bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spontaneous Transmembrane Pore Formation by Short-chain Synthetic Peptide
Authors: Koneru Jaya Krishna , Prakashchand Dube Dheeraj , Dube Namita , Ghosh Pushpita , Mondal Jagannath 
Published: February 2021

ABSTRACTAmphiphilicβ-peptides, which are synthetically designed short-chain helical foldamer ofβ-amino acids, are established potent biomimetic alternatives of natural antimicrobial peptides. An intriguing question is: how does the distinct molecular architecture of these short-chain and rigid synthetic peptides translates to its potent membrane disruption ability? Here, we address this question via a combination of all atom and coarse-grained molecular dynamics simulations of the interaction of mixed phospholipid bilayer with an antimicrobial 10-residue globally amphiphilic helicalβ-peptide at wide range of concentrations. The simulation demonstrates that multiple copies of this synthetic peptide, initially placed in aqueous solution, readily self-assemble and adsorb at membrane interface. Subsequently, beyond a threshold peptide-to-lipid ratio, the surface-adsorbed oligomeric aggregate moves inside the membrane and spontaneously forms stable water-filled transmembrane pore via a cooperative mechanism. The defects induced by these pores lead to the dislocation of interfacial lipid head groups, membrane thinning and substantial water leakage inside the hydrophobic core of the membrane. A molecular analysis reveals that, despite having a short architecture, these synthetic peptides, once inside the membrane, would stretch themselves towards the distal leaflet in favour of potential contact with polar head groups and interfacial water layer. The pore formed in coarse-grained simulation was found to be resilient upon structural refinement. Interestingly, the pore-inducing ability was found to be elusive in a non-globally amphiphilic sequence isomer of the sameβ-peptide, indicating strong sequence dependence. Taken together, this work put forward key perspectives of membrane-activity of minimally designed synthetic biomimetic oligomers relative to the natural antimicrobial peptides.STATEMENT OF SIGNIFICANCEThe development of bacterial resistance to conventional antibiotics is a major concern towards public health. Antimicrobial peptides, which provide a natural defence against a large range of pathogens, including bacteria and fungi, are emerging as a sustainable substitute of antibiotics. However, serious issues with the naturally occurring antimicrobial peptides which have prevented their wide-spread appreciations are their susceptibility to degradation and lack of specificity for microbial targets. In this regard, synthetic biomimetic peptides are coming up as a viable alternative. In this work we provide clarity on how these synthetic antimicrobial peptides, which often involves distinctly short architecture, acts on the membrane. We show that despite its short architecture, a 10-residue biomimetic peptide,β-peptide, can spontaneously form stable membrane-spanning pore and induce water-leakage inside the membrane.
Akkermansia muciniphilasecretome promotes α-synuclein aggregation in enteroendocrine cells
Authors: Amorim Neto Dionísio Pedro , Bosque Beatriz Pelegrini , Pereira de Godoy João Vitor , Rodrigues Paulla Vieira , Meneses Dario Donoso , Tostes Katiane , Costa Tonoli Celisa Caldana , González-Billault Christian , de Castro Fonseca Matheus 
Published: February 2021

ABSTRACTThe notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance ofAkkermansia muciniphilain Parkinson’s disease (PD) fecal samples. Nevertheless, a functional link betweenA.muciniphilaand sporadic PD remained unexplored. Here, we investigated whetherA.muciniphilasecretome could initiate the misfolding process of α-synuclein (αSyn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found thatA.muciniphilasecretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and αSyn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing αSyn aggregation in enteroendocrine cells.SYNOPSIS FIGURE DESCRIPTIONThe secretome isolated from the commensal gut bacteriumAkkermansia muciniphilatriggers intracellular Ca2+signaling in enteroendocrine cells, leading to increased mitochondrial Ca2+uptake. Mitochondrial Ca2+overload leads to ROS generation culminating with αSyn phosphorylation and aggregation (left panel). All these events were inhibited once mitochondrial Ca2+is buffered (right panel).Gram-negative gut bacteriumAkkermansia muciniphilais consistently found more abundant in Parkinson’s disease patients.Akkermansia muciniphilaprotein secretome composition is directly modulated by mucin and induces an IP3-independent endoplasmic reticulum (ER)-calcium release in enteroendocrine cells.This Ca2+release is triggered by direct activation of Ryanodine Receptors leading to increased mitochondrial Ca2+uptake.Mitochondrial Ca2+overload leads to ROS generation culminating with αSyn aggregation.Buffering mitochondrial Ca2+efficiently inhibitsA.muciniphila-induced αSyn aggregation in enteroendocrine cells.
Association of Germline BRCA Pathogenic Variants with Diminished Ovarian Reserve: A Meta-Analysis of Individual Patient-Level Data
Authors: Turan Volkan , Lambertini Matteo , Lee Dong-Yun , Wang Erica T , Clatot Florian , Karlan Beth Y , Demeestere Isabelle , Bang Heejung , Oktay Kutluk 
Published: February 2021

AbstractPurposeTo determine whether germline BRCA pathogenic variants (gBRCA) are associated with decreased ovarian reserve.Materials and MethodsAn individual patient-data meta-analysis was performed using 5 datasets on 828 evaluable women who were tested for gBRCA. Of those, 250 carried gBRCA while 578 had tested negative and served as controls. Of the women with gBRCA, four centers studied those affected with breast cancer (n=161) and one studied unaffected individuals (n=89). The data were adjusted for the center, age, body mass index, smoking and oral contraceptive pill use before the final analysis. Anti-mullerian hormone (AMH) levels in affected women were drawn before pre-systemic therapy.ResultsMean ages of women with vs. without gBRCA1/2 (34.1± 4.9 vs. 34.3± 4.8 years; p=0.48), and with gBRCA1 vs gBRCA2 (33.7± 4.9 vs. 34.6± 4.8 years; p=0.16) were similar. After the adjustments, women with gBRCA1/2 had significantly lower AMH levels compared to controls (23% lower; 95% CI: 4-38%, p=0.02). When the adjusted analysis was limited to affected women (157 with gBRCA vs. 524 without, after exclusions), the difference persisted (25% lower; CI: 9-38%, p=0.003). The serum AMH levels were lower in women with gBRCA1 (33% lower; CI: 12-49%, p=0.004) but not gBRCA2 compared to controls (7% lower; CI: 31% lower to 26% higher, p=0.64).ConclusionsYoung women with gBRCA pathogenic variants, particularly of those affected and with gBRCA1, have lower serum AMH levels compared to controls. They may need to be preferentially counselled about the possibility of shortened reproductive lifespan due to diminished ovarian reserve.ContextKey objectiveDNA repair deficiency is emerging as a joint mechanism for breast cancer and reproductive aging. Recent studies showed that ovarian reserve maybe lower in women with BRCA pathogenic variants (gBRCA) due to DNA repair deficiency. However, clinical studies using the most sensitive serum ovarian reserve marker Anti-Mullerian-Hormone (AMH) provided mixed results. Given the heterogeneity of the data from clinical studies, we performed an individual patient data (IPD) meta-analysis to determine if gBRCA are associated with lower ovarian reserve.Knowledge generatedgBRCA are associated with diminished ovarian reserve, as determined by serum AMH and this association is restricted to gBRCA1. This finding is firmer for affected women as this IPD meta-analysis predominantly studied those with breast cancer.RelevanceWomen with gBRCA may have shortened reproductive life span due to diminished ovarian reserve and should be proactively counseled for fertility preservation especially if faced with chemotherapy or delaying childbearing.
Effects of THAM Nasal Alkalinization on Airway Microbial Communities: A Pilot Study
Authors: Holliday Zachary M. , Launspach Janice L. , Durairaj Lakshmi , Singh Pradeep K. , Zabner Joseph , Stoltz David A. 
Published: February 2021

ABSTRACTObjectivesIn cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF.MethodsSubjects (n=32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period.ResultsAt baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of C. accolens detected, but increased the amount of C. pseudodiphtheriticum recovered on nasal swabs. A reduction in S. aureus nasal colonization was also found in subjects who grew C. pseudodiphtheriticum.ConclusionsThis study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities.
Inequities in childhood immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics in Kenya
Authors: Allan Simon , Adetifa Ifedayo M. O. , Abbas Kaja 
Published: February 2021

AbstractBackgroundThe global Immunisation Agenda 2030 highlights coverage and equity as a strategic priority goal to reach high equitable immunisation coverage at national levels and in all districts. We estimated inequities in full immunisation coverage associated with socioeconomic, geographic, maternal, child, and place of birth characteristics among children aged 12-23 months in Kenya.MethodsWe analysed full immunisation coverage (1-dose BCG, 3-dose DTP-HepB-Hib (diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B), 3-dose polio, 1-dose measles, and 3-dose pneumococcal vaccines) of 3,943 children aged 12–23 months from the 2014 Kenya Demographic and Health Survey. We disaggregated mean coverage by socioeconomic (household wealth, religion, ethnicity), geographic (place of residence, province), maternal (maternal age at birth, maternal education, maternal marital status, maternal household head status), child (sex of child, birth order), and place of birth characteristics, and estimated inequities in full immunisation coverage using bivariate and multivariate logistic regression.ResultsImmunisation coverage ranged from 82% [81–84] for the third dose of polio to 97.4% [96.7–98.2] for the first dose of DTP-HepB-Hib, while full immunisation coverage was 68% [66–71] in 2014. After controlling for other background characteristics through multivariate logistic regression, children of mothers with primary school education or higher have at least 54% higher odds of being fully immunised compared to children of mothers with no education. Children born in clinical settings had 41% higher odds of being fully immunised compared to children born in home settings. Children in the Coast, Western, Central, and Eastern regions had at least 74% higher odds of being fully immunised compared to children in the North Eastern region, while children in urban areas had 26% lower odds of full immunisation compared to children in rural areas. Children in the middle and richer wealth quintile households were 43–57% more likely to have full immunisation coverage compared to children in the poorest wealth quintile households. Children who were sixth born or higher had 37% lower odds of full immunisation compared to first-born children.ConclusionsChildren of mothers with no education, born in home settings, in regions with limited health infrastructure, living in poorer households, and of higher birth order are associated with lower rates of full immunisation. Targeted programmes to reach under-immunised children in these subpopulations will lower the inequities in childhood immunisation coverage in Kenya.
Neurological mechanism of sensory deficits after developmental exposure to non-dioxin-like polychlorinated biphenyls (PCBs)
Authors: Brun Nadja R. , Panlilio Jennifer M. , Zhang Kun , Zhao Yanbin , Ivashkin Evgeny , Stegeman John J. , Goldstone Jared V. 
Published: February 2021

AbstractThe most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to chemicals can result in neurobehavioral disorders. To uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits, we investigated the effects of the non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response using zebrafish as a vertebrate model. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. Morphological and biochemical data demonstrate that while exposure to PCB153 induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling is the dominant mechanism associated with motor movement. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and, with the startle response being critical for the survival of fish, to evolutionary adaptation in wildlife.
Flexible analysis of TSS mapping data and detection of TSS shifts with TSRexploreR
Authors: Policastro Robert A. , McDonald Daniel J. , Brendel Volker P. , Zentner Gabriel E. 
Published: February 2021

AbstractHeterogeneity in transcription initiation has important consequences for transcript stability and translation, and shifts in transcription start site (TSS) usage are prevalent in various disease and developmental contexts. Accordingly, numerous methods for global TSS profiling have been developed, including our recently published Survey of TRanscription Initiation at Promoter Elements with high-throughput sequencing (STRIPE-seq), a method to profile transcription start sites (TSSs) on a genome-wide scale with minimal cost and time. In parallel to our development of STRIPE-seq, we built TSRexploreR, an R package for end-to-end analysis of TSS mapping data. TSRexploreR provides functions for TSS and TSR detection, normalization, correlation, visualization, and differential TSS/TSR analysis. TSRexploreR is highly interoperable, accepting the data structures of TSS and TSR sets generated by several existing tools for processing and alignment of TSS mapping data, such as CAGEr for Cap Analysis of Gene Expression (CAGE) data. Lastly, TSRexploreR implements a novel approach for the detection of shifts in TSS distribution.
Paths to Oblivion: Common Neural Mechanisms of Anaesthesia and Disorders of Consciousness
Authors: Luppi Andrea I. , Mediano Pedro A.M. , Rosas Fernando E. , Allanson Judith , Pickard John D. , Williams Guy B. , Craig Michael M , Finoia Paola , Peattie Alexander R.D. , Coppola Peter , Owen Adrian , Naci Lorina , Menon David K. , Bor Daniel , Stamatakis Emmanuel A. 
Published: February 2021

AbstractThe human brain generates a rich repertoire of spatiotemporal dynamics during normal wakefulness, supporting a wide variety of conscious experiences and cognitive functions. However, neural dynamics are reconfigured, in comparable ways, when consciousness is lost either due to anaesthesia or disorders of consciousness (DOC). Here, leveraging a neurobiologically realistic whole-brain computational model informed by functional MRI, diffusion MRI, and PET, we sought to identify the neurobiological mechanisms that explain the common reconfiguration of neural dynamics observed both for transient pharmacological intervention and chronic neuroanatomical injury. Our results show that, by incorporating local inhibitory action through a PET-based GABA receptor density map, our model can reproduce the brain dynamics of subjects undergoing propofol anaesthesia, and that this effect depends specifically on the spatial distribution of GABA receptors across cortical regions. Additionally, using a structural connectome obtained from DOC patients, we demonstrate how the dynamics that characterise loss of consciousness can emerge from changes in neuroanatomical connectivity. Crucially, we find that each of these two interventions generalises across datasets: a model with increased GABA-mediated inhibition can reproduce the dynamics of DOC patients’ brains, and a model with a DOC connectome is also compatible with brain dynamics observed during propofol anaesthesia. These results demonstrate how increased inhibition and connectome randomisation represent different neurobiological paths towards the characteristic dynamics of the unconscious brain. Overall, the present findings begin to disentangle the neurobiological mechanisms by which highly dissimilar perturbations of the brain’s neurodynamics can lead to unconsciousness.
Adenylnucleotide-mediated binding of the PII-like protein SbtB contributes to controlling activity of the cyanobacterial bicarbonate transporter SbtA
Authors: Förster Britta , Mukherjee Bratati , Rourke Loraine M. , Kaczmarski Joe A. , Jackson Colin J. , Price G. Dean 
Published: February 2021

AbstractCyanobacteria have evolved a remarkably powerful CO2concentrating mechanism (CCM), enabling high photosynthetic rates in environments with limited inorganic carbon (Ci). Therefore, this CCM is a promising system for integration into higher plant chloroplasts to boost photosynthetic efficiency and yield. The CCM depends on active Ci uptake, facilitated by bicarbonate transporters and CO2pumps, to elevate CO2concentration around the active sites of the primary CO2fixing enzyme, Rubisco, which is encapsulated in cytoplasmic micro-compartments (carboxysomes). The essential CCM proteins have been identified, but the molecular signals and regulators that coordinate function in response to light, Ci availability and other environmental cues are largely unknown. Here, we provide evidence, based on a novelin vitrobinding system, for a role of the PII-like SbtB protein in regulating Ci uptake by the bicarbonate transporter, SbtA, in response to the cellular adenylate energy charge (AEC) through dynamic protein-protein interaction. Binding of the SbtA and SbtB proteins from two phylogenetically distant species,Cyanobium sp. PCC7001 andSynechococcus elongatusPCC7942, was inhibited by high ATP, and promoted by low [ATP]:[ADP or AMP] ratiosin vitro, consistent with a sensory response to the AEC mediated through adenylnucleotide ligand-specific conformation changes in SbtB.In vivo, cell cultures of S. elongatus showed up to 70% SbtB-dependent down-regulation of SbtA bicarbonate uptake activity specifically in the light activation phase during transitions from dark to low light when low cellular AEC is expected to limit metabolic activity. This suggests SbtB may function as a curfew protein during prolonged low cellular AEC and photosynthetically unfavourable conditions to prevent energetically futile and physiologically disadvantageous activation of SbtA.
Prostate cancer screening in hospitalized patients: Results from the Nationwide Inpatient Sample
Authors: Irfan Furqan B. , Ahmed Fahad Shabbir , Masucci Monica V. , Cerimele Angelina A. , Nguyen Thu , Sharrak Aryana , Nguyen David M , Tariq Tooba , Baydoun Hussein , Hasan Ahmad , Awad Mohamed E , Saleh Khaled , Karabon Patrick 
Published: February 2021

ABSTRACTBackgroundProstate cancer (PCa) is the most common non-skin cancer in American men. The aim of the study was to determine the nationwide prevalence, trends, and predictors of inpatient PCa screening encounters in patients with average risk of PCa using the National Inpatient Sample (NIS) database.MethodsThe NIS database from 2006 to 2014 was used to evaluate PCa screening among hospitalized patients in the United States (US). All hospitalized male patients between the ages of 45 and 69 at average risk for PCa were included. The outcome was whether a patient had an encounter for prostate cancer as noted on their discharge record. Variables analyzed included demographic factors, hospital characteristics, and other concomitant diagnoses for prostate or male urinary problems.ResultsThe prevalence of inpatient PCa screening was 2.57 per 100,000 hospital discharges. In a multivariate setting, the following were significant factors associated with greater odds of inpatient PCa screening: Medicare (AOR: 3.07; P = 0.0016), Self-Pay or Uninsured patients (AOR: 1.74; P = 0.0371), rural (AOR: 11.9; P = < 0.0001) or urban nonteaching hospitals (AOR: 5.26; P = < 0.0001), receiving care in the Midwest (AOR: 4.90; P = < 0.0001), a diagnosis for urinary tract infections (P = 0.0367), genitourinary symptoms (P < 0.0001), hyperplasia of prostate (P = 0.0006), or other male genital disorder (P < 0.0001).ConclusionAccording to current cancer screening guidelines, PSA screening should include shared decision making between physicians and patients. In light of unequal access to quality healthcare, there exist disparities in uninsured and rural patients for cancer screening. Screening tools such as prostate specific antigen (PSA) are minimally invasive modalities in the inpatient setting that can help screen individuals at increased risk for the development of prostate cancer, allowing for early detection, prevention, improved rates of cure and ultimately, decreased rates of mortality.