increased as herbivory evolved in theScaptomyzalineage. Through a genome-wide association study, we then dissected the genomic architecture of variation in ovipositor bristle number withinS. flava. Top-associated variants were enriched for transcriptional repressors, and the strongest associations included genes contributing to peripheral nervous system development. Individual genotyping supported the association at a variant upstream ofGαi, a neural development gene, contributing to a gain of 0.58 bristles/major allele. These results suggest that regulatory variation involving conserved developmental genes contributes to this key morphological trait involved in plant colonization.
Patient Knowledge and Perception about Antibiotics in Community Pharmacy
Authors: Chand Priya Pritika
Published: November 2022

Introduction

The emergence and spread of antibiotic resistance is on the rise around the world, posing a serious threat to public health in the twenty-first century. Several research conducted in various nations have found that the general public plays a pivotal role in the increase and spread of antibiotic resistance. The present study was designed to determine the patient knowledge and perception about antibiotics in community pharmacy.

Methods

200 participants were recruited by convenience sampling from patients visiting the pharmacy with a prescription for antibiotics and those fulfilling the eligibility criteria for this research. A structured questionnaire was used to access the patient’s knowledge and perception regarding antibiotics. Data collected were analyzed using Microsoft excel and Epi Info Software version 7 which was used to determine predictors of low antibiotic knowledge.

Results

Overall, 200 questionnaires were analyzed. 70.5% of the respondents had an intermediate level of knowledge. Misconceptions that antibiotics would work on viral infections were reported. 82% of the respondents could correctly identify that misuse of antibiotics can cause antibiotic resistance. The age, educational level, and whether or not the participants’ were studying or working in medical field were found to be important predictors of antibiotic knowledge.

Conclusion

The findings of this study demonstrate that the public surveyed has misunderstandings and a lack of knowledge in some crucial aspects of prudent antibiotic use. Also, negative attitudes regarding rational use of antibiotics were evident. Educational interventions are required to promote rationale use of antibiotics among the general public.
Influences of race and clinical variables on psychiatric genetic research participation: Results from a schizophrenia sample
Authors: Xavier Rose Mary , Shanavas Yuktha , Britt Brian M. , George Wales T.
Published: November 2022

Objective

Advances in genetics has led to a better understanding of both genetic and environmental contributions to psychiatric mental health disorders. But psychiatric genetics research is predominantly Eurocentric, and individuals of non-European ancestry continue to be significantly underrepresented in research studies. The objective of this study was to examine factors associated with genetic study participation in a schizophrenia sample.

Methods

The study sample was extracted from the Clinical Antipsychotics Trial of Intervention Effectiveness (CATIE) schizophrenia study which enrolled patients with schizophrenia between the ages of 18-65 and incorporated an optional genetic sub-study. Using regression models, we examined sociodemographic and clinical factors that were independently associated with participation in the genetic sub-study.

Results

The genetic sub-study had a lower proportion of Black (30% in genetic vs 40% in CATIE overall) and Other race (4% vs 6%) participants. Severe psychopathology symptoms (odds ratio [OR]=0.78, p=0.004) and better reasoning scores (OR = 1.16,p= 0.036) influenced the odds of genetic study participation. Compared to Black participants, White participants were significantly more likely to participate in the genetic sub-study (OR=1.43, p=0.009)

Conclusion

Race and clinical variables significantly impact genetic study participation of individuals with schizophrenia. Future studies should examine the interactive effects of race and clinical variables for a nuanced understanding of how individuals diagnosed with severe psychiatric illnesses choose to participate in genetics studies.
Isoniazid preventive therapy completion and factors associated with non-completion among patients on antiretroviral therapy at Kisenyi Health Centre IV, Kampala, Uganda
Authors: Amanya Ian , Muhoozi Michael , Aruhomukama Dickson , Ssebagereka Anthony , Mugambe Richard
Published: November 2022

Background

Isoniazid preventive therapy (IPT) is given to HIV patients to reduce the risk of active tuberculosis (TB). However, treatment completion remains sub-optimal among those that are initiated. This study aimed to determine the completion level of IPT and the factors associated with non-completion among people on antiretroviral therapy (ART) at Kisenyi Health Center IV in Kampala, Uganda.

Methods

A facility-based retrospective cohort study utilizing routinely collected data of 341 randomly selected HIV patients initiated on IPT was conducted. Data extracted from the registers were used to determine the IPT completion. Modified Poisson regression with robust error variances was used to determine the associated factors of IPT non-completion while in-depth interviews were conducted to explore barriers to IPT completion from the patient’s perspective.

Results

A total of 341 patients who started on isoniazid (INH) were retrospectively followed up, with 69% (236/341) being female. Overall IPT completion was at 83%. Multivariable analysis revealed the prevalence of IPT non-completion among males was 2.24 times the prevalence among females [aPR 2.24, 95% CI: 1.40-3.58]. The prevalence of IPT non-completion among patients with a non-suppressed HIV viral load was 3.00 times the prevalence among those with a suppressed HIV viral load [aPR 3.00, 95% CI: 1.44-6.65]. Patients who were married/cohabiting had a 69% lower prevalence of IPT non-completion compared to those who were single [aPR 0.31, 95% CI: 0.17-0.55]. Lack of IPT-related health education, pill burden, distance to the health facility, and patient relocation were reported as the barriers to IPT completion.

Conclusion

IPT completion was found to be at 83% among the cohort studied. However, lower completion levels persist among males and HIV virally non-suppressed patients. Lack of IPT-related health education, pill burden, distance to the health facility, and patient relocation were reported as the barriers to IPT completion. Interventions that target these groups of people need to be intensified.
Mutations in the tail domain of the neurofilament heavy chain gene increase the risk of amyotrophic lateral sclerosis
Authors: Marriott Heather , Spargo Thomas P. , Khleifat Ahmad Al , Fogh Isabella ,   Project MinE ALS Sequencing Consortium, Andersen Peter M , Başak Nazli A. , Cooper-Knock Johnathan , Corcia Philippe , Couratier Philippe , de Carvalho Mamede , Drory Vivian , Glass Jonathan D. , Gotkine Marc , Hardiman Orla , Landers John E. , McLaughlin Russell , Mora Pardina Jesús S. , Morrison Karen E. , Pinto Susana , Povedano Monica , Shaw Christopher E. , Shaw Pamela J. , Silani Vincenzo , Ticozzi Nicola , van Damme Philip , van den Berg Leonard H. , Vourc’h Patrick , Weber Markus , Veldink Jan H. , Dobson Richard J. , Schwab Patrick , Al-Chalabi Ammar , Iacoangeli Alfredo
Published: November 2022

Objective

Genetic variation in the neurofilament heavy chain gene (NEFH) has been convincingly linked to the pathogenesis of multiple neurodegenerative diseases, however, the relationship betweenNEFHmutations and ALS susceptibility has not been robustly explored. We therefore wanted to determine if genetic variants inNEFHmodify ALS risk.

Methods

We performed fixed and random effects model meta-analysis of published case-control studies reportingNEFHvariant frequencies using next-generation sequencing, microarray or PCR-based approaches. Comprehensive screening and rare variant burden analysis ofNEFHvariation in the Project MinE ALS whole-genome sequencing data set was also conducted.

Results

We identified 12 case-control studies that reportedNEFHvariant frequencies, for a total of 9,496 samples (4,527 ALS cases and 4,969 controls). Fixed effects meta-analysis found that rare (MAF<1%) missense variants in the tail domain ofNEFHincrease ALS risk (OR 4.56, 95% CI 2.13-9.72, p<0.0001). A total of 591 rareNEFHvariants, mostly novel (78.2%), were found in the Project MinE dataset (8,903 samples: 6,469 cases and 2,434 controls). Burden analysis showed ultra-rare (MAF <0.1%) pathogenic missense variants in the tail domain are associated with ALS (OR 1.94, 95% CI 0.86-4.37, Madsen-Browning p=0.039), replicating and confirming the meta-analysis finding. High-frequency rare (MAF 0.1-1%) tail in-frame deletions also confer susceptibility to ALS (OR 1.18, 95% CI 0.67-2.07, SKAT-O p=0.03), which supports previous findings.

Interpretation

This study shows thatNEFHtail domain variants are a risk factor of ALS and supports the inclusion of missense and in-frame deletionNEFHvariants in ALS genetic screening panels.
Antibody response durability following three-dose COVID-19 vaccination in people with HIV receiving suppressive ART
Authors: Lapointe Hope R. , Mwimanzi Francis , Cheung Peter K. , Sang Yurou , Yaseen Fatima , Speckmaier Sarah , Barad Evan , Moran-Garcia Nadia , Datwani Sneha , Duncan Maggie C. , Kalikawe Rebecca , Ennis Siobhan , Young Landon , Ganase Bruce , Omondi F. Harrison , Umviligihozo Gisele , Dong Winnie , Toy Junine , Sereda Paul , Burns Laura , Costiniuk Cecilia T. , Cooper Curtis , Anis Aslam H. , Leung Victor , Holmes Daniel , DeMarco Mari L. , Simons Janet , Hedgcock Malcolm , Prystajecky Natalie , Lowe Christopher F. , Romney Marc G. , Barrios Rolando , Guillemi Silvia , Brumme Chanson J. , Montaner Julio S.G. , Hull Mark , Harris Marianne , Niikura Masahiro , Brockman Mark A. , Brumme Zabrina L.
Published: November 2022

Background

Limited data exist regarding longer-term antibody responses following three-dose COVID-19 vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-(WT), Omicron BA.1- and Omicron BA.5-specific responses up to six months post-third dose in 64 PLWH and 117 controls who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time.

Design

Longitudinal observational cohort.

Methods

We quantified WT- and Omicron-specific Anti-Spike receptor-binding domain IgG concentrations, ACE2 displacement activities and live virus neutralization at one, three and six months post-third vaccine dose.

Results

Third doses boosted all antibody measures above two-dose levels, but BA.1-specific responses remained significantly lower than WT-specific ones, with BA.5-specific responses lower still. Serum IgG concentrations declined at similar rates in COVID-19-naive PLWH and controls post-third dose (median WT- and BA.1-specific half-lives were between 66-74 days for both groups). Antibody function also declined significantly yet comparably between groups: six months post-third dose, BA.1-specific neutralization was undetectable in >80% of COVID-19 naive PLWH and >90% of controls. Breakthrough SARS-CoV-2 infection boosted antibody concentrations and function significantly above vaccine-induced levels in both PLWH and controls, though BA.5-specific neutralization remained significantly poorer than BA.1 even post-breakthrough.

Conclusions

Following three-dose COVID-19 vaccination, antibody response durability in PLWH receiving ART is comparable to controls. PLWH also mounted strong responses to breakthrough infection. Due to temporal response declines however, COVID-19-naive individuals, regardless of HIV status, would benefit from a fourth dose within 6 months of their third.
Sexual abuse and harsh punishment in early life are associated with more obsessive-compulsive symptoms in adulthood: An online survey
Authors: Król M. , Cao Y. , Kirkham E.J.
Published: November 2022

Introduction

Childhood and adolescent maltreatment (CAM) is associated with many psychiatric conditions, including obsessive-compulsive disorder (OCD). However, it remains unclear whether the severity of OCD symptoms vary according to the type of stress encountered in early life.

Method

A sample of 345 participants (174 of whom had OCD) completed online measures of CAM (Child Abuse and Trauma Scale; CATS), OCD (Obsessive-Compulsive Inventory-Revised; OCI-R), anxiety, and depression (Hospital Anxiety and Depression Scale; HADS).

Regression analysis was used to examine associations between OCD symptoms and four subtypes of CAM: emotional abuse, neglect/home environment, punishment, and sexual abuse. Anxiety and depression were included as control variables.

Results

Higher levels of sexual abuse and punishment were significantly associated with more OCD symptoms irrespective of scores on measures of anxiety and depression. Emotional abuse and neglect/home environment were not significantly associated with OCD symptoms.

Discussion

These findings highlight the prospect of a specific role for harsh punishment and sexual abuse in the development of OCD. Future studies should examine this possibility using longitudinal designs. Health professionals should be mindful that individuals with OCD may have experienced heightened levels of CAM, especially in the domains of punishment and sexual abuse.
Large-scale Analyses of CAV1 and CAV2 Suggest Their Expression is Higher in Post-mortem ALS Brain Tissue and Affects Survival
Authors: Adey Brett N , Cooper-Knock Johnathan , Khleifat Ahmad Al , Fogh Isabella , van Damme Philip , Corcia Philippe , Couratier Philippe , Hardiman Orla , McLaughlin Russell , Gotkine Marc , Drory Vivian , Silani Vincenzo , Ticozzi Nicola , Veldink Jan H. , van den Berg Leonard H. , de Carvalho Mamede , Pinto Susana , Mora Pardina Jesus S. , Povedano Monica , Andersen Peter M. , Weber Markus , Başak Nazli A. , Shaw Christopher E , Shaw Pamela J. , Morrison Karen E. , Landers John E. , Glass Jonathan D. , Vourc’h Patrick , Dobson Richard JB , Breen Gerome , Al-Chalabi Ammar , Jones Ashley R , Iacoangeli Alfredo
Published: November 2022

Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in ALS. Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Using large ALS whole-genome sequencing andpost-mortemRNA sequencing datasets (5987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across variouspost-mortembrain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion.
Effects of Different Mask Policies in 2020: A Comparative Analysis
Authors: Liu Xue-Jing
Published: November 2022

The research around the public’s usage of masks to prevent the spread of COVID-19 is developing quickly. In this work, we analyzed data from 50 nations to assess the long-term effectiveness of mask policies with different levels using the Poisson regression model and generalized linear mixed model. Over the long term, stricter obligatory mask regulations were linked to more stable patterns and slower increases in Covid-19 case occurrences. The mitigation of disease transmission by mask policies was shown to have substantial major impacts throughout the entire year of 2020, whereas the incidence of illness displays increasing trends over time under various policies. When compared to no mask policy deployment, mask policies might reduce incidence growth by 13.5% to 17.8%, although the incidence under every policy climbed 1.5% to 1.9% on average every ten days. The mask policy is effective in controlling illness, according to the bulk of the data shown above. This result confirms the mask policy’s importance as a governing approach in the context of the worldwide pandemic.
TRANSGENERATIONAL EFFECT OF EARLY CHILDHOOD FAMINE EXPOSURE IN THE COHORT OF LENINGRAD SIEGE SURVIVORS’ OFFSPRING
Authors: Tolkunova Kristina , Usoltsev Dmitrii , Moguchaia Ekaterina , Boyarinova Maria , Kolesova Ekaterina , Erina Anastasia , Voortman Trudy , Vasilyeva Elena , Kostareva Anna , Shlyakhto Evgeny , Konradi Alexandra , Rotar Oxana , Artomov Mykyta
Published: November 2022

Introduction

Environmental exposure during early life development can affect disease risk in late-life period. There is little data on the transmission of phenotypic features from famine-exposed individuals to the next generations.

Objective

The purpose of our study was to investigate the association of parental starvation in the perinatal period and the period of early childhood with the phenotypic features observed in two generations of descendants of Leningrad Siege survivors (DLSS).

Design and methods

We examined 54 children and 30 grandchildren of 58 besieged Leningrad residents who suffered from starvation in early childhood and prenatal age during the Second World War. Controls from the population-based national epidemiological ESSE-RF study (n=175) were matched on sex, age and body mass index (BMI). Anthropometry, blood pressure (BP) measurement, and blood tests were performed for both groups. Sociodemographic and lifestyle information was collected via questionnaires. Phenotypes of controls and descendants (combined and children and grandchildren separately) were compared, taking into account multiple testing.

Results

Comparison of two generations descendants with corresponding control groups revealed significantly higher creatinine level and lower glomerular filtration rate (GFR), both in meta-analysis and in both generations independently. The mean values of GFR for all groups were detected within the normal range. Additionally, independent of the creatinine level, differences in the eating pattern were detected: insufficient fish consumption and excessive red meat consumption were significantly more frequent in the children of the Leningrad siege survivors compared with controls. BP and blood lipids did not differ between the groups.

Conclusions

Ancestral famine exposure in the prenatal period and early childhood may contribute to a decrease of in kidney filtration capacity and altered eating pattern in at least two generations of besieged Leningrad offspring.
Integrated Network Pharmacology and Experimental Analysis Unveil Modulation of EGFR/MAPK Signaling Cascades in Acute Cerebral Ischemia-Reperfusion Injury by Qing-Tong-Hua-Yu Decoction
Authors: Hu Jiajing , Zuo Long , Qu Wenyu , He Hongdun , Bao Jie , Zhang Wenyan , Zhang Yunyang , Zhu Meizhen , Li Tian
Published: November 2022

Objective

Based on network pharmacology, the response of Qing-tong-hua-yu Decoction (QTHY) to the regulation of EGFR/MAPK signaling cascade in cerebral ischemia-reperfusion injury was discussed and the possible mechanism of the protective effect of QTHY on the cerebral ischemia-reperfusion injury was studied.

Methods

A compound-target disease-function-pathway network was established and analyzed based on the network pharmacology approach used in Chinese medicine. The correlation, which is between effect of the components of QTHY Decoction against CI/RI with EGFR/MAPK signalling cascade response, was observed. And then the degree of neurological deficits in each group was assessed after cerebral ischemia for 2 hours and reperfusion for 3 hours, 24 hours, 3 days and 7 days. Expression levels of EGFR and p44/42MAPK in ischemic brain tissue at different time points in various groups of rats were tested by Western bolt (WB), real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC).

Results

Network pharmacology analysis revealed that QTHY-mediated treatment involved 439 key targets, in which the effect of QTHY groups against CI/RI was associated with EGFR/MAPK signaling cascade. QTHY treatment reduced neurological deficit scores and improved ischemic changes in rats. In addition, QTHY promoted EGFR and p44/42MAPK expression in the SVZ through the EGFR/MAPK signaling cascade, with varying degrees of improvement at different time points.

Conclusion

QTHY can better improve cerebral ischemia injury in CI / RI rats and exert the neuroprotective effect of cerebral ischemia-reperfusion injury. This may be related to the potential of QTHY to activate the EGFR / MAPK signaling cascade, which is consistent with the results of network pharmacology analysis.
Identification of Multiple Iron Uptake Mechanisms inEnterococcus faecalisand Their Relationship to Virulence
Authors: Brunson Debra N. , Colomer-Winter Cristina , Lam Ling Ning , Lemos José A.
Published: November 2022

Among the unfavorable conditions bacteria encounter within the host is restricted access to essential trace metals such as iron. To overcome iron deficiency, bacteria deploy multiple strategies to scavenge iron from host tissues with abundant examples of iron acquisition systems being implicated in bacterial pathogenesis. Yet, the mechanisms utilized by the major nosocomial pathogenEnterococcus faecalisto maintain intracellular iron balance are poorly understood. In this report, we conducted a systematic investigation to identify and characterize the iron acquisition mechanisms ofE. faecalisand to determine their contribution to virulence. Bioinformatic analysis and literature surveys revealed thatE. faecalispossesses three conserved iron uptake systems. Through transcriptomics, we discovered two novel ABC-type transporters that mediate iron uptake. While inactivation of a single transporter had minimal impact on the ability ofE. faecalisto maintain iron homeostasis, inactivation of all five systems (Δ5Fe strain) disrupted intracellular iron homeostasis and considerably impaired cell growth under iron-deficiency. Virulence of the Δ5Fe strain was generally impaired in different animal models but showed niche-specific variations in mouse models, leading us to suspect that heme can serve as an iron source toE. faecalisduring mammalian infections. Indeed, heme supplementation restored growth of Δ5Fe under iron-depletion and virulence in an invertebrate infection model. Collectively, this study reveals that the collective contribution of five iron transporters promotesE. faecalisvirulence and that the ability to acquire and utilize heme as an iron source is critical to the systemic dissemination ofE. faecalis.
In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation
Authors: Morley Victoria , Singh Dolt Karamjit , Alcaide-Corral Carlos J. , Walton Tashfeen , Lucatelli Christophe , Mashimo Tomoji , Tavares Adriana A. S. , Kunath Tilo
Published: November 2022

Parkinson’s disease (PD) is a neurodegenerative condition with several major hallmarks, including loss ofsubstantia nigraneurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations inSNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous ratSNCAgene.SNCAG51D/+andSNCAG51D/G51Drats were born in Mendelian ratios and did not exhibit any severe behavourial defects.L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT),SNCAG51D/+andSNCAG51D/G51Drats were characterised over the course of ageing (5, 11, and 16 months old) using18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of18F-DOPA in the striatum relative to the cerebellum in WT,SNCAG51D/+andSNCAG51D/G51Drats. A significant reduction inEDVRwas observed inSNCAG51D/G51Drats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in agedSNCAG51D/G51Drats. The increased and asymmetric dopamine turnover observed in the striatum of agedSNCAG51D/G51Drats is similar to prodromal PD, which suggests the presence of compensatory mechanisms.SNCAG51Drats represent a novel genetic model of PD, and kinetic modelling of18F-DOPA PET data has identified a highly relevant early disease phenotype.
Isolation and characterization of bacteriophages against IMP-6-producingKlebsiella pneumoniaeisolated from clinical settings in Japan
Authors: Kondo Kohei , Nakano Satoshi , Hisatsune Junzo , Sugawara Yo , Kataoka Michiyo , Kayama Shizuo , Sugai Motoyuki , Kawano Mitsuoki
Published: November 2022

Carbapenemase-producingEnterobacteriaceae(CPE) are one of the most detrimental species of antibiotic-resistant bacteria worldwide. Phage therapy has emerged as an effective strategy for the treatment of infections caused by CPE pathogens. In west Japan, the increasing occurrence ofKlebsiella pneumoniaeharboring the pKPI-6 plasmid, which encodesblaIMP-6, is a growing concern. To manage such major antimicrobial-resistant pathogens, we isolated 29 novel phages from sewage in Japan, targeting 31 strains ofK. pneumoniaeand one strain ofEscherichia coliharboring the pKPI-6 plasmid. Electron microscopy analysis indicated that of the 29 isolated phages, 21 (72.4%), 5 (17.2%), and 3 (10.3%) belonged toMyoviridae, Siphoviridae, andPodoviridae, respectively. Host range analysis revealed that 20Myoviridaemembers in isolated phages infected 25–26 strains ofK. pneumoniae, indicating that most of the isolated phages have a broad host range. TheK. pneumoniaeKp21 can only be infected by phage øKp_21, while Kp22 can be infected by more than 20 phages. We applied a phage cocktail, which consists of 10 phages, against Kp21 and Kp22 and found that the phage cocktail delayed the emergence of phage-resistant bacteria for Kp21 strain but not for the Kp22 strain. Furthermore, phage-resistant Kp21 (Kp21r) became prone to be infected from other bacteriophages as a “trade-off” of resistance to phage øKp_21. Our proposed phage set has an adequate number of phages to combat theK. pneumoniaestrain isolated in Japan. Notably, our work demonstrates how a suitable phage cocktail diminishes the occurrence of phage-resistant bacteria.

Importance

Klebsiella pneumoniaeharboring the plasmid carryingblaIMP-6is becoming an increasingly hazardous species in Japan. We collected and characterized 29 novel bacteriophages that infectK. pneumoniaecarrying the pKPI-6 plasmid, isolated in clinical settings of west Japan. Our phages showed broad host ranges. We applied a phage cocktail treatment constructed from 10 phages against two host strains, Kp21 and Kp22, which show different phage susceptibility patterns each other. Although the phage cocktail delayed phage-resistant Kp21 emergence, the emergence of phage-resistant Kp22 could not be delayed. Moreover, phage-resistant Kp21 became sensitive to other phages, which did not originally infect wild-type Kp21. Our study demonstrates how a suitable phage cocktail can diminish the occurrence of phage-resistant bacteria.
Musical expertise enhances neural alignment-to-young in sensorimotor regions that predicts older adults’ audiovisual speech-in-noise perception
Authors: Zhang Lei , Wang Xiuyi , Du Yi
Published: November 2022

Musical training can offset age-related decline in speech-in-noise perception. However, how lifelong musical expertise affects the functional reorganization of older brain in speech-in-noise perception has not yet been systematically investigated. Here, we address this issue by analyzing fMRI responses of older musicians, older non-musicians and, young non-musicians identifying noise-masked audiovisual syllables. First, we confirmed that older musicians outperformed older non-musicians and even equaled young non-musicians. Then, we showed that both older groups showed decreased auditory activation and increased visual activation compared to young non-musicians, while older musicians showed higher activation in speech motor regions and greater deactivation of default mode network (DMN) regions than older non-musicians. Next, we revealed that musical expertise counteracted the age-related neural dedifferentiation of speech representation, making older musicians exhibit higher neural alignment-to-young in bilateral sensorimotor areas. Finally, we disentangled that greater activation in speech motor areas and stronger deactivation in DMN regions were correlated with higher neural alignment in sensorimotor areas, which strongly predicted better performance in older adults. Together, long-term musical expertise mitigates age-related deficits in audiovisual speech-in-noise processing through enhanced compensatory scaffolding that reserves youth-like representation in sensorimotor areas. Our findings provide a comprehensive perspective on understanding age- and experience-related brain reorganization during speech perception.
Exploring the genome and protein space of viruses
Authors: Lu Congyu , Wu Yifan , Zhang Zheng , Mao Longfei , Ge Xingyi , Wu Aiping , Sun Fengzhu , Jiang Yongqiang , Peng Yousong
Published: November 2022

Recent metagenomic studies have identified a vast number of viruses. However, the systematic assessment of the true genetic diversity of the whole virus community on our planet remains to be investigated. Here, we explored the genome and protein space of viruses by simulating the process of virus discovery in viral metagenomic studies. Among multiple functions, the power function was found to best fit the increasing trends of virus diversity and was therefore used to predict the genetic space of viruses. The estimate suggests that there are at least 8.23e+08 viral Operational Taxonomic Units (vOTUs) and 1.62e+09 viral protein clusters on Earth when assuming the saturation of the virus genetic space, taking into account the balance of costs and the identification of novel viruses. It’s noteworthy that less than 3% of the viral genetic diversity has been uncovered thus far, emphasizing the vastness of the unexplored viral landscape. To saturate the genetic space, a total of 3.08e+08 samples would be required. Analysis of viral genetic diversity by ecosystem yielded estimates consistent with those mentioned above. Furthermore, the estimate of the virus genetic space remained robust when accounting for the redundancy of sampling, sampling time, sequencing platform, and parameters used for protein clustering. This study provides a guide for future sequencing efforts in virus discovery and contributes to a better understanding of viral diversity in nature.
Establishment and characterisation of oviductal organoids from farm and companion animals
Authors: Lawson Edwina F. , Ghosh Arnab , Blanch Victoria , Grupen Christopher G. , Aitken R John , Lim Rebecca , Drury Hannah R. , Baker Mark A. , Gibb Zamira , Tanwar Pradeep S.
Published: November 2022

Organoid technology has provided us with a unique opportunity to study early human development and decipher various steps involved in the pathogenesis of human diseases. The technology is already used in clinics to improve human patient outcomes. However, limited knowledge of the methodologies required to establish organoid culture systems in domestic animals has slowed the advancement and application of organoid technology in veterinary medicine. Here, we have developed a platform to grow organoids from animal tissue samples and characterized oviductal organoids from five domestic animal species. Organoids were grown progressively from single cells derived from the enzymatic digestion of freshly collected equine, bovine, feline, canine, and porcine oviducts. The addition of WNT, TGFB, BMP, Rock, and Notch signalling pathway activators or inhibitors in the culture medium suggested remarkable conservation of the molecular signals involved in oviductal epithelial development and differentiation across species. The gross morphology of organoids from all the domestic species was initially similar. However, some differences in size, complexity, and growth rate were observed and described. Well-defined and synchronised motile ciliated cells were observed in differentiated organoids in mature populations. Histopathologically, oviductal organoids mimicked their respective native tissue. In summary, we have developed a detailed cross-species comparison of oviductal organoid models, which will be valuable for advancing assisted reproductive technologies and fertility studies in these animal species in the future.

Summary sentence

Organoids can be derived from the oviductal epithelium of cow, cat, dog, horse, and pig to advance assisted reproductive technologies in animals.
Xist ribonucleoproteins promote female sex-biased autoimmunity
Authors: Dou Diana R. , Zhao Yanding , Belk Julia A. , Zhao Yang , Casey Kerriann M. , Chen Derek C. , Li Rui , Yu Bingfei , Srinivasan Suhas , Abe Brian T. , Kraft Katerina , Hellström Ceke , Sjöberg Ronald , Chang Sarah , Feng Allan , Goldman Daniel W. , Shah Ami A. , Petri Michelle , Chung Lorinda S. , Fiorentino David F. , Lundberg Emma K. , Wutz Anton , Utz Paul J. , Chang Howard Y.
Published: November 2022

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long noncoding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex, comprised of numerous autoantigenic components, is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form ofXistin male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multiorgan pathology in pristane-induced model of lupus than wild-type males. Xist expression in males reprogrammed T and B cell population and chromatin states to more resemble wild type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

HIGHLIGHTS

Transgenic mouse models inducibly express Xist in male animals.

Xist expression in males induce autoantibodies and autoimmune pathology.

Xist in males reprograms T and B cell populations to female-like patterns.

Autoantibodies to Xist RNP characterize female-biased autoimmune diseases.
Microprism-based two-photon imaging of the mouse inferior colliculus reveals novel organizational principles of the auditory midbrain
Authors: Ibrahim Baher A. , Shinagawa Yoshitaka , Douglas Austin , Xiao Gang , Asilador Alexander R. , Llano Daniel A.
Published: November 2022

To navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring nonlemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.
Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2
Authors: Lee Yunjeong , Yeo In Seo , Kim Namhee , Lee Dong-Keun , Kim Kyung-Tai , Yoon Jiyoung , Hong Young Bin , Choi Byung-Ok , Kosodo Yoichi , Kim Daesoo , Park Jihwan , Song Mi-Ryoung
Published: November 2022

The fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between these pools. In the developing spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from the muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to successively restrict specific motor neuronal fates during neural development; however, it remains unclear to what extent they contribute to limb-based motor pools and locomotor circuits. Here, we showed in mice that deletion ofIsl2resulted in scattered motor pools, primarily in the median motor column and lateral LMC (LMCl) populations, and lacked Pea3 expression in the hindlimb motor pools, accompanied by reduced terminal axon branching and disorganized neuromuscular junctions. Transcriptomic analysis ofIsl2- deficient spinal cords revealed that a variety of genes involved in motor neuron differentiation, axon development, and synapse organization were downregulated in hindlimb motor pools. Moreover, the loss ofIsl2impaired sensorimotor connectivity and hindlimb locomotion. Together, our studies indicate thatIsl2plays a critical role in organizing motor pool position and sensorimotor circuits in hindlimb motor pools.
Normalized Semi-Covariance Co-Efficiency Analysis of Spike Proteins from SARS-CoV-2 variant Omicron and Other Coronaviruses for their Infectivity and Virulence
Authors: Xu Tong , Zhou Shanyue , Huang Jun Steed , Zhang Wandong
Published: November 2022

Spectrum-based Mass-Charge modeling is increasingly used in biological analysis. To explain statistical phenomenon with positive and negative fluctuations of amino acid charges in spike protein sequences from Omicron and other coronaviruses, we propose calculation-based Mass-Charge modeling, a normalized derivation algorithm with exact Excel and MATLAB tool involving separate quadrant extension to normalized covariance, which is still compatible with Pearson covariance co-efficiency. The number of amino acids, molecular weight, isoelectric point, amino acid composition, charged residues, mass-charge ratio, hydropathicity of the proteins were taken into consideration in the analyses, and the relative peak and dip of the average with spike protein sequences based on hydrophobic mass to isoelectric charges of amino acids were also examined. The analyses with the algorithm provide more clear insights leading to revealing underline evolving trends of the viral proteins. Spike proteins from SARS-CoV-2 variants, seasonal and murine coronaviruses were taken as representative examples in this study. The analyses demonstrate that the Mass-Charge covariance co-efficiency can distinguish subtle differences between biological properties of spike proteins and correlate well with viral infectivity and virulence.
COMPUTATIONAL EVIDENCE FOR MULTI-LAYER CROSSTALK BETWEEN THE CADHERIN-11 AND PDGFR PATHWAYS
Authors: Karagöz Zeynep , Passanha Fiona R. , Robeerst Lars , van Griensven Martijn , LaPointe Vanessa L. S. , Carlier Aurélie
Published: November 2022

Various cell surface receptors play an important role in the differentiation and self-renewal of human mesenchymal stem cells (hMSCs). One example of such receptors are the cadherins, which maintain cell–cell adhesion and mechanically couple cells together. Recently, cadherin-11, which is a member of the type II classical cadherin family, has been shown to be involved in the fate commitment of hMSCs. Interestingly, cadherin-11 has no known intrinsic signaling activity and is thought to affect cell behavior via interactions with other cell surface receptors. Members of the platelet-derived growth factor receptor (PDGFR) family are hypothesized to be one of the interaction partners of cadherin-11. Experiments confirmed that PDGFR-α binding to extracellular cadherin-11 regions increases the PDGFR-α activity, whereas the interaction between PDGFR-β and cadherin-11 suppresses the activity of the growth factor receptor. Cadherin-11 knockdown experiments also decreased cell proliferation. These interactions between cadherin-11 and PDGFRs indicate a crosstalk between these receptors and their downstream signaling activities but the nature of this crosstalk is not entirely known. In this study, we used a computational model to represent the experimentally proven interactions between cadherin-11 and the two PDGFRs and we inspected whether the crosstalk also exists downstream of the signaling initiated by the two receptor families. The computational framework allowed us to monitor the relative activity levels of each protein in the network. We performed model simulations to mimic the conditions of previous cadherin-11 knockdown experiments and to predict the effect of crosstalk on cell proliferation. Overall, our predictions suggest the existence of another layer of crosstalk, namely between β-catenin (downstream to cadherin-11) and an ERK inhibitor protein (e.g. DUSP1), different than the crosstalk at the receptor level between cadherin-11 and PDGFR-α and -β. By investigating the multi-level crosstalk between cadherin and PDGFRs computationally, this study contributes to an improved understanding of the effect of cell surface receptors on hMSCs proliferation.
Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection
Authors: Milighetti Martina , Peng Yanchun , Tan Cedric , Mark Michal , Nageswaran Gayathri , Byrne Suzanne , Ronel Tahel , Peacock Tom , Mayer Andreas , Chandran Aneesh , Rosenheim Joshua , Whelan Matthew , Yao Xuan , Liu Guihai , Felce Suet Ling , Dong Tao , Mentzer Alexander J. , Knight Julian C. , Balloux Francois , Greenstein Erez , Reich-Zeliger Shlomit , Pade Corrina , Gibbons Joseph M. , Semper Amanda , Brooks Tim , Otter Ashley , Altmann Daniel M , Boyton Rosemary J , Maini Mala K , McKnight Aine , Manisty Charlotte , Treibel Thomas A. , Moon James C. ,   COVIDsortium Investigators, Noursadeghi Mahdad , Chain Benny
Published: November 2022

We analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naïve repertoire. High frequency naïve precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.

One-Sentence Summary

High frequency naïve precursors underly the rapid T cell response during the crucial early phases of acute viral infection.
What drives chorismate mutase to top performance? Insights from a combinedin silicoandin vitrostudy
Authors: Thorbjørnsrud Helen V. , Bressan Luca , Khatanbaatar Tamjidmaa , Carrer Manuel , Würth-Roderer Kathrin , Cordara Gabriele , Kast Peter , Cascella Michele , Krengel Ute
Published: November 2022

Unlike typical chorismate mutases, the enzyme fromMycobacterium tuberculosis(MtCM) has only low activity on its own. Remarkably, its catalytic efficiencykcat/Kmcan be boosted more than 100-fold by complex formation with a partner enzyme. Recently, an autonomously fully active MtCM variant was generated using directed evolution, and its structure solved by X-ray crystallography. However, key residues were involved in crystal contacts, challenging the functional interpretation of the structural changes. Here, we address these challenges by microsecond molecular dynamics simulations, followed up by additional kinetic and structural analyses of selected sets of specifically engineered enzyme variants. A comparison of wild-type MtCM with naturally and artificially activated MtCMs revealed the overall dynamic profiles of these enzymes as well as key interactions between the C-terminus and the active site loop. In the artificially evolved variant of this model enzyme, this loop is pre-organized and stabilized by Pro52 and Asp55, two highly conserved residues in typical, highly active chorismate mutases. Asp55 stretches across the active site and helps to appropriately position active site residues Arg18 and Arg46 for catalysis. The role of Asp55 can be taken over by another acidic residue, if introduced at position 88 close to the C-terminus of MtCM, as suggested by MD simulations and confirmed by kinetic investigations of engineered variants.