bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamics of colistin resistance in carbapenemase-producing Klebsiella pneumoniae: the double-edged sword of heteroresistance and adaptive resistance
Authors: Meletiadis Joseph , Paranos Paschalis , Tsala Marilena , Pournaras Spyros , Vourli Sofia
Published: October 2022

Introduction. The presence of heteroresistant subpopulations and the development of resistance during drug exposure (adaptive resistance) limits colistin’s efficacy against carbapenemase-producing

Klebsiella pneumoniae

(CP-Kp) isolates.

Hypothesis/Gap statement. The pharmacokinetic/pharmacodynamic (PK/PD) characteristics of both types of colistin resistance against CP-Kp are unknown.

Aim. We therefore studied the PK/PD characteristics of colistin resistance in an in vitro PK/PD model simulating clinical colistin exposures.

Methods. Two

K. pneumoniae

clinical isolates, one non-CP-Kp and one CP-Kp, with colistin MICs of 0.5–1 mg l−1 at a final inoculum of 107 c.f.u. ml−1 were used in an in vitro PK/PD dialysis/diffusion closed model simulating 4.5 MU q12h and 3 MU q8h clinical dosing regimens. Heteroresistant (HRS, bacteria with stable high-level resistance present before drug exposure) and adaptive resistant (ARS, bacteria with reversible low-level resistance emerging after drug exposure) subpopulations were measured and optimal PK/PD targets for reducing both ARS and HRS were determined. Cumulative fractional response (CFR) was calculated with Monte Carlo simulation for 9 MU q24h, 4.5 MU q12h and 3 MU q8h clinical dosing regimens.

Results. A 2–5 log10c.f.u. ml–1 decrease of the total bacterial population was observed within the first 2 h of exposure, followed by regrowth at 12 h. Colistin exposure was positively and negatively correlated with HRS and ARS 24–0 h c.f.u. ml–1 changes, respectively. An optimal PK/PD (~0.5log10 increase) target of 35 fAUC/MIC (the ratio of the area under the unbound concentration–time curve to the MIC) was found for reducing both HRS and ARS of high-level resistance (MIC >16 mg l−1). The 4.5 MU q12h regimen had slightly higher CFR (74 %) compared to the other dosing regimens.

Conclusions. High colistin exposures reduced high-level adaptive resistance at the expense of selection of heteroresistant subpopulations.
How to make calibration less painful – a proposition of an automatic, reliable and time-efficient procedure
Authors: Swider Karolina , Bruña Ricardo , Moratti Stephan
Published: October 2022

Background

In neurophysiological pain studies, multiple types of calibration methods are used to quantify the individual pain sensation stimuli that have different modalities. However, such studies often lack calibration procedure implementation, have a vague protocol description, do not provide data quality quantification, or even omit required control for gender pain differences. All this hampers not only study repetition but also interexperimental comparisons. Moreover, typical calibration procedures are long and require a high number of stimulations which may cause participants’ discomfort and stimuli habituation.

Method

To overcome those shortcomings, we present an automatic staircase pain calibration method for A-delta-specific electrical stimulation adjusted to the magnetoencephalography environment. We provide an in-depth data analysis of the collected self-reports from seventy healthy volunteers (37 males) and propose a method based on a dynamic truncated linear regression model (tLRM). We compare its estimates for the sensation (t), and pain (T) thresholds, as well as for the mid-pain stimulation (MP), with those calculated using a traditional threshold method and standard linear regression models.

Results

Compared to the other threshold methods, tLRM exhibits higher R2and requires 36% fewer stimuli application and has significantly highertand lowerTandMPintensities. Regarding sex differences, both lowertandTwere found for females compared to males, regardless of the calibration method.

Conclusions

The proposed tLRM method quantifies the quality of the calibration procedure, minimizes its duration and invasiveness, as well as provides validation of linearity between stimuli intensity and subjective scores, making it an enabling technique for further studies. Moreover, our results highlight the importance of control for gender in pain studies.

The purpose of this study was to shorten and automatize the calibration method which is an enabling technique for realizing neurophysiological studies on pain. The proposed method is based on a dynamic truncated linear regression model and was shown to require 36% fewer stimuli application compared to the traditional staircase method. Furthermore, the calibration was adjusted to A-delta specific intraepidermal electrical stimulation, quantifies the quality of the resulting calibration parameters and provides a validation of linearity between stimuli intensity and subjective scores. The results also highlight the importance of control for participant gender in studies where different types of stimulation are used to induce pain sensation.
Enhanced clinical assessment of hematologic malignancies through routine paired tumor:normal sequencing
Authors: Ptashkin Ryan N. , Ewalt Mark D. , Jayakumaran Gowtham , Kiecka Iwona , Bowman Anita S. , Yao JinJuan , Casanova Jacklyn , Lin Yun-Te David , Petrova-Drus Kseniya , Mohanty Abhinita S. , Bacares Ruben , Benhamida Jamal , Rana Satshil , Razumova Anna , Vanderbilt Chad , Remav Anoop Balakrishnan , Rijo Ivelise , Son-Garcia Julie , de Bruijn Ino , Zhu Menglei , Lachhander Sean , Wang Wei , Haque Mohammad S. , Seshan Venkatraman E. , Wang Jiajing , Liu Ying , Nafa Khedoudja , Borsu Laetitia , Zhang Yanming , Aypar Umut , Suehnholz Sarah P. , Chakravarty Debyani , Park Jae H. , Abdel-Wahab Omar , Mato Anthony R. , Xiao Wenbin , Roshal Mikhail , Yabe Mariko , Batlevi Connie Lee , Giralt Sergio , Salles Gilles , Rampal Raajit , Tallman Martin , Stein Eytan M. , Younes Anas , Levine Ross L. , Perales Miguel-Angel , van den Brink Marcel R. M. , Dogan Ahmet , Ladanyi Marc , Berger Michael F. , Brannon A. Rose , Benayed Ryma , Zehir Ahmet , Arcila Maria E.
Published: October 2022

Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.
Enhanced mTORC1 signaling and Protein Synthesis in Parkinson’s Disease Pathogenesis Disease Pathogenesis
Authors: Khan Mohammed Repon , Yin Xiling , Kang Sung-Ung , Mitra Jaba , Wang Hu , Brahmachari Saurav , Karuppagounder Senthilkumar S. , Kimura Yasuyoshi , Jhaldiyal Aanishaa , Kim Hyun Hee , Gu Hao , Chen Rong , Redding-Ochoa Javier , Troncoso Juan , Ha Taekjip , Dawson Valina L. , Dawson Ted M.
Published: October 2022

Pathologic α-syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD.

Pathological α-synuclein (α-syn) plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic α-syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the α-syn preformed fibril (PFF) and Drosophila α-syn transgenic models of pathologic α-syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic α-syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.
Integration of silicon chip microstructures for in-line microbial cell lysis in soft microfluidics
Authors: Krishna Nittala Pavani Vamsi , Hohreiter Allison , Linhard Emilio Rosas , Dohn Ryan , Mishra Suryakant , Konda Abhiteja , Divan Ralu , Guha Supratik , Basu Anindita
Published: October 2022

The paper presents fabrication methodologies that integrate silicon components into soft microfluidic devices to perform microbial cell lysis for biological applications. The integration methodology consists of a silicon chip that is fabricated with microstructure arrays and embedded in a microfluidic device, which is driven by piezoelectric actuation to perform cell lysis by physically breaking microbial cell walls via micromechanical impaction. We present different silicon microarray geometries, their fabrication techniques, integration of said microarrays into microfluidic devices, device operation and testing on synthetic microbeads and microbial cells to evaluate their efficacy. The generalized strategy developed for silicon chip integration into soft polymeric devices can serve as an important process step for a new class of hybrid silicon-polymeric devices for future cellular processing applications. The proposed integration methodology can be scalable and integrated as an in-line cell lysis tool with existing microfluidics assays.
The 5:2 diet does not increase adult hippocampal neurogenesis or enhance spatial memory in mice
Authors: Roberts Luke D. , Hornsby Amanda K. E. , Thomas Alanna , Sassi Martina , Kinzett Aimee , Hsiao Nathan , David Bethan R , Good Mark , Wells Timothy , Davies Jeffrey S.
Published: October 2022

New neurones are generated throughout life in the mammalian brain in a process known as adult hippocampal neurogenesis (AHN). Since this phenomenon grants a high degree of neuroplasticity influencing learning and memory and mood related behaviour, identifying factors that regulate AHN may be important for ameliorating age-related cognitive decline and neurodegeneration. Calorie restriction (CR), in the absence of malnutrition, has been shown to enhance AHN and improve hippocampal-dependent memory, mediated by the stomach hormone, ghrelin. Intermittent fasting (IF), a dietary strategy offering more flexibility than conventional CR, also promotes aspects of AHN. The 5:2 diet is a popular form of IF linked to a range of health benefits, however its effects on AHN and spatial memory are not well characterised. We hypothesised that the 5:2 diet would enhance AHN in a ghrelin-dependent manner.

To assess this, we used immunohistochemistry to quantify new adult-born neurones and new neural stem cells (NSCs) in the hippocampal DG of adolescent and adult wild-type and mice lacking the ghrelin receptor following six weeks on a 5:2 diet. We report an age-related decline in neurogenic processes and identify a novel role for ghrelin-receptor in regulating the formation of new adult born NSCs in an age-dependent manner. However, the 5:2 diet did not affect new neurone or NSC formation in the DG. Consistent with this finding the 5:2 diet did not alter performance on a spatial learning and memory task. These data suggest that the 5:2 diet used in this study does not increase AHN or improve associated spatial memory function.

Highlights

5:2 diet does not increase adult hippocampal neurogenesis

5:2 diet does not enhance spatial memory performance

There is an age-related decline in adult hippocampal neurogenesis

Ghrelin-receptor regulates new neural stem cell and new neurone number in an age-related manner

Ghrelin-receptor is required for intact spatial memory
Altered secretion, constitution, and functional properties of the gastrointestinal mucus in a rat model of sporadic Alzheimer’s disease
Authors: Homolak Jan , De Busscher Joke , Lucio Miguel Zambrano , Joja Mihovil , Virag Davor , Perhoc Ana Babic , Knezovic Ana , Barilar Jelena Osmanovic , Salkovic-Petrisic Melita
Published: October 2022

Accumulating evidence supports the involvement of the gastrointestinal (GI) system in Alzheimer’s disease (AD), however, it is currently unknown whether GI alterations arise as a consequence of central nervous system (CNS) pathology or play a causal role in the pathogenesis of the disease. The GI mucus system is a possible mediator of GI dyshomeostasis in neurological disorders as CNS controls mucus production and secretion via the efferent arm of the brain-gut axis. The aim was to use a brain-first model of sporadic AD induced by intracerebroventricular streptozotocin (STZ-icv) to dissect the efferent (i.e. brain-to-gut) effects of isolated central neuropathology on the GI mucus system. Quantification and morphometric analysis of goblet cell mucigen granules revealed altered GI mucus secretion in the AD model possibly mediated by the insensitivity of AD goblet cells to neurally-evoked mucosal secretion confirmed by ex vivo cholinergic stimulation of isolated duodenal rings. The dysfunctional efferent control of the GI mucus secretion results in altered biochemical composition of the mucus associated with reduced glycoprotein aggregation and binding capacity in vitro. Finally, functional consequences of the reduced barrier-forming capacity of the AD mucus are demonstrated using the in vitro two-compartment caffeine diffusion interference model. Isolated central AD-like neuropathology results in the loss of efferent control of GI homeostasis via the brain-gut axis characterized by the insensitivity to neurally-evoked mucosal secretion, altered mucus constitution, and reduced barrier-forming capacity potentially increasing the susceptibility of STZ-icv rat model of AD to GI and systemic inflammation induced by intraluminal toxins, microorganisms, and drugs.
Entropic control of the free energy landscape of an archetypal biomolecular machine
Authors: Ray Korak Kumar , Kinz-Thompson Colin D. , Fei Jingyi , Wang Bin , Lin Qiao , Gonzalez Ruben L.
Published: October 2022

Biomolecular machines are complex macromolecular assemblies that utilize thermal and chemical energy to perform essential, multistep, cellular processes. Despite possessing different architectures and functions, an essential feature of the mechanisms-of-action of all such machines is that they require dynamic rearrangements of structural components. Surprisingly, biomolecular machines generally possess only a limited set of such motions, suggesting that these dynamics must be repurposed to drive different mechanistic steps. Although ligands that interact with these machines are known to drive such repurposing, the physical and structural mechanisms through which ligands achieve this remain unknown. Using temperature-dependent, single-molecule measurements analyzed with a time-resolution-enhancing algorithm, here we dissect the free energy landscape of an archetypal biomolecular machine, the bacterial ribosome, to reveal how its dynamics are repurposed to drive distinct steps during ribosome-catalyzed protein synthesis. Specifically, we show that the free energy landscape of the ribosome encompasses a network of allosterically coupled structural elements that coordinates the motions of these elements. Moreover, we reveal that ribosomal ligands which participate in disparate steps of the protein synthesis pathway repurpose this network by differentially modulating the structural flexibility of the ribosomal complex (i.e., the entropic component of the free energy landscape). We propose that such ligand-dependent entropic control of free energy landscapes has evolved as a general strategy through which ligands may regulate the functions of all biomolecular machines. Such entropic control is therefore an important driver in the evolution of naturally occurring biomolecular machines and a critical consideration for the design of synthetic molecular machines.
A graph-matching based metric of functional connectome distance between pairs of individuals varies with their ages, cognitive performances and familial relationships
Authors: Bukhari Hussain , Su Chang , Dhamala Elvisha , Gu Zijin , Jamison Keith , Kuceyeski Amy
Published: October 2022

Functional connectomes (FCs), represented by networks or graphs that summarize coactivation patterns between pairs of brain regions, have been related at a population level to age, sex, cognitive/behavioral scores, life experience, genetics and disease/disorders. However, quantifying FC differences between pairs of individuals also provides a rich source of information with which to map to differences in those individuals’ biology, experience, genetics or behavior. In this study, graph matching is used to create a novel inter-individual FC metric, called swap distance, that quantifies the distance between pairs of individuals’ FCs. We apply graph matching to align FCs between pairs of individuals from the the Human Connectome Project (N = 997) and find that swap distance i) increases with increasing familial distance, ii) increases with subjects’ ages, iii) is smaller for pairs of females compared to pairs of males, and iv) is larger for females with lower cognitive scores compared to females with larger cognitive scores. Regions that contributed most to individuals’ swap distances were in higher-order networks, i.e. default-mode and fronto-parietal, that underlie executive function and memory. These higher-order networks’ regions also had swap frequencies that varied monotonically with familial relatedness of the individuals in question. We posit that the proposed graph matching technique provides a novel way to study inter-subject differences in FC and enables quantification of how FC may vary with age, relatedness, sex and behavior.
Competing neural representations of choice shape evidence accumulation in humans
Authors: Bond Krista , Rasero Javier , Madan Raghav , Bahuguna Jyotika , Rubin Jonathan , Verstynen Timothy
Published: October 2022

Changing your mind requires shifting the way streams of information lead to a decision. Usingin silicoexperiments we show how the cortico-basal ganglia-thalamic (CBGT) circuits can feasibly implement shifts in the evidence accumulation process. When action contingencies change, dopaminergic plasticity redirects the balance of power, both within and between action representations, to divert the flow of evidence from one option to another. This finding predicts that when competition between action representations is highest, the rate of evidence accumulation is lowest. We then validate this prediction in a sample ofhomo sapiensas they perform an adaptive decision-making task while whole-brain hemodynamic responses are recorded. These results paint a holistic picture of how CBGT circuits manage and adapt the evidence accumulation process in mammals.

One-sentence Summary

Interactions between cortical and subcortical circuits in the mammalian brain flexibly control the flow of information streams that drive decisions by shifting the balance of power both within and between action representations.
Key performance indicators of COVID-19 contact tracing in Belgium from September 2020 to December 2021
Authors: Kremer Cécile , Willem Lander , Boone Jorden , Arrazola de Oñate Wouter , Hammami Naïma , Faes Christel , Hens Niel
Published: October 2022

Background

Contact tracing aims to prevent onward transmission of infectious diseases and data obtained during tracing provide unique information on transmission characteristics. A key performance indicator that has been proposed to evaluate contact tracing is the proportion of cases arising from known contacts. However, few empirical studies have investigated the effectiveness of contact tracing.

Methods

Using data collected between September 2020 and December 2021 in Belgium, we investigated the impact of contact tracing on SARS-CoV-2 transmission. We compared confirmed cases that were previously identified as a close contact to those that were not yet known, in terms of their traced contacts and secondary cases as well as the serial interval. In addition, we established contact and transmission patterns by age.

Findings

Previously traced, hence ‘known’, cases comprised 20% of all cases and they were linked to relatively fewer close contacts as well as fewer secondary cases and a lower secondary attack rate compared to cases that were not already known. In addition we observed a shorter serial interval for ‘known’ cases. There was a relative increase in transmission from children to adults during circulation of the Delta and Omicron variants, without an increase in the extent of contact between these age groups.

Interpretation

These results suggest that contact tracing in Belgium has been effective in reducing onward transmission and that individuals aware of their exposure to SARS-CoV-2 seemed more reserved in their social contact behaviour. Data from a reference period or region are needed to measure the impact of contact tracing in terms of the number of cases and deaths averted.
Does de-identification of data from wearable Biometric Monitoring Technologies give us a false sense of security? A systematic review
Authors: Chikwetu Lucy , Miao Yu , Woldetensae Melat K. , Bell Diarra , Goldenholz Daniel M. , Dunn Jessilyn
Published: October 2022

It remains unknown whether de-identifying wearable biometric monitoring data is sufficient to protect the privacy of individuals in the dataset. This systematic review seeks to shed light on this. We searched Web of Science, IEEE Xplore Digital Library, PubMed, Scopus, and the ACM Digital Library on December 6, 2021 (PROSPERO CRD42022312922). We also performed manual searches in journals of interest until April 12, 2022. Though our search strategy had no language restrictions, all retrieved studies were in English. We included studies demonstrating re-identification, identification, or authentication using data from wearables. Our search returned 17,625 studies, and 72 studies met our inclusion criteria. Our findings demonstrate that substantial re-identification risk exists in data from sensors generally not thought to generate identifiable information, such as the electrocardiogram and electromyogram. In many cases, only a small amount of data (1-300 seconds of recording) is sufficient for re-identification.
Comparative whole genome analysis reveals re-emergence of typical human Wa-like and DS-1-like G3 rotaviruses after Rotarix vaccine introduction in Malawi
Authors: Mhango Chimwemwe , Banda Akuzike , Chinyama End , Mandolo Jonathan J. , Kumwenda Orpha , Malamba-Banda Chikondi , Barnes Kayla G. , Kumwenda Benjamin , Jambo Kondwani , Donato Celeste M. , Esona Mathew D. , Mwangi Peter N. , Steele A. Duncan , Iturriza-Gomara Miren , Cunliffe Nigel A. , Ndze Valentine N. , Kamng’ona Arox W. , Dennis Francis E. , Nyaga Martin M. , Chaguza Chrispin , Jere Khuzwayo C.
Published: October 2022

Genotype G3 rotaviruses rank among the most common rotavirus strains worldwide in humans and animals. However, despite a robust long-term rotavirus surveillance system from 1997 in Blantyre, Malawi, these strains were only detected from 1997 to 1999 and then disappeared and re-emerged in 2017, five years after the introduction of the Rotarix rotavirus vaccine. Here we analysed 27 whole genome sequences to understand how G3 strains re-emerged in Malawi. We randomly selected samples each month between November 2017 and August 2019 from stool samples of children hospitalised with acute diarrhoea at the Queen Elizabeth Hospital in Blantyre, Malawi. We found three genotypes namely G3P[4] (n=20), G3P[6] (n=1) and G3P[8] (n=6) associated with the re-emergence of G3 strains in Malawi post-Rotarix vaccine introduction. The identified genotypes co-circulated at different time points and were associated with three typical human G3 strains consisting of either a Wa-like or DS-1-like genetic constellation and reassortant strains possessing Wa-like and DS-1-like genetic backbones. Time-resolved phylogenetic trees demonstrated that the most recent common ancestor for each segment of the re-emerged G3 strains emerged between 1996 and 2012, possibly through introductions from outside the country due to the limited genetic similarity with G3 strains which circulated before their disappearance in the late 1990s. Further genomic analysis revealed that the reassortant DS-1-like G3P[4] strains acquired a Wa-like NSP2 genome segment (N1 genotype) through intergenogroup reassortment; an artiodactyl-like VP3 through intragenogroup interspecies reassortment; and VP6, NSP1 and NSP4 segments through intragenogroup reassortment likely before importation into Malawi. Additionally, the re-emerged G3 strains contain amino acid substitutions within the antigenic regions of the VP4 proteins which could potentially impact the binding of rotavirus vaccine-induced antibodies. Altogether, our findings shows that multiple rather than a single genotype have driven the re-emergence of G3 strains likely from other countries highlighting the role of human mobility and genome reassortment events in the dissemination and evolution of rotavirus strains in Malawi necessitating the need for long-term genomic surveillance of rotavirus in high disease burden settings to inform disease prevention and control.
Maternal per- and poly-fluoroalkyl substances exposures associated with higher depressive symptom scores among immigrant women in the Chemicals in Our Bodies cohort in San Francisco
Authors: Aung Max T. , Eick Stephanie M. , Padula Amy M. , Smith Sabrina , Park June-Soo , DeMicco Erin , Woodruff Tracey J. , Morello-Frosch Rachel
Published: October 2022

Background

Exposure to per- and poly-fluoroalkyl substances (PFAS) remains an important public health issue due to their widespread detection and persistence in environmental media, slow metabolism in humans, and influences physiological processes such as neurological signaling. Maternal depression is highly prevalent during pregnancy and the postpartum period and is an important neurological outcome that is potentially sensitive to PFAS. The health risks associated with PFAS may be further amplified in historically marginalized communities, including immigrants.

Objective

We evaluated the extent to which maternal concentrations of PFAS were associated with depression scores during pregnancy and whether effects differed between US born and immigrant women.

Methods

Our analytical sample included 282 US born and 235 immigrant pregnant women enrolled in the Chemicals in Our Bodies prospective birth cohort based in San Francisco, CA. We measured 12 PFAS in serum samples collected in the second trimester and depressive symptom scores were assessed using the Center for Epidemiologic Studies Depression Scale in the same period. Associations were estimated using multiple linear regression, adjusting for maternal age, education, pre-pregnancy body mass index, and parity. Associations with a PFAS mixture were estimated using quantile g-computation.

Results

In adjusted linear regression models, a natural log unit increase in two PFAS was associated with higher depression scores in the overall sample, and this association persisted only among immigrant women (β[95% confidence interval]: perfluorooctane sulfonic acid (1.3 [0.3-2.3]) and methyl-perfluorooctane sulfonamide acetic acid (1.5 [0.6-2.3]). Using quantile g-computation, we observed that simultaneously increasing all PFAS in the mixture by one quartile was associated with increased depressive symptoms among immigrant women (mean change per quartile increase= 1.12 [0.002, 2.3]), and associations were stronger compared to US born women (mean change per quartile increase= 0.09 [-1.0, 0.8]).

Conclusions

Findings provide new evidence that PFAS are associated with higher depression symptoms among immigrant women during pregnancy. Results can inform efforts to address environmental factors that may affect depression among US immigrants.
Excitation-inhibition imbalance in Alzheimer’s disease using multiscale neural model inversion of resting-state fMRI
Authors: Li Guoshi , Hsu Li-Ming , Wu Ye , Bozoki Andrea C , Shih Yen-Yu Ian , Yap Pew-Thian
Published: October 2022

Alzheimer’s disease (AD) is a serious neurodegenerative disorder without a clear understanding of the etiology and pathophysiology. Recent experimental data has suggested neuronal excitation-inhibition (E-I) imbalance as an essential element and critical regulator of AD pathology, but E-I imbalance has not been systematically mapped out for either local or large-scale neuronal circuits in AD. By applying a Multiscale Neural Model Inversion (MNMI) framework to the resting-state functional MRI (rs-fMRI) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we identified brain regions with disrupted E-I balance based on impaired mesoscale excitatory and inhibitory connection strengths in a large network during AD progression. We observed that both intra-regional and inter-regional E-I balance is progressively disrupted from cognitively normal individuals, to mild cognitive impairment (MCI) and to AD, and E-I difference (or ratio) can be abnormally increased or decreased, depending on specific region. Also, we found that (local) inhibitory connections are more significantly impaired than excitatory ones and the strengths of the majority of connections are reduced in MCI and AD, leading to gradual decoupling of neural populations. Moreover, we revealed a core AD network comprised mainly of limbic and cingulate regions including the hippocampus, pallidum, putamen, nucleus accumbens, inferior temporal cortex and caudal anterior cingulate cortex (cACC). These brain regions exhibit consistent and stable E-I alterations across MCI and AD, and thus may represent early AD biomarkers and important therapeutic targets. Lastly, the E-I difference (or ratio) of multiple brain regions (precuneus, posterior cingulate cortex, pallium, cACC, putamen and hippocampus) was found to be significantly correlated with the Mini-Mental State Examination (MMSE) score, indicating that the degree of E-I impairment is behaviorally related to MCI/AD cognitive performance. Overall, our study constitutes the first attempt to delineate E-I imbalance in large-scale neuronal circuits during AD progression, which may facilitate the development of new treatment paradigms to restore pathological E-I balance in AD.
Evaluation of the Abbott Panbio™ COVID-19 antigen detection rapid diagnostic test among healthcare workers in elderly care
Authors: Eikelenboom-Boskamp Andrea , Ouden Martijn den , de Groot Theun , Stobernack Tim , Wertheim Heiman , Voss Andreas
Published: October 2022

Background

Coronavirus disease 2019 (COVID-19) has been especially dangerous for elderly people. To reduce the risk of transmission from healthcare workers to elderly people, it is of utmost importance to detect possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive healthcare workers as early as possible. We aimed to determine whether the Abbott Panbio™ COVID-19 antigen detection rapid diagnostic test (Ag-RDT) could be used as an alternative to reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The second aim was to compare the cycle threshold (Ct) in RT-qPCR with the results of the Ag-RDT.

Methods

A prospective diagnostic evaluation of the Abbott Panbio™ COVID-19 Ag-RDT among healthcare workers across three elderly care facilities as well as home-based elderly care workers who met clinical criteria for COVID-19 during the second wave of the COVID-19 pandemic. Per healthcare worker, the first nasopharyngeal swab was obtained to perform the Ag-RDT and the second swab for RT-qPCR. A Ct-value of < 40 was interpreted as positive, ≥ 40 as negative.

Results

A total of 683 healthcare workers with COVID-19 symptoms were sampled for detection of SARS-CoV-2 by both Ag-RDT and RT-qPCR. Sixty-three healthcare workers (9.2%) tested positive for SARS-CoV-2 by RT-qPCR. The overall sensitivity of Ag-RDT was 81.0% sensitivity (95%CI: 69.6-88.8%) and 100% specificity (95%CI: 99.4-100%). Using a cut-off Ct-value of 32, the sensitivity increased to 92.7% (95% CI: 82.7-97.1%). Negative Ag-RDT results were moderately associated with higher Ct-values (r = 0.62) compared to positive Ag-RDT results.

Conclusion

The Panbio™ COVID-19 Ag-RDT can be used to quickly detect positive SARS-CoV-2 healthcare workers. Negative Ag-RDT should be confirmed by RT-qPCR. In case of severe understaffing and with careful consideration, fully vaccinated healthcare workers with Ag-RDT negative results could work with a mask pending PCR results.
Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose
Authors: Filardi Bruno Andraus , Monteiro Valter Silva , Schwartzmann Pedro Vellosa , Martins Vivian do Prado , Rosa Zucca Luis Eduardo , Baiocchi Gabriela Crispim , Hahn Anne M. , Chen Nicholas F. G. , Pham Kien , Pérez-Then Eddy , Miric Marija , Brache Vivian , Cochon Leila , Larocca Rafael A. ,   Yale SARS-CoV-2 Genomic Surveillance Initiative, Mendez Roberto Della Rosa , Silveira Douglas Bardini , Pinto Aguinaldo Roberto , Croda Julio , Yildirim Inci , Omer Saad B. , Ko Albert I. , Vermund Sten H. , Grubaugh Nathan D. , Iwasaki Akiko , Lucas Carolina
Published: October 2022

The emergence of the SARS-CoV-2 Omicron sublineages resulted in drastically increased transmission rates and reduced protection from vaccine-induced immunity. To counteract these effects, multiple booster strategies were used in different countries, although data comparing their efficiency in improving protective immunity remains sparse, especially among vulnerable populations, including older adults. The inactivated CoronaVac vaccine was among the most widely distributed worldwide, particularly in China, and South America. However, whether homologous versus heterologous booster doses in those fully vaccinated with CoronaVac induce distinct humoral responses and whether these responses vary across age groups remain unknown. We analyzed plasma antibody responses from CoronaVac-vaccinated younger or older individuals in central and south America that received a homologous CoronaVac or heterologous BNT162b2 or ChAdOx1 booster vaccines. We found that both IgG levels against SARS-CoV-2 spike or RBD, as well as neutralization titers against Omicron sublineages, were substantially reduced in participants that received homologous CoronaVac when compared to heterologous BNT162b2 or ChAdOx1 booster. This effect was specifically prominent in recipients older than 50 years of age. In this group, CoronaVac booster induced low virus-specific IgG levels and failed to elevate their neutralization titers against any omicron sublineage. Our results point to significant inefficiency in mounting protective anti-viral humoral immunity in those who were primed with CoronaVac followed by CoronaVac booster, particularly among older adults, urging a heterologous regimen in high-risk populations fully vaccinated with CoronaVac.

One Sentence Summary

Homologous CoronaVac boosters do not improve neutralization responses against current VOCs in older adults in contrast to heterologous regimens.
α-synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased uptake into neurons
Authors: Stephens Amberley D. , Villegas Ana Fernandez , Chung Chyi Wei , Vanderpoorten Oliver , Pinotsi Dorothea , Mela Ioanna , Ward Edward , McCoy Thomas M. , Cubitt Robert , Routh Alexander F. , Kaminski Clemens F. , Schierle Gabriele S. Kaminski
Published: October 2022

Monomeric alpha-synuclein (aSyn) is a well characterised as a lipid binding protein. aSyn is known to form amyloid fibrils which are also localised with lipids and organelles in so called Lewy bodies, insoluble structures found in Parkinson’s disease patient’s brains. It is still unclear under which conditions the aSyn-lipid interaction can start to become pathological. Previous work to address pathological interactions has focused on using synthetic lipid membranes, which lack the complexity of physiological lipid membranes which not only have a more complex lipid composition, but also contain lipid interacting proteins. Here, we investigate how either monomeric or fibrillar aSyn interact with physiological synaptic vesicles (SV) isolated from rodent brain. Using small angle neutron scattering and high-resolution imaging we observe that aSyn fibrils disintegrate SV, whereas aSyn monomers cause clustering of SV. Furthermore, SV enhance the aggregation rate of aSyn, however increasing the SV:aSyn ratio causes a reduction in aggregation propensity. SV lipids appear as an integrated part of aSyn fibrils and while the fibril morphology differs to aSyn fibrils alone, the core fibril structure remains the same. We finally demonstrate that lipid-associated aSyn fibrils are more easily taken up into cortical i3Neurons derived from induced pluripotent stem cells. Our study sheds light on differences between interactions of aSyn with synthetic lipid vesicles and physiological SV. We show how aSyn fibrils may enhance pathology by disintegrating SV, which in turn may have fatal consequences for neurons. Furthermore, disease burden may additionally be impacted by an increased uptake of lipid-associated aSyn by neurons, leading to more SV damage and enhancing aSyn aggregation.
Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration
Authors: Molina-Gonzalez Irene , Holloway Rebecca K. , Jiwaji Zoeb , Dando Owen , Emelianova Katie , Lloyd Amy F. , Forbes Lindsey H. , Mahmood Ayisha , Skripuletz Thomas , Gudi Viktoria , Febery James A. , Johnson Jeffrey A. , Fowler Jill H. , Kuhlmann Tanja , Williams Anna , Chandran Siddharthan , Stangel Martin , Howden Andrew J.M. , Hardingham Giles E. , Miron Veronique E.
Published: October 2022

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
A reevaluation of the relationship between EGL-43 (EVI1/MECOM) and LIN-12 (Notch) duringC. elegansanchor cell invasion
Authors: Martinez Michael A. Q. , Mullarkey Angelina A. , Yee Callista , Zhao Chris Z. , Zhang Wan , Shen Kang , Matus David Q.
Published: October 2022

Development of theC. elegansreproductive tract is orchestrated by the anchor cell (AC). Among other things, this occurs through a cell invasion event that connects the uterine and vulval tissue. Several key transcription factors regulate AC invasion, such as EGL-43, HLH-2, and NHR-67. Specifically, these transcription factors function together to maintain the post-mitotic state of the AC, a requirement for AC invasion. EGL-43 is theC. eleganshomolog of the human EVI1/MECOM proto-oncogene, and recently, a mechanistic connection has been made between its loss and AC cell-cycle entry. The current model states that EGL-43 represses LIN-12 (Notch) expression to prevent AC proliferation, suggesting that Notch signaling is mitogenic in the absence of EGL-43. To reevaluate the relationship between EGL-43 and LIN-12, we designed and implemented a heterologous co-expression system called AIDHB that combines the auxin-inducible degron (AID) system of plants with a live cell-cycle sensor based on human DNA helicase B (DHB). After validating the AIDHB approach using AID-tagged GFP, we sought to test this approach using AID-tagged alleles ofegl-43andlin-12. Auxin-inducible degradation of either EGL-43 or LIN-12 resulted in the expected AC phenotypes. Lastly, we seized the opportunity to pair AIDHB with RNAi to co-deplete LIN-12 and EGL-43, respectively. This combined approach revealed that LIN-12 is not required for AC proliferation following loss of EGL-43, which contrasts with a double RNAi experiment directed against these same targets. The addition of AIDHB to theC. eleganstransgenic toolkit should facilitate functionalin vivoimaging of cell-cycle associated phenomena.
Real-time inactivation of airborne SARS-CoV-2 using ultraviolet-C
Authors: Koutras Carolina , Wade Richard L.
Published: October 2022

COVID-19 is a life-threatening respiratory infection that has had a profound impact on indoor air quality awareness. Ultraviolet-C (UV-C) is a physical disinfection process that triggers microbial inactivation through creating irreversible genetic material damage. An upper room device equipped with germicidal UV-C (UR GUV) was evaluated against airborne SARS-CoV-2 for antimicrobial efficacy using a robust aerosol testing protocol. In 30 minutes, it led to a virucidal efficacy of 99.994 % in a large, room-sized chamber. UR GUV is a promising mitigation strategy for airborne pathogens.
Large-scale crowdsourced radiotherapy segmentations across a variety of cancer anatomic sites: Interobserver expert/non-expert and multi-observer composite tumor and normal tissue delineation annotations from a prospective educational challenge
Authors: Wahid Kareem A. , Lin Diana , Sahin Onur , Cislo Michael , Nelms Benjamin E. , He Renjie , Naser Mohammed A. , Duke Simon , Sherer Michael V. , Christodouleas John P. , Mohamed Abdallah S. R. , Murphy James D. , Fuller Clifton D. , Gillespie Erin F.
Published: October 2022

Clinician generated segmentation of tumor and healthy tissue regions of interest (ROIs) on medical images is crucial for radiotherapy. However, interobserver segmentation variability has long been considered a significant detriment to the implementation of high-quality and consistent radiotherapy dose delivery. This has prompted the increasing development of automated segmentation approaches. However, extant segmentation datasets typically only provide segmentations generated by a limited number of annotators with varying, and often unspecified, levels of expertise. In this data descriptor, numerous clinician annotators manually generated segmentations for ROIs on computed tomography images across a variety of cancer sites (breast, sarcoma, head and neck, gynecologic, gastrointestinal; one patient per cancer site) for the Contouring Collaborative for Consensus in Radiation Oncology challenge. In total, over 200 annotators (experts and non-experts) contributed using a standardized annotation platform (ProKnow). Subsequently, we converted data into NIfTI format with standardized nomenclature for ease of use. In addition, we generated consensus segmentations for experts and non-experts using the STAPLE method. These standardized, structured, and easily accessible data are a valuable resource for systematically studying variability in segmentation applications.
Influenza Vaccine Effectiveness Against Influenza A(H3N2)-Related Illness in the United States During the 2021–2022 Influenza Season
Authors: Price Ashley M. , Flannery Brendan , Talbot H. Keipp , Grijalva Carlos G. , Wernli Karen J. , Phillips C. Hallie , Monto Arnold S. , Martin Emily T. , Belongia Edward A. , McLean Huong Q. , Gaglani Manjusha , Mutnal Manohar , Geffel Krissy Moehling , Nowalk Mary Patricia , Tartof Sara Y. , Florea Ana , McLean Callie , Kim Sara S. , Patel Manish M. , Chung Jessie R.
Published: October 2022

Background

In the United States, influenza activity during the 2021-2022 season was modest and sufficient enough to estimate influenza vaccine effectiveness for the first time since the beginning of the COVID-19 pandemic. We estimated influenza vaccine effectiveness against lab-confirmed outpatient acute illness caused by predominant A(H3N2) viruses.

Methods

Between October 2021 and April 2022, research staff across 7 sites enrolled patients aged ≥6 months seeking outpatient care for acute respiratory illness with cough. Using a test-negative design, we assessed VE against influenza A(H3N2). Due to strong correlation between influenza and SARS-CoV-2 vaccination, participants who tested positive for SARS-CoV-2 were excluded from vaccine effectiveness estimations. Estimates were adjusted for site, age, month of illness, race/ethnicity and general health status.

Results

Among 6,260 participants, 468 (7%) tested positive for influenza only, including 440 (94%) for A(H3N2). All 206 sequenced A(H3N2) viruses were characterized as belonging to genetic group 3C.2a1b subclade 2a.2, which has antigenic differences from the 2021–2022 season A(H3N2) vaccine component that belongs to clade 3C.2a1b subclade 2a.1. After excluding 1,948 SARS-CoV-2 positive patients, 4,312 patients were included in analyses of influenza VE; 2,463 (57%) were vaccinated against influenza. Effectiveness against A(H3N2) for all ages was 36% (95%CI, 20-49%) overall; 40% (95%CI, 24-53%) for those aged 6 months-49 years; and 10% (95%CI, -60-49%) for those aged ≥50 years.

Conclusion

Influenza vaccination in 2021–2022 provided protection against influenza A(H3N2)-related outpatient visits among young persons, with no measurable protection among older adults.
Hormone overdose and misuse in Chinese transgender and gender non-conforming population: A mixed-methods study protocol
Authors: Zeng Ben-tuo , Pan Hui-qing , Li Li-ping , Lan Tian-meng , Ye Zhen-yu , Wang Peng-fei , Liu Yang
Published: October 2022

Background

There is no existing research on hormone overdose and misuse (HODM) in Chinese transgender and gender non-conforming (TGNC) population, and little is known in this field.

Objectives

We aim to determine the definition and criteria of HODM in Chinese TGNCs, address the rate of HODM in Chinese TGNC population, explore related factors and behavioral risks, identify the probable causes, and explore long-term effects.

Methods

We propose: (1) a mixed-method study comprising expert panel meetings and stakeholder engagement to identify HODM criteria, types and grades; (2) a cross-sectional study to quantify HODM prevalence, related factors and behavioral risks; (3) semi-structured interviews and focus groups to explore HODM motivations and reasons; and (4) a prospective cohort study to evaluate HODM long-term effects.

Ethics

The study protocol was approved by the Medical Ethics Committee of Xiamen University (XDYX202210K27).

Dissemination

Results will be published in international peer-reviewed journals, and a public-oriented version of the main findings will be prepared and disseminated through social media and online communities. The study will be completed before September 2023 except for the cohort study. Preliminary findings of the cohort study will be reported by March 2026.