bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk factors for pneumococcal carriage in adults living with HIV on antiretroviral therapy in the infant pneumococcal vaccine era in Malawi
Authors: Thindwa Deus , Mwalukomo Thandie S , Msefula Jacquline , Jambo Kondwani C , Brown Comfort , Kamng’ona Arox , Mwansambo Charles , Ojal John , Flasche Stefan , French Neil , Heyderman Robert S , Swarthout Todd D
Published: May 2022

Objective

Adults living with HIV (ALWHIV) on antiretroviral therapy (ART) are at high risk of pneumococcal carriage and disease. To help evaluate carriage risk in African ALWHIV in the infant pneumococcal conjugate vaccination era, we assessed association between carriage and potential risk factors.

Methods

Nasopharyngeal swabs were collected from adults aged 18-40 years attending an ART clinic during rolling, cross-sectional surveys in Blantyre, Malawi between 2015-2019. We fitted generalised additive models to estimate the risk of sex, social economic status (SES), living with a child <5y, and ART duration on carriage.

Results

Of 2,067 adults, median age was 33y (range 28-37), 1,427 (69.0%) were females, 1,087 (61.4%) were in low-middle socio-economic-status (SES), 910 (44.0%) were living with a child <5y, and median ART duration was 3.0 years (range 0.004-17). We estimated 38.2% and 60.6% reductions in overall and vaccine-serotype carriage prevalence. Overall carriage was associated with low SES, living with a child <5y and shorter duration on ART. By contrast, vaccine-type carriage was associated with living without a child <5y and male sex.

Conclusion

Despite temporal reductions in overall and vaccine-serotype carriage, there is evidence of incomplete VT indirect protection. A targeted-vaccination campaign should be considered for ALWHIV, along with other public health measures to further reduce vaccine-serotype carriage and therefore disease.
CHARACTERISTICS AND OUTCOMES OF INDIVIDUALS WITH COVID-19: EVIDENCE FROM A HOSPITAL BASED STUDY
Authors: Simushi P. , Zambwe M. , Chipimo P.J.
Published: May 2022

Objective

To determine the characteristics and outcomes of Covid-19 patients at Livingstone teaching hospital.

Methods

A database cross sectional review of COVID 19 patients at Livingstone Teaching Hospital. Data on demographics and clinical characteristics were obtained along with the comorbidities presented with by the patients using a structured data collection form. Data were analysed using STATA 64. Mann-Whitney and t-test were used on continuous independent variables. Chi-square test was used to determine associations between two categorical variables. Logistic regression was used to control for confounders.

Results

A total of 222 (62.54%) were male and 133 (37.46%) were female. Discharged were 274 (77.18%), while 81 (22.82%) died. Among those who died were the older clients with a median age of 65 (p <0.001). The median interquartile range (IQR)] age was 48.5 years. Patients presented with a cough 180 (50.7%), chest pain 123 (34.65%) and shortness of breath 121 (34.04%). Statistically significant comorbidities recorded included Hypertension 121 (34.08%), Diabetes mellitus 69 (19.44%), and HIV 38 (10.7%). The most prevalent underlying condition observed was hypertension 121 (34.08).

Conclusion

HIV positive and diabetics had an increased odds of succumbing to COVID-19 death. It is recommended that targeted policies should be considered the risky groups.
Effect modification in network meta-analyses of treatments for relapsing refractory multiple myeloma (RRMM): systematic review, meta-analysis, and simulation
Authors: Rose Christopher James , Ohm Ingrid Kristine , Giske Liv , Næss Gunn Eva , Fretheim Atle
Published: May 2022

Aims

Network meta-analysis (NMA) has been used in several systematic reviews on relapsing refractory multiple myeloma (RRMM). NMAs have been questioned on the basis that effect modification may invalidate the underpinning assumptions. We aimed to systematically review and meta-analyze the evidence for effect modification of hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) with respect to refractory status and number of treatment lines.

Methods

We extracted stratified HR estimates from 42 phase 2 and 3 randomized controlled trials (RCTs). We tested for within-study effect modification and used meta-analyses to estimate ratios of hazard ratios (RHRs) across trial under assumptions that strongly favor the modification hypothesis. RHR estimates were used in simulations to estimate how many NMA results would be expected to differ in the presence versus absence of effect modification.

Results

Most (95%) publications could have reported stratified estimates but only 14% (OS) and 43% (PFS) did. Within-study evidence for effect modification is very weak (p > 0.05 for 47 of 49 sets of stratified estimates). The largest RHR estimated was 1.31 (95% CI 1.16–1.47), for the modifying effect of refractory status on HR for PFS. Simulations suggest that, in the worst case, effect modification would result in 4.48% (95% CI 4.42%–4.53%) of NMA estimates differing statistically significantly in the presence versus absence of effect modification.

Conclusions

Effect modification is essentially undetectable in phase 2 and 3 trials. In the worst case, it is unlikely to affect more than about 5% of random-effects NMA estimates.
Identifying key multifunctional components shared by critical cancer and normal liver pathways via sparseGMM
Authors: Bakr Shaimaa , Brennan Kevin , Mukherjee Pritam , Argemi Josepmaria , Hernaez Mikel , Gevaert Olivier
Published: May 2022

Despite the abundance of multi-modal data, suitable statistical models that can improve our understanding of diseases with genetic underpinnings are challenging to develop. Here we present SparseGMM, a novel statistical approach for gene regulatory network discovery. SparseGMM uniquely uses latent variable modeling with sparsity constraints regulators to learn gaussian mixtures from multi-omic data. By combining co-expression patterns with a Bayesian framework, sparseGMM quantitatively measures confidence in regulators and uncertainty in target gene assignment by computing gene entropy. We apply SparseGMM to liver cancer and normal liver tissue data and evaluate the discovered gene modules in an independent scRNA-seq dataset. sparseGMM identifies PROCR as a regulator of angiogenesis, and PDCD1LG2 and HNF4A as regulators of immune response and blood coagulation in cancer, respectively. Additionally, we show that more genes have significantly higher entropy in cancer compared to normal liver; among high entropy genes are key multifunctional components shared by critical pathways, such as p53 and estrogen signaling.

Software availability

The software is available athttps://hub.docker.com/r/shaimaabakr/sparse_gmm

One-sentence summary

A novel statistical approach for gene regulatory network discovery recovers modules and corresponding regulators of diverse normal liver functions, important liver cancer processes, as well as shared biology between liver cancer and normal tissue.
Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma
Authors: Hamel Andrew R. , Yan Wenjun , Rouhana John M. , Monovarfeshani Aboozar , Jiang Xinyi , Mehta Puja A. , Advani Jayshree , Luo Yuyang , Liang Qingnan , Rajasundaram Skanda , Shrivastava Arushi , Duchinski Katherine , Mantena Sreekar , Wang Jiali , van Zyl Tavé , Pasquale Louis R. , Swaroop Anand , Gharahkhani Puya , Khawaja Anthony P. , MacGregor Stuart ,   International Glaucoma Genetics Consortium (IGGC), Chen Rui , Vitart Veronique , Sanes Joshua R. , Wiggs Janey L. , Segrè Ayellet V.
Published: May 2022

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide; however, the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP GWAS loci and of overlapping eQTLs and sQTLs in 49 GTEx tissues and retina prioritized causal genes for 60% of loci. These genes were enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealed that the colocalizing genes and genome-wide POAG and IOP associations were enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominated IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.
What are effective strategy to constrain COVID-19 pandemic crisis? lessons learned from a comparative policy analysis between Italian regions to cope with next pandemic impact
Authors: Coccia Mario , Benati Igor
Published: May 2022

The pandemic of Coronavirus Disease 2019 (COVID-19) and its variants is rapidly spreading all over the world, generating a high number of infections, deaths and negative impact on socioeconomic system of countries. As vaccines and appropriate drugs for treatment of the COVID-19 can reduce the effectiveness in the presence of variants and/or new viral agents, one of the questions in social studies of medicine is effective public policy responses to reduce the impact of COVID-19 global pandemic and similar infectious diseases on health of people and on economies. This study analyzes public policy responses to the pandemic crisis across Italian regions that were the first areas to experience a rapid increase in confirmed cases and deaths of COVID-19. The analysis of regional strategies, from January to July 2020, reveals differences in public policy responses to delay and reduce the height of epidemic peak and to afford health-care systems more time to expand and respond to this new emergency. Veneto Region in North-East Italy has managed health policy responses with: a) a timely and widespread testing of individuals, b) units of epidemiological investigation for tracing all contacts of infected people in an effective contact tracing system. This public policy response has reduced total deaths and the final size of COVID-19 pandemic on health of people. Other regions have done public interventions without a clear strategy and goals to cope with diffusion of COVID-19 and as a consequence, they have had a higher negative impact on public health. Lesson learned can be important to design an effective public policy that can be generalized in different regional and national systems to prevent and/or reduce future epidemics or pandemics similar to the COVID-19.
Neutralization Escape by the SARS-CoV-2 Omicron Variants BA.2.12.1 and BA.4/BA.5
Authors: Hachmann Nicole P. , Miller Jessica , Collier Ai-ris Y. , Ventura John D. , Yu Jingyou , Rowe Marjorie , Bondzie Esther Apraku , Powers Olivia , Surve Nehalee , Hall Kevin , Barouch Dan H.
Published: May 2022

Multiple lineages of the SARS-CoV-2 Omicron variant (B.1.1.529) have emerged, and BA.1 and BA.2 have demonstrated substantial escape from neutralizing antibodies (NAbs). BA.2.12.1 has now become dominant in the United States, and BA.4 and BA.5 have become dominant in South Africa. Our data show that BA.2.12.1 and BA.4/BA.5 substantially escape NAbs induced by both vaccination and infection. Moreover, BA.4/BA.5 NAb titers, and to lesser extent BA.2.12.1 NAb titers, were lower than BA.1 and BA.2 NAb titers, suggesting that the SARS-CoV-2 Omicron variant has continued to evolve with increasing neutralization escape. These findings have important public health implications and provide immunologic context for the current surges with BA.2.12.1 and BA.4/BA.5 in populations with high rates of vaccination and BA.1/BA.2 infection.
A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part
Authors: Mukae Hiroshi , Yotsuyanagi Hiroshi , Ohmagari Norio , Doi Yohei , Imamura Takumi , Sonoyama Takuhiro , Fukuhara Takahiro , Ichihashi Genki , Sanaki Takao , Baba Keiko , Takeda Yosuke , Tsuge Yuko , Uehara Takeki
Published: May 2022

For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. Sixty-nine patients enrolled from 56 sites were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was change from baseline in SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.8, 40.4, and 38.0 years, respectively). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], −2.42 [1.42]; P = 0.0712) and 250 mg (−2.81 [1.21]; P = 0.0083) versus placebo (−1.54 [0.74]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by −1.4 to −1.5 log10 copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).
Effect of various hormonal and non-hormonal contraceptive methods on the vaginal milieu -A narrative review
Authors: Tandon Deepti , Patil Anushree D , Goriwale Mayuri
Published: May 2022

Globally the use of modern contraceptive methods has risen to 851 million. Use of these contraceptive methods does influence the vaginal health, which in turn affects the susceptibility towards acquiring RTI/STI. Methods to assess the vaginal health have also evolved over decades. The objective of this narrative review is to assess the influence of contraceptive methods on the vaginal health and also evaluate the methods used to assess the vaginal milieu. Suitable articles published in literature from 2007-2020 were identified from PubMed, Google Scholar using relevant keywords. Hormonal contraceptives included were combined oral contraceptive pills (COCP), Depot medroxyprogesterone acetate (DMPA)and Levonorgestrel IUCD(LNG-IUS). Non hormonal methods included were barrier methods, copper IUCD, diaphragm and vaginal sponge. Outcome parameter recorded were Nugent score, vaginal pH, bacterial vaginosis or defined microbiome profile.

COCP have been shown to protect the vaginal ecosystem primarily due to their oestrogen component. The use of IUCD causes initial dysbiosis chiefly due to associated irregular bleeding but long term use of LNG IUS stabilizes the microbiome. Use of injectable DMPA though does not increase the susceptibility to HIV but can promote growth of anaerobic organisms. Literature regarding condom, diaphragm and sponge is very scanty to draw a meaningful conclusion. Hence contraceptive methods can affect the vaginal health. There is need to periodically assess the vaginal milieu using test which is appropriate as per available expertise, infrastructure and cost and treat vaginal dysbiosis in respective cohorts to prevent reproductive morbidity.
Towards individualized Medicine in Stroke – the TiMeS project: protocol of longitudinal, multi-modal, multi-domain study in stroke
Authors: Fleury L , Koch PJ , Wessel MJ , Bonvin C , San Millan D , Constantin C , Vuadens P , Adolphsen J , Cadic-Melchior AG , Brügger J , Beanato E , Ceroni M , Menoud P , de Leon Rodriguez D , Zufferey V , Meyer N , Egger P , Harquel S , Popa T , Raffin E , Girard G , Thiran JP , Vaney C , Alvarez V , Turlan J-L , Mühl A , Leger B , Morishita T , Micera S , Blanke O , Van de Ville D , Hummel FC
Published: May 2022

Despite recent improvements, complete motor recovery occurs in less than 15% of stroke patients. To improve the therapeutic outcomes, there is a strong need to tailor treatments to each individual patient. However, there is a lack of knowledge concerning the precise neuronal mechanisms underlying the degree and course of motor recovery and its individual differences, especially in the view of network properties despite the fact that it became more and more clear that stroke is a network disorder. The TiMeS project is a longitudinal exploratory study aiming at characterizing stroke phenotypes of a large, representative stroke cohort through an extensive, multi-modal and multi-domain evaluation. The ultimate goal of the study is to identify prognostic biomarkers allowing to predict the individual degree and course of motor recovery and its underlying neuronal mechanisms paving the way for novel interventions and treatment stratification for the individual patients. A total of up to 100 patients will be assessed at 4 timepoints over the first year after the stroke: during the first (T1) and third (T2) week, then three (T3) and twelve (T4) months after stroke onset. To assess underlying mechanisms of recovery with a focus on network analyses and brain connectivity, we will apply synergistic state-of-the-art systems neuroscience methods including functional, diffusion, and structural magnetic resonance imaging (MRI), and electrophysiological evaluation based on transcranial magnetic stimulation (TMS) coupled with electroencephalography (EEG) and electromyography (EMG). In addition, an extensive, multi-domain neuropsychological evaluation will be performed at each timepoint, covering all sensorimotor and cognitive domains. This project will significantly add to the understanding of underlying mechanisms of motor recovery with a strong focus on the interactions between the motor and other cognitive domains and multimodal network analyses. The population-based, multi-dimensional dataset will serve as a basis to develop biomarkers to predict outcome and promote personalized stratification towards individually tailored treatment concepts using neuro-technologies, thus paving the way towards personalized precision medicine approaches in stroke rehabilitation.
A longitudinal causal graph analysis investigating modifiable risk factors and obesity in a European cohort of children and adolescents
Authors: Foraita Ronja , Witte Janine , Börnhorst Claudia , Gwozdz Wencke , Pala Valeria , Lissner Lauren , Lauria Fabio , Reisch Lucia A , Molnár Dénes , De Henauw Stefaan , Moreno Luis , Veidebaum Toomas , Tornaritis Michael , Pigeot Iris , Didelez Vanessa
Published: May 2022

Childhood obesity is a complex disorder that appears to be influenced by an interacting system of many factors. Taking this complexity into account, we aim to investigate the causal structure underlying childhood obesity. Our focus is on identifying potential early, direct or indirect, causes of obesity which may be promising targets for prevention strategies. Using a causal discovery algorithm, we estimate a cohort causal graph (CCG) over the life course from childhood to adolescence. We adapt a popular method, the so-called PC-algorithm, to deal with missing values by multiple imputation, with mixed discrete and continuous variables, and that takes background knowledge such as the time-structure of cohort data into account. The algorithm is then applied to learn the causal relations among 51 variables including obesity, early life factors, diet, lifestyle, insulin resistance, puberty stage and cultural background of 5,112 children from the European IDEFICS/I.Family cohort across three waves (2007-2014). The robustness of the learned causal structure is addressed in a series of alternative and sensitivity analyses; in particular, we use bootstrap resamples to assess the stability of aspects of the learned CCG. Our results suggest some but only indirect possible causal paths from early modifiable risk factors, such as audio-visual media consumption and physical activity, to obesity (measured by age- and sex-adjusted BMI z-scores) six years later.
Preceding anti-spike IgG levels predicted risk and severity of COVID-19 during the Omicron-dominant wave in Santa Fe city, Argentina
Authors: Eberhardt Ayelen T. , Simoncini Melina , Piña Carlos , Galoppo Germán , Parachú-Marco Virginia , Racca Andrea , Arce Sofía , Viotto Evangelina , Facelli Florencia , Valli Florencia , Botto Cecilia , Scarpa Leonardo , Junges Celina , Palavecino Cintia , Beccaria Camila , Sklar Diego , Mingo Graciela , Genolet Alicia , de Toro Mónica Muñoz , Aimar Hugo , Marignac Verónica , Bossio Juan Carlos , Armando Gustavo , Fernández Hugo , Beldomenico Pablo M.
Published: May 2022

The SARS-CoV-2 Omicron variant has increased infectivity and immune escape compared with previous variants, and caused massive COVID-19 waves globally. Despite a vast majority (∼90%) of the population of Santa Fe city, Argentina, had been vaccinated and/or had been infected by SARS-CoV-2 by the arrival of Omicron, the epidemic wave that followed was by far the largest one experienced in the city. A serosurvey conducted prior to the arrival of Omicron allowed to assess the acquired humoural defences preceding the wave and to evaluate associations with infection risk and severity during the wave. A very large proportion of the 1455 sampled individuals had immunological memory against COVID-19 at the arrival of Omicron (almost 90%), and about half (48.9%) had high anti-Spike IgG levels (>200 UI/ml). The antibody titres were strongly associated with the number of vaccine shots and the vaccine platform received, and also depended markedly on prior COVID-19 diagnosis and the days elapsed since last antigen exposure (vaccine shot or natural infection). Following-up 514 participants provided real-world data linking antibody levels with protection against COVID-19 during a period of high risk of exposure to an immune-escaping highly transmissible variant. Pre-wave antibody titres were strongly associated with COVID-19 incidence and severity of symptoms during the wave. Also, receiving a vaccine shot during the follow-up period reduced the COVID-19 risk drastically (15-fold). These results highlight the importance of maintaining high defences through vaccination anticipating or during a period of high risk of exposure to immune-escaping variants.
Accelerated Aging Mediates the Associations of Unhealthy Lifestyles with Cardiovascular Disease, Cancer, and Mortality: Two Large Prospective Cohort Studies
Authors: Li Xueqin , Cao Xingqi , Zhang Jingyun , Fu Jinjing , Mohedaner Mayila , Danzengzhuoga  , Sun Xiaoyi , Yang Gan , Yang Zhenqing , Kuo Chia-Ling , Chen Xi , Cohen Alan A , Liu Zuyun
Published: May 2022

With a well-validated aging measure – Phenotypic Age Acceleration (PhenoAgeAccel), this study examined whether and to what extent aging mediates the associations of unhealthy lifestyles with adverse health outcomes. Data were from 405,944 adults (40-69 years) from UK Biobank (UKB) and 9,972 adults (20-84 years) from US National Health and Nutrition Examination Surveys (NHANES). The mediation proportion of PhenoAgeAccel in associations of unhealthy lifestyles with incident cardiovascular disease, incident cancer, and all-cause mortality were 20.0%, 17.8%, and 26.6% (P values <0.001) in UKB, respectively. The mediation proportion of PhenoAgeAccel in associations of lifestyles with cancer mortality, and all-cause mortality were 25.7%, and 35.2% (P values <0.05) in NHANES, respectively. This study demonstrated that accelerated aging partially mediated the associations of lifestyles with adverse health outcomes in UK and US populations. The findings reveal a novel pathway and the potential of geroprotective programs in mitigating health inequality in late-life beyond lifestyle interventions.
A Novel Hybrid Classical- Quantum Network to Detect Epileptic Seizures
Authors: Sameer Mustafa , Gupta Bharat
Published: May 2022

Background

Machine learning (ML) has paved the way for scientists to develop effective computer-aided diagnostic (CAD) systems. In recent years, epileptic seizure detection using Electroencephalogram (EEG) data and deep learning models has gained much attention. However, in deep learning networks, the bottleneck is a large number of learnable parameters.

Method

In this study, a novel approach comprising a 1D-Convolutional Neural Network (CNN) model for feature extraction followed by classical-quantum hybrid layers for classification purpose has been proposed. The proposed technique has only 745 learning parameters, which is the least reported to date.

Result

The proposed method has achieved a maximum accuracy, sensitivity, and specificity of 100% for binary classification on the Bonn EEG dataset. In addition, the noise robustness of the proposed model has also been checked. To the best of the author’s knowledge, this is the first study to employ quantum machine learning (QML) to detect epileptic seizures.

Conclusion

Thus, the developed hybrid system will help neurologists to detect seizures in online mode.
Temporally dissociable mechanisms of spatial, feature, and motor selection during working memory-guided behavior
Authors: Ester Edward , Weese Rachel
Published: May 2022

Working Memory (WM) is a capacity- and duration-limited system that forms a temporal bridge between fleeting sensory phenomena and possible actions. But how are the contents of WM used to guide behavior? A recent high-profile study reported evidence for simultaneous access to WM content and linked motor plans during WM-guided behavior, challenging serial models where task-relevant WM content is first selected and then mapped on to a task-relevant motor response. However, the task used in that study was not optimized to distinguish the selection of spatial versus non-spatial visual information stored in memory, nor to distinguish whether or how the chronometry of selecting non-spatial visual information stored in memory might differ from the selection of linked motor plans. Here, we revisited the chronometry of spatial, feature, and motor selection during WM-guided behavior using a task optimized to disentangle these processes. Concurrent EEG and eye position recordings revealed clear evidence for temporally dissociable spatial, feature, and motor selection mechanisms during this task, partially replicating yet also extending previous findings. More generally, our data reveal the existence of multiple WM selection mechanisms that belie conceptualizations of WM-guided behavior based on purely serial or parallel visuomotor processing.
Evidence for different greater-persistence strategies under lower and higher challenge for alcohol in female rats
Authors: De Oliveira Sergio Thatiane , Darevsky David , de Paula Soares Vanessa , de Cassia Albino Maryelle , Maulucci Danielle , Wean Sarah , Hopf Frederic W.
Published: May 2022

Problem alcohol drinking is a substantial social and economic burden. Studies show that the misuse of alcohol is increasing in women, and that women can face higher consequences from alcohol exposure, but females have historically been understudied. Thus, there is considerable interest in understanding potential sex-different and -similar cognitive/emotional strategies, and underlying mechanisms, for alcohol responding, which would inform more effective, personalized treatments. Here, we used large cohorts of adult Wistar rats (28 females, 30 males) to provide robust assessment of potential sex differences in responding for alcohol-only and under compulsion-like drinking with moderate or higher challenge (since intake despite negative consequences can be a major obstacle to human treatment). Females had similar total licking but higher intake for all drinking conditions. However, females had significantly longer bouts under alcohol-only and moderate challenge, but not higher challenge. Further, under higher challenge, females retained several aspects of responding not seen in males, including more efficient lick volume and earlier onset of longer bouts. In addition, females overall licked slightly faster, but licking speed averaged within-bout showed no sex differences, and female intake level under alcohol-only and moderate challenge was unlinked from licking speed (unlike males, where slower licking predicted lower intake). We interpret these differences as greater persistence-like responding but not vigor per se in females, and with different strategies under lower versus higher challenge. Finally, drinking levels did not differ across the estrous cycle, although ovariectomy reduced alcohol-only and moderate-challenge intake. Together, while many aspects were sex-similar, suggesting some common drinking mechanisms, there was clear evidence for (perhaps more nuanced) sex-different alcohol strategies, which might make an outsized contribution to excessive drinking since women can have more drinking problems. Thus, our studies provide important context for future work examining sex differences in pathological drinking mechanisms.
Narrowband gamma oscillations propagate and synchronize throughout the mouse thalamocortical visual system
Authors: Shin Donghoon , Peelman Kayla , Rosario Joseph Del , Haider Bilal
Published: May 2022

Rhythmic oscillations of neural activity permeate sensory systems. Studies in the visual system propose that broadband gamma oscillations (30 – 80 Hz) facilitate neuronal communication underlying visual perception. However, broadband gamma oscillations within and across visual areas show widely varying frequency and phase, providing constraints for synchronizing spike timing. Here, we analyzed data from the Allen Brain Observatory and performed new experiments that show narrowband gamma (NBG) oscillations (50 – 70 Hz) propagate and synchronize throughout the awake mouse thalamocortical visual system. Lateral geniculate (LGN) neurons fired with millisecond precision relative to NBG phase in primary visual cortex (V1) and multiple higher visual areas (HVAs). NBG in HVAs depended upon retinotopically aligned V1 activity, and neurons that fired at NBG frequencies showed enhanced functional connectivity within and across visual areas. Remarkably, LGN ON versus OFF neurons showed distinct and reliable spike timing relative to NBG oscillation phase across LGN, V1, and HVAs. Taken together, NBG oscillations may serve as a novel substrate for precise coordination of spike timing in functionally distinct subnetworks of neurons spanning multiple brain areas during awake vision.
Whole-genome scanning reveals selection mechanisms in epipelagic Chaetoceros diatom populations
Authors: Nef Charlotte , Madoui Mohammed-Amin , Pelletier Éric , Bowler Chris
Published: May 2022

Diatoms form a diverse and abundant group of photosynthetic protists that are essential players in marine ecosystems. However, the microevolutionary structure of their populations remains poorly understood, particularly in polar regions. Exploring how closely related diatoms adapt to different oceanic ecoregions is essential given their short generation times, which may allow rapid adaptations to different environments; and their prevalence in marine regions dramatically impacted by climate change, such as the Arctic and Southern Oceans. Here, we address genetic diversity patterns in Chaetoceros, the most abundant diatom genus and one of the most diverse, using 11 metagenome-assembled genomes (MAGs) reconstructed from Tara Oceans metagenomes. Genome-resolved metagenomics on these MAGs confirmed a prevalent distribution of Chaetoceros in the Arctic Ocean with lower dispersal in the Pacific and Southern Oceans as well as in the Mediterranean Sea. Single nucleotide variants identified within the different MAG populations allowed us to draw a first landscape of Chaetoceros genetic diversity and to reveal an elevated genetic structure in some Arctic Ocean populations with FST levels ranging up to ≥ 0.2. Genetic differentiation patterns of closely related Chaetoceros populations appear to be correlated with abiotic factors rather than with geographic distance. We found clear positive selection of genes involved in nutrient availability responses, in particular for iron (e.g., ISIP2a, flavodoxin), silicate and phosphate (e.g., polyamine synthase), that were further confirmed in Chaetoceros transcriptomes. Altogether, these results provide new insights and perspectives into diatom metapopulation genomics through the integration of metagenomic and environmental data.
IMPROVE-DD: Integrating Multiple Phenotype Resources Optimises Variant Evaluation in genetically determined Developmental Disorders
Authors: Aitken Stuart , Firth Helen V , Wright Caroline F , Hurles Matthew E , FitzPatrick David R , Semple Colin A.
Published: May 2022

Diagnosing rare developmental disorders using genome-wide sequencing data commonly necessitates review of multiple plausible candidate variants, often using ontologies of categorical clinical terms. We show that Integrating Multiple Phenotype Resources Optimises Variant Evaluation in Developmental Disorders (IMPROVE-DD) by incorporating additional classes of data commonly available to clinicians and recorded in health records. In doing so, we quantify the distinct contributions of gender, growth, and development in addition to Human Phenotype Ontology (HPO) terms, and demonstrate added value from these readily-available information sources. We use likelihood ratios for nominal and quantitative data and propose a novel classifier for HPO terms in this framework. This Bayesian framework results in more robust diagnoses. Using data systematically collected in the DDD study, we considered 77 genes with pathogenic/likely pathogenic variants in >10 probands. All genes showed at least a satisfactory prediction by ROC when testing on training data (AUC≥0.6), and HPO terms were the best individual predictor for the majority of genes, though a minority (13/77) of genes were better predicted by other phenotypic data types. Overall, classifiers based upon multiple integrated phenotypic data sources performed better than those based upon any individual source, and importantly, integrated models produced notably fewer false positives. Finally, we show that IMPROVE-DD models with good predictive performance on cross-validation can be constructed from relatively few cases. This suggests new strategies for candidate gene prioritisation, and highlights the value of systematic clinical data collection to support diagnostic programmes.
Optical Genome Mapping Identifies a Novel Pediatric Embryonal Tumor Subtype with a ZNF532-NUTM1 Fusion
Authors: Bornhorst Miriam , Eze Augustine , Bhattacharya Surajit , Putnam Ethan , Almira-Suarez M. Isabel , Rossi Christopher , Kambhampati Madhuri , Almalvez Miguel , Turner Joyce , Myseros John , Vilain Eric , Packer Roger J. , Nazarian Javad , Rood Brian , Barseghyan Hayk
Published: May 2022

Molecular characteristics of pediatric brain tumors have not only allowed for tumor subgrouping but have introduced novel treatment options for patients with specific tumor alterations. Therefore, an accurate histologic and molecular diagnosis is critical for optimized management of all pediatric patients with brain tumors, including central nervous system embryonal tumors. We present a case where optical genome mapping identified a ZNF532-NUTM1 fusion in a patient with a unique tumor best characterized histologically as a central nervous system embryonal tumor with rhabdoid features. Additional analyses including immunohistochemistry for NUT protein, methylation array, whole genome, and RNA-sequencing was done to confirm the presence of the fusion in the tumor. This is the first description of a pediatric patient with a ZNF532-NUTM1 fusion, yet the histology of this tumor is similar to that of adult cancers with ZNF-NUTM1 fusions and other NUTM1-fusion positive brain tumors reported in literature. Although rare, the distinct pathology and underlying molecular characteristics of these tumors separate them from other embryonal tumors. Therefore, the NUTM-rearrangement appears to define a novel subgroup of pediatric central nervous system embryonal tumors with rhabdoid/epithelioid features that may have a unique response to treatment. Screening for a NUTM1-rearrangement should be considered for all patients with unclassified central nervous system tumors with rhabdoid features to ensure accurate diagnosis so this can ultimately inform therapeutic management for these patients.
Spatial memory training reverses GirK channels modulation in the transgenic APPSw,Ind Alzheimer’s disease mouse model
Authors: Temprano-Carazo Sara , Contreras Ana , Saura Carlos A. , Navarro-López Juan , Jiménez-Díaz Lydia
Published: May 2022

Alzheimer’s disease (AD) is a dementia characterized by progressive memory decline and neurodegeneration caused by the accumulation of amyloid-β (Aβ) peptides. Last findings point to an imbalance between excitatory and inhibitory neurotransmission as the initial impairment in early stages, and the hippocampus as one of the most susceptible brain areas.

The G-protein-gated inwardly rectifying potassium (GirK) channel has been proposed as a potential target to restore excitatory/inhibitory balance in amyloidosis models. Moreover, cognitive training may counteract early AD symptoms, although its effect on GirK channels remains unknown.

Here, the effect of genotype, age, and training in a hippocampal-dependent memory task on the protein expression of GirK subunits and modulators were studied using APPSw,Ind mice. Results showed a reduction of GirK2 expression as well as an increased expression of SNX27 in the hippocampus of 6-month-old APPSw,Ind mice. Training in a memory task restored GirK2 and SNX27 levels. Thus, the effect of Aβ on GirK2 could account for the excitatory/inhibitory imbalance transmission found in AD models, and training in a cognitive hippocampal-dependent task reverses this effect and lessens early Aβ-dependent AD deficits.

Summary statement

Aβ decreases hippocampal GirK2 expression in APPSw,Ind mice, which could contribute to early hyperexcitability found in Alzheimer’s disease models. Training in spatial memory tasks has shown to counteract this reduction.
Connectivity by the Frontal Aslant Tract (FAT) explains local functional specialization of the superior and inferior frontal gyri in humans while choosing predictive over reactive strategies: a tractography-guided TMS study
Authors: Tagliaferri Marco , Giampiccolo Davide , Parmigiani Sara , Amorosino Gabriele , Avesani Paolo , Cattaneo Luigi
Published: May 2022

Predictive and reactive behaviors represent two mutually exclusive strategies for successfully completing a sensorimotor task. It is thought that predictive actions are based on the medial premotor system, in the superior frontal gyrus (SFG) and reactive stimulus-response behaviors rely on a lateral premotor system, in the inferior frontal gyrus (IFG). The frontal aslant tract (FAT), a white matter tract connecting SFG and IFG, is a possible neural substrate of the predictive/reactive interactions. We used diffusion-weighted imaging (DWI) of 17 male and female healthy human volunteers, to dissect 3 sub-bundles of fibers belonging to the left FAT (bundles 1, 2 and 3), arising ventrally from 1) the ventral precentral gyrus, 2) midway between the PCG and pars opercularis (POp) and 3) the POp and terminating dorsally in 3 different parts of the SFG, in a caudal-rostral order. We applied online transcranial magnetic stimulation (TMS) to 6 spots, corresponding to the medial and lateral terminations of bundles 1-3 during the fixed-duration set period of a delayed reaction task, that can be solved using a predictive (anticipatory) strategy or with a reactive strategy. Results showed that TMS changed the frequency of predictive/reactive strategies only when applied over 2 spots, the SFG and IFG terminations of bundle 2. Importantly, the effects of TMS were opposite when applied to the SFG or to the IFG. Our data show that the SFG and the IFG have opposite roles in producing predictive or reactive behavior and that reciprocal integration or competition is probably mediated by the FAT.

Significance Statement

As is well-known by athletes at starting blocks, interaction with the world can occur with a predictive strategy (anticipating a GO-signal) or a reactive strategy (waiting for the GO-signal to be manifest) and they are mutually exclusive. Here we showed, by using non-invasive brain stimulation (TMS), that two specific cortical regions in the superior frontal gyrus (SFG) and the inferior frontal gyrus (IFG) have opposite roles in facilitating a predictive or a reactive strategy. Importantly these two very distant regions but with highly interconnected functions are specifically connected by a small white matter bundle, which probably mediates the competition between predictive and reactive strategies. More generally, we show that the implementing anatomical connectivity in TMS studies strongly reduces spatial noise.
Lipid nanoparticle topology regulates endosomal escape and delivery of RNA to the cytoplasm
Authors: Zheng Lining , Bandara Sarith R. , Leal Cecilia
Published: May 2022

RNA therapeutics have the potential to resolve a myriad of diseases caused by gene deficiency. Lipid nanoparticles (LNPs) are one of the most successful RNA delivery systems. However, expanding their application hinges on the discovery of next generation LNPs with high potency, cyto-specific targeting, and low side effects. Overcoming the difficulty of releasing cargo from endocytosed LNPs remains a significant hurdle. The endosomal escape of viral and non-viral nanoparticles relies on the topological transformation of membrane fusion pore formation followed by RNA translocation into the cytosol. In this study we show that LNP-RNA nanostructure modulates the energetic cost of LNP fusion with a target membrane. The inclusion of a new class of structurally-active lipids leads to superior LNP endosomal fusion, fast evasion of endosomal entrapment, and efficacious RNA delivery. Specifically, bicontinuous cubic RNA-LNPs, cuboplexes, have significantly higher endosomal escape rates and deliver more RNA compared to regular lamellar LNPs.
Effects of altered cellular ultrastructure on energy metabolism in diabetic cardiomyopathy – an in-silico study
Authors: Ghosh Shouryadipta , Guglielmi Giovanni , Orfanidis Ioannis , Spill Fabian , Hickey Anthony , Hanssen Eric , Rajagopal Vijay
Published: May 2022

Diabetic cardiomyopathy is a leading cause of heart failure in diabetes. At the cellular level, diabetic cardiomyopathy leads to altered mitochondrial energy metabolism and cardiomyocyte ultrastructure. We combined electron microscopy and computational modelling to understand the impact of diabetes induced ultrastructural changes on cardiac bioenergetics.

We collected transverse micrographs of multiple control and type I diabetic rat cardiomyocytes using electron microscopy. Micrographs were converted to finite element meshes, and bioenergetics was simulated over them using a biophysical model. The simulations also incorporated depressed mitochondrial capacity for oxidative phosphorylation and creatine kinase reactions to simulate diabetes induced mitochondrial dysfunction.

Analysis of micrographs revealed a 14% decline in mitochondrial area fraction in diabetic cardiomyocytes, and an irregular arrangement of mitochondria and myofibrils. Simulations predicted that this irregular arrangement, coupled with depressed activity of mitochondrial creatine kinase enzymes, leads to large spatial variation in ADP/ATP profile of diabetic cardiomyocytes. However, when spatially averaged, myofibrillar ADP/ATP ratios of a cardiomyocyte do not change with diabetes. Instead, average concentration of inorganic phosphate rises by 40% due to lower mitochondrial area fraction and dysfunction in oxidative phosphorylation. These simulations indicate that a disorganized cellular ultrastructure negatively impacts metabolite transport in diabetic cardiomyopathy.
Automated annotation of human centromeres with HORmon
Authors: Kunyavskaya Olga , Dvorkina Tatiana , Bzikadze Andrey V. , Alexandrov Ivan A. , Pevzner Pavel A.
Published: May 2022

Recent advances in long-read sequencing opened a possibility to address the long-standing questions about the architecture and evolution of human centromeres. They also emphasized the need for centromere annotation (partitioning human centromeres into monomers and higher-order repeats [HORs]). Although there was a half-century-long series of semi-manual studies of centromere architecture, a rigorous centromere annotation algorithm is still lacking. Moreover, an automated centromere annotation is a prerequisite for studies of genetic diseases associated with centromeres and evolutionary studies of centromeres across multiple species. Although the monomer decomposition (transforming a centromere into a monocentromere written in the monomer alphabet) and the HOR decomposition (representing a monocentromere in the alphabet of HORs) are currently viewed as two separate problems, we show that they should be integrated into a single framework in such a way that HOR (monomer) inference affects monomer (HOR) inference. We thus developed the HORmon algorithm that integrates the monomer/HOR inference and automatically generates the human monomers/HORs that are largely consistent with the previous semi-manual inference.
A complete pedigree-based graph workflow for rare candidate variant analysis
Authors: Markello Charles , Huang Charles , Rodriguez Alex , Carroll Andrew , Chang Pi-Chuan , Eizenga Jordan , Markello Thomas , Haussler David , Paten Benedict
Published: May 2022

Methods that use a linear genome reference for genome sequencing data analysis are reference-biased. In the field of clinical genetics for rare diseases, a resulting reduction in genotyping accuracy in some regions has likely prevented the resolution of some cases. Pangenome graphs embed population variation into a reference structure. Although pangenome graphs have helped to reduce reference mapping bias, further performance improvements are possible. We introduce VG-Pedigree, a pedigree-aware workflow based on the pangenome-mapping tool of Giraffe and the variant calling tool DeepTrio using a specially trained model for Giraffe-based alignments. We demonstrate mapping and variant calling improvements in both single-nucleotide variants (SNVs) and insertion and deletion (indel) variants over those produced by alignments created using BWA-MEM to a linear-reference and Giraffe mapping to a pangenome graph containing data from the 1000 Genomes Project. We have also adapted and upgraded deleterious-variant (DV) detecting methods and programs into a streamlined workflow. We used these workflows in combination to detect small lists of candidate DVs among 15 family quartets and quintets of the Undiagnosed Diseases Program (UDP). All candidate DVs that were previously diagnosed using the Mendelian models covered by the previously published methods were recapitulated by these workflows. The results of these experiments indicate that a slightly greater absolute count of DVs are detected in the proband population than in their matched unaffected siblings.