bluuebunny/crossref_metadata_2025 huggingface dataset:
CD4+T cell mitochondrial genotype in Multiple Sclerosis: a cross-sectional and longitudinal analysis
Authors: Cortes-Figueiredo Filipe , Asseyer Susanna , Chien Claudia , Zimmermann Hanna G. , Ruprecht Klemens , Schmitz-Hübsch Tanja , Bellmann-Strobl Judith , Paul Friedemann , Morais Vanessa A.
Published: March 2023

2.

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), with a largely unknown etiology, where mitochondrial dysfunction significantly contributes to neuroaxonal loss and brain atrophy. Mirroring the CNS, peripheral immune cells from patients with MS, particularly CD4+T cells, show inappropriate mitochondrial phenotypes and/or oxidative phosphorylation (OxPhos) insufficiency, with a still unknown contribution of mitochondrial DNA (mtDNA). We hypothesized that mitochondrial genotype in CD4+T cells might influence MS disease activity and progression.

Thus, we performed a retrospective cross-sectional and longitudinal study on patients with a recent diagnosis of either Clinically Isolated Syndrome (CIS) or Relapsing-Remitting MS (RRMS) at two timepoints: six months (VIS1) and 36 months (VIS2) after disease onset. Our primary outcomes were the differences in mtDNA extracted from CD4+T cells between: (I) patients with CIS/RRMS (PwMS) at VIS1 and age- and sex-matched healthy controls (HC), in the cross-sectional analysis, and (II) different diagnostic evolutions in PwMS from VIS1 to VIS2, in the longitudinal analysis.

We successfully performed mtDNA whole genome sequencing (WGS) (mean coverage: 2055.77 reads/base pair) in 183 samples (61 triplets). Nonetheless, mitochondrial genotype was not associated with a diagnostic of CIS/RRMS, nor with longitudinal diagnostic evolution.
What are the priority needs for those caring for children and young people with complex neurodisability within an ethnically diverse UK context? - The feasibility phase of the ENCOMPASS study
Authors: Prest Kirsten , Wilson Emma , Vassiliadou Io , Ali Sayeeda , Lakhanpaul Monica , Morris Christopher , Tann Cally , Harniess Phillip , Lewis-Jackson Sasha , Kuper Hannah , Heys Michelle
Published: March 2023

Background

Children and young people (CYP) with complex neurodisability experience multiple physical, communication, educational and social challenges which require complex packages of multidisciplinary care. Cerebral palsy, an exemplar complex neurodisability condition, is the most common cause of serious physical disabilities among children globally. It is unclear the best way to meet the emotional, social, practical, and empowerment needs of CYP with complex neurodisability and their caregivers. The aim of this study was to determine the needs and priorities of those caring for CYP with complex neurodisability. This forms part of the feasibility phase of a wider study (ENCOMPASS) which aims to adapt the ‘Baby Ubuntu’ intervention, a participatory caregiver programme for families of CYP with complex neurodisability, to an ethnically diverse urban UK context.

Methods

Two rounds of semi-structured interviews were conducted with 12 caregivers of CYP with complex neurodisability and six healthcare professionals from a variety of disciplines, recruited from a community child health service in London Borough of Newham, UK in 2020. The interviews included open-ended questions to explore caregiving trajectories, experiences of navigating health services and perceived service gaps. Transcripts were analysed using a data-driven inductive thematic analysis.

Results

Three themes were identified that related to the aim of understanding caregivers’ experiences and unmet needs relating to current service provision. These were (1) Caregiver Mental Health, (2) A Thirst for Knowledge and (3) The Need for Holistic Support. Mental health difficulties were reported, particularly around the period of diagnosis. Priority needs included the provision of clear information about the diagnosis and services offered, opportunities to forge peer support networks and for services across the community to collaborate.

Conclusions

The delivery of health services for CYP with neurodisability should encompass the broad needs of the family as well as meeting the clinical needs of the CYP.
Sleep features and long-term incident neurodegeneration: a polysomnographic study
Authors: Ibrahim Abubaker , Cesari Matteo , Heidbreder Anna , Defrancesco Michaela , Brandauer Elisabeth , Seppi Klaus , Kiechl Stefan , Högl Birgit , Stefani Ambra
Published: March 2023

While a growing body of studies suggests a link between sleep disturbances and neurodegenerative diseases’ (NDDs) development, prior studies have been hindered by small sample sizes, short follow-up times and a lack of objective sleep measures.

In this cohort study, patients who underwent polysomnography (PSG) at the Innsbruck Sleep Disorders Unit from January 2004 to December 2007, aged ≥18 years, without NDDs at baseline or within five years post PSG, and with at least five years clinical follow-up were included. The main outcome measure was NDDs diagnosis at least five years after polysomnography, assessed until December 2021.

Of 1454 patients assessed for eligibility, 999 (68.7%) met inclusion criteria (683 (68.3%) men; median age 54.9 (interquartile range, IQR 33.9-62.7) years. Seventy-five patients (7.5%) developed NDDs, 924 (92.5%) remained disease-free after 12.8 (IQR 9.9-14.6) years median follow-up. After adjusting for demographic, sleep, and clinical covariates, each percent decrease in sleep efficiency, N3 sleep, or REM sleep was associated with 1.9%, 6.5%, and 5.2% increased risk of incident NDDs (hazard ratio, HR, 1.019, CI:1.002-1.035; HR 1.065, CI:1.007-1.118; HR 1.052, CI:1.012-1.085,), respectively whereas one percent decrease in night-time wakefulness represented a 2.2% reduced risk (HR 0.978, CI:0.958-0.997). Random forest analysis identified wake, followed by N3 and REM sleep percentages, as the most important feature associated with NDDs development. Additionally, multiple sleep features combination offered more robust discrimination of incident NDDs compared to single sleep stages.

These findings support contribution of sleep architecture changes to NDDs pathogenesis and provide insights into the temporal window during which these changes are detectable, pointing to sleep as early NDDs marker and potential target of neuroprotective strategies.
Association between maternal high-risk fertility behaviour and perinatal mortality in Bangladesh: evidence from the Demographic and Health Survey
Authors: Khan Md Nuruzzaman , Harris Melissa L.
Published: March 2023

Background

High risk fertility behaviours including pregnancy early or late in the reproductive life course, higher parity and short birth intervals are ongoing concerns in Low- and Middle-Income Countries (LMICs) such as Bangladesh. Although such factors have been identified as major risk factors for perinatal mortality, there has been a lack of progress in the area despite the implementation of the Millennium and Sustatinable Development Goals. We therefore explored the effects of high risk maternal fertility behaviour on the occurrence of perinatal mortality in Bangladesh.

Methods

A total of 8,930 singleton pregnancies of seven or more months gestation were extracted from 2017/18 Bangladesh Demographic and Health Survey for analysis. Perinatal mortality was the outcome variable (yes, no) and the primary exposure variable was high-risk fertility behaviour in the previous five years (yes, no). The association between the exposure and outcome variable was determined using a mixed-effect multilevel logistic regression model, adjusted for covariates.

Results

Forty-six percent of the total births that occurred in the five years preceding the survey were high-risk. After adjusting for potential confounders, a 1.87 times (aOR, 1.87, 95% CI, 1.61-2.14) higher odds of perinatal mortality was found among women with any high-risk fertility behaviour as compared to women having no high-risk fertility behaviours. The odds of perinatal mortality were also found to increase in line with an increasing number of high-risk behaviour. A 1.77 times (95% CI, 1.50-2.05) increase in odds of perinatal mortality was found among women with single high-risk fertility behaviour and a 2.30 times (95% CI, 1.96-2.64) increase in odds was found among women with multiple high-risk fertility behaviours compared to women with no high-risk fertility behaviour.

Conclusion

Women’s high-risk fertility behaviour is an important predictor of perinatal mortality in Bangladesh. Increased contraceptive use to allow appropriate birth spacing, educational interventions around the potential risks associated with high risk fertility behaviour (including short birth interval) in future pregnacies, and improved continuity of maternal healthcare service use among this population are required to improve birth outcomes in Bangladesh.
Epigenetic clock acceleration is linked to earlier onset and phenoconversion age in REM sleep behavior disorder
Authors: Senkevich Konstantin , Pelletier Amélie , Sato Christine , Keil Allison , Gan-Or Ziv , Lang Anthony E. , Postuma Ronald , Rogaeva Ekaterina
Published: March 2023

Rapid-eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA-methylation-age (DNAm-age) is an epigenetic clock that could reflect biological aging. We evaluated whether RBD age-at-onset/phenoconversion are associated with DNAm-age-acceleration in 162 RBD patients. We found an association of DNAm-age-acceleration with RBD age-at-onset at baseline (P=2.59e-08) and at follow-up (N=45; P=9.73e-06). RBD patients with faster aging had 4.6 years earlier onset than patients with slow/normal aging. Similarly, earlier age-at-phenoconversion was associated with DNAm-age-acceleration (N=53; P=1.26e-04). We demonstrated that epigenetic clock acceleration is linked with an earlier RBD age-at-onset and, hence with earlier phenoconversion.
Role of non-classical monocytes in HIV-associated vascular cognitive impairment
Authors: Singh Meera V , Uddin Md Nasir , Vidalle Mae Covacevich , Sutton Karli R. , Boodoo Zachary D. , Peterson Angelique N. , Tyrell Alicia , Brenner Raeann , Tivarus Madalina E , Wang Henry Z. , Sahin Bogachan , Zhong Jianhui , Weber Miriam , Wang Lu , Qiu Xing , Maggiwar Sanjay B. , Schifitto Giovanni
Published: March 2023

Despite antiretroviral treatment (cART), people living with HIV (PLWH) are more susceptible to neurocognitive impairment (NCI), probably due to synergistic/additive contribution of traditional cerebrovascular risk factors. Specifically, altered blood brain barrier (BBB) and transmigration of inflammatory monocytes are risk factors for developing cerebral small vessel disease (CSVD). In order to investigate if inflammatory monocytes exacerbate CSVD and cognitive impairment, 110 PLWH on cART and 110 age-, sex- and Reynold’s cardiovascular risk score-matched uninfected individuals were enrolled. Neuropsychological testing, brain magnetic resonance imaging and whole blood analyses to measure platelet-monocyte interaction and monocyte, endothelial activation were performed. Results demonstrated that PLWH exhibited increased levels of platelet-monocyte complexes (PMCs) and higher expression of activation molecules on PMCs. PLWH with CSVD had the poorest cognitive performance and the highest circulating levels of non-classical monocytes which exhibited significant inverse correlation with each other. Furthermore, markers of monocyte and endothelium activation were significantly positively correlated indicating BBB impairment. Our results confirm that interaction with platelets activates and drives monocytes towards an inflammatory phenotype in PLWH. In particular, elevated levels of non-classical monocytes may represent a common pathway to neuroinflammation, CSVD and subsequent cognitive impairment, warranting further longitudinal studies to evaluate responsiveness of this potential biomarker.
Bacterial Isolates and their Sensitivity Profile from CSF Samples – A 5 Year Study at a Tertiary Care Hospital
Authors: Ali Muhammad Moaaz , Kaleem Fatima , Farwa Umme , Ali Haider , Ishtiaq Saima , Javed Samina , Syed Saima , Abbasi Shahid Ahmad
Published: March 2023

The death rates of medical situations like bacterial meningitis are always quite high. Cerebrospinal fluid (CSF) culture is the most common and reliable test to confirm the diagnosis of bacterial meningitis. All CSF samples that were received in the microbiology lab between January 2017 and December 2021 were included in the study. The study removed all duplicate samples and samples from patients who had recently started taking antibiotics. During the course of the trial, 2000 CSF samples were received. Just 157 of these samples successfully tested positive for the presence of infections. The results of the current investigation showed that the typical pathogens associated with meningitis were not isolated from CSF samples in our method. In contrast, in our setups, highly resistant microorganisms were isolated from CSF. primarily from patients with ventriculoperitoneal shunts.
PRERISK: A Personalized, daily and AI-based stroke recurrence predictor for patient awareness and treatment compliance
Authors: Colangelo Giorgio , Ribo Marc , Montiel Estefania , Dominguez Didier , Olive Marta , Muchada Marian , Garcia-Tornel Alvaro , Requena Manuel , Pagola Jorge , Juega Jesus , Rodriguez-Luna David , Rodriguez-Villatoro Noelia , Rizzo Federica , Taborda Belen , Molina Carlos A. , Rubiera Marta
Published: March 2023

BACKGROUND

The risk prediction of stroke recurrence for individual patients is a difficult task. Individualised prediction may enhance stroke survivors selfcare engagement. We have developed PRERISK: a statistical and Machine Learning (ML) classifier to predict individual stroke recurrence risk.

METHODS

We analysed clinical and socioeconomic data from a prospectively collected public healthcare-based dataset of 44623 patients admitted with stroke diagnosis in 88 public hospitals over 6 years in Catalonia-Spain. We trained several supervised-ML models to provide individualised risk along time and compared them with a Cox regression model.

RESULTS

Overall, 16% of patients presented a stroke recurrence along a median follow-up of 2.65 years. Models were trained for predicting early, late and long-term recurrence risk, within 90, 91-365 and >365 days, respectively. Most powerful predictors of stroke recurrence were time since index stroke, Barthel index, atrial fibrillation, dyslipidemia, haemoglobin and body mass index, which were used to create a simplified model with similar performance. The balanced AUROC were 0.77 (±0.01), 0.61 (±0.01) and 0.71 (±0.01) for early, late and long-term recurrence risk respectively (Cox risk class probability: 0.74(±0.01), 0.59(±0.01) and 0.68(±0.01), c-index 0.88). Overall, the ML approach showed statistically significant improvement over the Cox model. Stroke recurrence curves can be simulated for each patient under different degrees of control of modifiable factors.

CONCLUSION

PRERISK represents a novel approach that provides continuous, personalised and fairly accurate risk prediction of stroke recurrence along time according to the degree of modifiable risk factors control.

CLINICAL PERSPECTIVE

What is new?

Stroke recurrence is frequent after stroke despite advances in stroke treatments, and it is difficult to predict the individual risk of one patient.

We have created PRERISK, a predictive model based on machine learning (ML) which provides individualised information of the probability of stroke recurrence and can be re-calculated according to risk factors control.

What are the clinical implications?

PRERISK information can be used as feedback for secondary prevention strategies and enhance patient engagement and treatment compliance.

It could be scalable to optimise ML-based prevention strategies in other chronic conditions.
Facility-based and virtual cardiac rehabilitation in young patients with heart disease during the COVID-19 era
Authors: Aronoff Elizabeth B. , Chin Clifford , Opotowsky Alexander R. , Mays Wayne A. , Knecht Sandra K. , Goessling Jennah E. , Rice Malloree C. , Shertzer Justine , Wittekind Samuel G. , Powell Adam W.
Published: March 2023

Background

Cardiac rehabilitation (CR) is an important tool for improving fitness and quality of life in those with heart disease (HD). Few pediatric centers use CR to care for these patients, and virtual CR is rarely used. Additionally, it is unclear how the COVID-19 era has changed CR outcomes.

Objectives

This study assessed fitness improvements in young HD patients participating in both facility-based and virtual CR during the COVID-19 pandemic.

Methods

This retrospective single-center cohort study included new patients who completed CR from March 2020 through July 2022. CR outcomes included physical, performance, and psychosocial measures. Comparison between serial testing was performed with a paired t-test with P<0.05 was considered significant. Data are reported as mean±standard deviation.

Results

There were 47 patients (19±7.3 years-old; 49% male) who completed CR. Improvements were seen in peak oxygen consumption (VO2, 62.3±16.1 v 71±18.2% of predicted, p=0.0007), 6-minute walk (6MW) distance (401±163.8 v 480.7±119.2 meters, p=<0.0001), sit to stand (16.2±4.9 v 22.1±6.6 repetitions; p=<0.0001), Patient Health Questionnaire-9 (PHQ-9) (5.9±4.3 v 4.4±4.2; p=0.002), and Physical Component Score (39.9±10.1 v 44.9±8.8; p=0.002). Facility-based CR enrollees were less likely to complete CR than virtual patients (60%, 33/55 v 80%, 12/15; p=0.005). Increases in peak VO2(60±15.3 v 70.2±17.8 % of predicted; p=0.002) were seen among those that completed facility-based CR; this was not observed in the virtual group. Both groups demonstrated improvement in 6MW distance, sit-to-stand repetitions, and sit-and-reach distance.

Conclusions

Completion of a CR program resulted in fitness improvements during the COVID-19 era regardless of location.
Intra-Host Mutation Rate of Acute SARS-CoV-2 Infection During the Initial Pandemic Wave
Authors: El-Haddad Kim , Adhikari Thamali M , Jin Tu Zheng , Cheng Yu-Wei , Leng Xiaoyi , Zhang Xiangyi , Rhoads Daniel , Ko Jennifer S. , Worley Sarah , Li Jing , Rubin Brian P. , Esper Frank P.
Published: March 2023

Background

Our understanding of SARS-CoV-2 evolution and mutation rate is limited. The rate of SARS-CoV-2 evolution is minimized through a proofreading function encoded byNSP-14and may be affected by patient comorbidity. Current understanding of SARS-CoV-2 mutational rate is through population based analysis while intra-host mutation rate remains poorly studied.

Methods

Viral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) ≥0.25, ≥0.5 and ≥0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with (ΔNSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity.

Results

Forty paired samples with median interval of 13 days [IQR 8.5-20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI:90.8-96.4], 40.7 (95%CI:38.9-42.6) and 34.7 (95%CI:33.0-36.4) substitutions/genome/year at AF ≥0.25, ≥0.5, ≥0.75 respectively. Mutation rate in ΔNSP-14 were significantly elevated at AF>0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies.

Discussion

Intra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.
A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19
Authors: Van Damme Karel F.A. , Hoste Levi , Declercq Jozefien , Leeuw Elisabeth De , Maes Bastiaan , Martens Liesbet , Colman Roos , Browaeys Robin , Bosteels Cédric , Verwaerde Stijn , Vermeulen Nicky , Lameire Sahine , Debeuf Nincy , Deckers Julie , Stordeur Patrick , Guilliams Martin , Schetters Sjoerd T.T. , Haerynck Filomeen , Tavernier Simon J. , Lambrecht Bart N.
Published: March 2023

To improve COVID-19 therapy, it is essential to understand the mechanisms driving critical illness. The complement system is an essential part of innate host defense that can also contribute to injury. All complement pathways have been implicated in COVID-19 pathogenesis, however the upstream drivers and downstream consequences on tissue injury remain ill-defined. Here, we demonstrate that complement activation is mediated by the alternative pathway and we provide a comprehensive atlas of the alterations in complement around the time of respiratory deterioration. Proteome and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal and myeloid cells in the production of complement, in addition to liver-derived factors. Upstream, IL-6 drives complement responses, linking complement dysregulation to approved COVID-19 therapies. In an exploratory proteomic study, C5 inhibition improves epithelial damage and markers of disease severity. Collectively, these results identify complement dysregulation as a key druggable feature of COVID-19.
A phenotypically robust model of Spinal and Bulbar Muscular Atrophy inDrosophila
Authors: Richardson Kristin , Sengupta Medha , Sujkowski Alyson , Libohova Kozeta , Harris Autumn C. , Wessells Robert , Merry Diane E. , Todi Sokol V.
Published: March 2023

Spinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit theandrogen receptor(AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA inDrosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same “safe harbor” site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool towards future investigations of this incurable disease.
Left or right: Handedness in free-ranging Hanuman langurs (Semnopithecus entellus) residing in an urban ecosystem
Authors: Dutta Akash , Dasgupta Dishari , Banerjee Arnab , Hasnain Sk Anzar , Sen Debadrita , Kuleri Milan Sahadevan , Bhattacharjee Pritha , Paul Manabi
Published: March 2023

Examining manual lateralization (handedness) in nonhuman primates might be an interesting approach to gaining insight into the evolution of asymmetry in humans. Moreover, handedness could also reflect the effect of environmental alterations on the free-ranging animals who are forced to live with anthropogenic interferences. Despite addressing the handedness among monkeys and apes, only a few studies have focused on these free-ranging urban-adapted nonhuman primates, which could challenge our perception of habitat loss and deforestation. Here, we conducted 193 field-based experimental trials with two experimental tasks, one unimanual (simple reaching) and one bimanual (tube task) to explore manual lateralization in a highly human-provisioned group of free-ranging Hanuman langur (Semnopithecus entellus). Experimental outcomes revealed an asymmetrical hand-use distribution, with a bias toward the left hand. As bimanual tasks evoked a higher degree of lateralization, these tasks seem to be more suited to study manual laterality, and our results also highlight the significance of experimental tasks in establishing hand preference in langurs. Furthermore, this study also reveals that such lateralization developed with age as adults distinctly displayed their preference toward left-hand usage in contrast to juveniles and subadults who used both hands comparably. Mostly considered to be arboreal, the langurs of our study group spend a considerable amount of time with humans on the ground, thereby portraying a terrestrial tendency. Postural Origin Theory states that terrestrial animals tend to use their right hand and arboreal their left. Therefore, here the presence of group-level left-hand biasness in the adult langurs of Dakshineswar creates a dilemma in the Postural Origin Theory.
Frequent transitions in mating-type locus chromosomal organization inMalasseziaand early steps in sexual reproduction
Authors: Coelho Marco A. , Ianiri Giuseppe , David-Palma Márcia , Theelen Bart , Goyal Rohit , Narayanan Aswathy , Lorch Jeffrey M. , Sanyal Kaustuv , Boekhout Teun , Heitman Joseph
Published: March 2023

Fungi in the basidiomycete genusMalasseziaare the most prevalent eukaryotic microbes resident on the skin of human and other warm-blooded animals and have been implicated in skin diseases and systemic disorders. Analysis ofMalasseziagenomes revealed that key adaptations to the skin microenvironment have a direct genomic basis, and the identification of mating/meiotic genes suggests a capacity to reproduce sexually, even though no sexual cycle has yet been observed. In contrast to other bipolar or tetrapolar basidiomycetes that have either two linked mating-type-determining (MAT) loci or twoMATloci on separate chromosomes, inMalasseziaspecies studied thus far the twoMATloci are arranged in a pseudobipolar configuration (linked on the same chromosome but capable of recombining). By incorporating newly generated chromosome-level genome assemblies, and an improvedMalasseziaphylogeny, we infer that the pseudobipolar arrangement was the ancestral state of this group and revealed six independent transitions to tetrapolarity, seemingly driven by centromere fission or translocations in centromere- flanking regions. Additionally, in an approach to uncover a sexual cycle,Malassezia furfurstrains were engineered to express differentMATalleles in the same cell. The resulting strains produce hyphae reminiscent of early steps in sexual development and display upregulation of genes associated with sexual development as well as others encoding lipases and a protease potentially relevant for pathogenesis of the fungus. Our study reveals a previously unseen genomic relocation of mating-type loci in fungi and provides insight towards the discovery of a sexual cycle inMalassezia, with possible implications for pathogenicity.

Significance Statement

Malassezia, the dominant fungal group of the mammalian skin microbiome, is associated with numerous skin disorders. Sexual development and yeast-to-hyphae transitions, governed by genes at two mating-type (MAT) loci, are thought to be important for fungal pathogenicity. However,Malasseziasexual reproduction has never been observed. Here, we used chromosome-level assemblies and comparative genomics to uncover unforeseen transitions inMATloci organization withinMalassezia, possibly related with fragility of centromeric-associated regions. Additionally, by expressing differentMATalleles in the same cell, we show thatMalasseziacan undergo hyphal development and this phenotype is associated with increased expression of key mating genes along with other genes known to be virulence factors, providing a possible connection between hyphal development, sexual reproduction, and pathogenicity.
Cultivation of SAR202 Bacteria from the Ocean
Authors: Lim Yeonjung , Seo Ji-Hui , Giovannoni Stephen J. , Kang Ilnam , Cho Jang-Cheon
Published: March 2023

Here we report the first successful cultivation of SAR202 bacteria, a superorder in the phylumChloroflexota, which have long been at the top of “most wanted” lists of uncultivated microbial life. It has been proposed that ancient expansions of catabolic enzyme paralogs in SAR202 broadened the spectrum of organic compounds they could oxidize, leading to transformations of the Earth’s carbon cycle. We cultured the cells from surface seawater using dilution-to-extinction culturing. Their growth was very slow (0.18-0.24 day-1) and was inhibited by exposure to light. The genomes, of ca. 3.08 Mbp, encoded archaella, archaeal motility structures, and multiple sets of paralogs, including 80 genes in enolase superfamily and 44 genes in NAD(P)-dependent dehydrogenase family. We propose that these paralogs participate in multiple parallel pathways of non-phosphorylative sugar and sugar acid catabolism, and demonstrate that, as predicted by this scheme, the sugars ʟ-fucose and ʟ-rhamnose and their lactone and acid forms are utilized by these cells.
Stratified assessment for geriatric mental health using probabilistic graphical model: a cross-sectional observational study in India
Authors: Jha Indra Prakash , Mishra Shreya , Pandey Neetesh , Kumar Vibhor
Published: March 2023

Background

The mental health among seniors presents a diverse set of challenges that can be attributed to a number of different causes, including social factors, economic factors, and psychological factors. Researchers are attempting to understand its complexity; however, there is a limited amount of systematic robust analysis that has been conducted. It is, therefore, critical to identify and quantify the driver characteristics or factors that are related to mental health and conduct age-specific stratified analysis in order to guide and provide tailor-made policy-level interventions.

Methods

We used “Longitudinal Ageing Study in India (LASI) wave-1 survey” data of 72250 (47% male and 53% female) carried out in April 2017 to December 2018 spanning over 35 states and union territories with socioeconomic, behavioural, psychological, and health-related indicators. We utilised a probabilistic graphical model named Bayesian Network to identify key factors of mental health variables.

Results

Ageism, social discrimination (the inferred conditional probability difference is ∼30% with 95% CI: ∼5%) and Food insecurity (>19% with a 95% CI of >3%) were found to negatively impact mental health in older adults, while connectedness with family and friends (9.34% with 95% CI: 1.41%) positively affected mental health. The sense of general dissatisfaction or discontentment with one’s own life (17% with 95% of CI: ∼2.8%) is one of the factors that plays a significant role in mental health among elderly people. Additionally, multimorbidities of mental health problems in older adults, which were found to be arthritis, sleep disorders, and stroke. The incidence of multimorbidity due to mental issues were shown to be higher in older adults than younger adults, with sleep disorders being associated with mental health in older age groups. By incorporating age based stratification analysis, we also identified the specific age group when older people from India are most vulnerable to mental health issues.

Conclusion

The prevalence of mental illness in senior citizens in India needs to be reduced, and one way to do this is through the development of targeted policies to combat food insecurity and social discrimination, as well as to improve communication of older people with their loved ones. In addition to this, the issue of arthritis must be tackled in a more in-depth manner given the result that it also has a severe impact on the mental health among elderly.
Evaluation of antiviral drugs against newly emerged SARS-CoV-2 Omicron subvariants
Authors: Cho Junhyung , Shin Younmin , Yang Jeong-Sun , Kim Jun Won , Kim Kyung-Chang , Lee Joo-Yeon
Published: March 2023

The ongoing emergence of SARS-CoV-2 Omicron subvariants and their rapid worldwide spread pose a threat to public health. From November 2022 to February 2023, newly emerged Omicron subvariants, including BQ.1.1, BF.7, BA.5.2, XBB.1, XBB.1.5, and BN.1.9, became prevalent global strains (>5% global prevalence). These Omicron subvariants are resistant to several therapeutic antibodies. Thus, the antiviral activities of current drugs such as remdesivir, molnupiravir, and nirmatrelvir, which target highly conserved regions of SARS-CoV-2, against newly emerged Omicron subvariants need to be evaluated. We assessed the antiviral efficacy of the drugs using half maximal inhibitory concentration (IC50) against human isolated 23 Omicron subvariants and four former SARS-CoV-2 variants of concern (VOC) and compared them with the antiviral efficacy of these drugs against the SARS-CoV-2 reference strain (hCoV/Korea/KCDC03/2020). Maximal IC50fold changes of remdesivir, molnupiravir, and nirmatrelvir were 1.9- (BA.2.75.2), 1.2-(B.1.627.2), and 1.4-fold (BA.2.3), respectively, compared to median IC50values of the reference strain. Moreover, median IC50-fold changes of remdesivir, molnupiravir, and nirmatrelvir against the Omicron variants were 0.96, 0.4, and 0.62, similar to 1.02, 0.88, and 0.67, respectively, of median IC50-fold changes for previous VOC. Although K90R and P132H in Nsp 5, and P323L, A529V, G671S, V405F, and ins823D in Nsp 12 mutations were identified, these amino acid substitutions did not affect drug antiviral activity. Altogether, these results indicated that the current antivirals retain antiviral efficacy against newly emerged Omicron subvariants, and provide comprehensive information on the antiviral efficacy of these drugs.
Demixing model: A normative explanation for inter-item biases in memory and perception
Authors: Chetverikov Andrey
Published: March 2023

Many studies in perception and in the working memory literature demonstrate that human observers systematically deviate from the truth when estimating the features of one item in the presence of another. Such inter-item or contextual biases are well established but lack a coherent explanation at the computational level. Here, I propose a novel normative model showing that such biases exist for any observer striving for optimality when trying to infer the features of multiple similar objects from a mixture of sensory observations. The ‘demixing’ model predicts that bias strength and direction would vary as a function of the amount of sensory noise and the similarity between items. Crucially, these biases exist not because of the prior knowledge in any form, but simply because the biased solutions to this inference problem are more probable than unbiased ones, counter to the common intuition. The model makes novel predictions about the effect of discriminability along the dimension used to select the item to report (e.g., spatial location) and the relative amount of sensory noise. Although the model is consistent with previously reported data from human observers, more carefully controlled studies are needed for a stringent test of its predictions. The strongest point of the ‘demixing’ model, however, is that it shows that interitem biases are inevitable when observers lack perfect knowledge of which stimuli caused which sensory observations, which is, arguably, always the case.
SLAPSHOT reveals rapid dynamics of extracellularly exposed proteome in response to calcium-activated plasma membrane phospholipid scrambling
Authors: Tuomivaara Sami T. , Teo Chin Fen , Jan Yuh Nung , Jan Lily Y. , Wiita Arun P.
Published: March 2023

To facilitate our understanding of the often rapid and nuanced dynamics of extracellularly exposed proteomes during signaling events, it is important to devise robust workflows affording fast time resolution without biases and confounding factors. Here, we presentSurface-exposed proteinLabeling usingPeroxidaSe,H2O2, andTyramide-derivative (SLAPSHOT), to label extracellularly exposed proteins in a rapid, sensitive, and specific manner, while preserving cellular integrity. This experimentally simple and flexible method utilizes recombinant soluble APEX2 peroxidase that is applied to cells, thus circumventing biological perturbations, tedious engineering of tools and cells, and labeling biases. APEX2 neither requires metal cations for activity nor contains disulfide bonds, conferring versatility for a wide spectrum of experimental setups. We applied SLAPSHOT followed by quantitative mass spectrometry-based proteomics analysis to examine the immediate and extensive cell surface expansion and ensuing restorative membrane shedding upon the activation of Scott syndrome-linked TMEM16F, a ubiquitously expressed calcium-dependent phospholipid scramblase and ion channel. Time-course data ranging from one to thirty minutes of calcium stimulation using wild-type and TMEM16F deficient cells revealed intricate co-regulation of known protein families, including those in the integrin and ICAM families. Crucially, we identified proteins that are known to reside in intracellular organelles, including ER, as occupants of the freshly deposited membrane, and mitovesicles as an abundant component and contributor to the extracellularly exposed proteome. Our study not only provides the first accounts of the immediate consequences of calcium signaling on the extracellularly exposed proteome, but also presents a blueprint for the application of SLAPSHOT as a general approach for monitoring extracellularly exposed protein dynamics.

Highlights

An enzyme-driven method to tag extracellularly exposed proteins in an unbiased manner with a superior combination of temporal resolution, spatial specificity, and sensitivity

A general approach applicable to primary and scarce cells without involving cellular engineering

Short time scale proteome dynamics of Jurkat cells with and without TMEM16F revealed by SLAPSHOT coupled with quantitative mass spectrometry provide insights into phospholipid scrambling-mediated plasma membrane remodeling
FIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination
Authors: Ito Masaru , Furukohri Asako , Matsuzaki Kenichiro , Fujita Yurika , Toyoda Atsushi , Shinohara Akira
Published: March 2023

The formation of RAD51/DMC1 filaments on single-stranded (ss)DNAs essential for homology search and strand exchange in DNA double-strand break (DSB) repair is tightly regulated. FIGNL1 AAA+++ ATPase controls RAD51-mediated recombination in human cells. However, its role in gametogenesis remains unsolved. Here, we characterized a germ-line-specific conditional knockout (cKO) mouse ofFIGNL1.Fignl1cKO male mice showed defective chromosome synapsis and impaired meiotic DSB repair with the accumulation of RAD51/DMC1 on meiotic chromosomes, supporting a positive role of FIGNL1 in homologous recombination at a post-assembly stage of RAD51/DMC1 filaments.Fignl1cKO spermatocytes also accumulate RAD51/DMC1 on chromosomes in pre-meiotic S-phase. These RAD51/DMC1 assemblies are independent of meiotic DSB formation. We also showed that purified FIGNL1 dismantles RAD51 filament on double-stranded (ds)DNA as well as ssDNA. These results suggest an additional role of FIGNL1 in limiting the non-productive assembly of RAD51/DMC1 on native dsDNAs during pre-meiotic S-phase and meiotic prophase I.
Cooperative Motility, Force Generation and Mechanosensing in a Foraging Non-Photosynthetic Diatom
Authors: Zheng Peng , Kumadaki Kayo , Quek Christopher , Lim Zeng Hao , Ashenafi Yonatan , Yip Zhi Ting , Newby Jay , Alverson Andrew J. , Jie Yan , Jedd Gregory
Published: March 2023

Diatoms are ancestrally photosynthetic microalgae. However, some underwent a major evolutionary transition, losing photosynthesis to become obligate heterotrophs. The molecular and physiological basis for this transition is unclear. Here, we isolate and characterize new strains of non-photosynthetic diatoms from the coastal waters of Singapore. These diatoms occupy diverse ecological niches and display glucose-mediated catabolite repression, a classical feature of bacterial and fungal heterotrophs. Live-cell imaging reveals deposition of secreted extracellular polymeric substance (EPS). Diatoms moving on pre-existing EPS trails (runners) move faster than those laying new trails (blazers). This leads to cell-to-cell coupling where runners can push blazers to make them move faster. Calibrated micropipettes measure substantial single cell pushing forces, which are consistent with high-order myosin motor cooperativity. Collisions that impede forward motion induce reversal, revealing navigation-related force sensing. Together, these data identify aspects of metabolism and motility that are likely to promote and underpin diatom heterotrophy.
Subject classification and cross-time prediction based on functional connectivity and white matter microstructure features in a rat model of Alzheimer’s using machine learning
Authors: Diao Yujian , Jelescu Ileana Ozana
Published: March 2023

Background

The pathological process of Alzheimer’s disease (AD) typically takes up decades from onset to clinical symptoms. Early brain changes in AD include MRI-measurable features such as aItered functional connectivity (FC) and white matter degeneration. The ability of these features to discriminate between subjects without a diagnosis, or their prognostic value, is however not established.

Methods

The main trigger mechanism of AD is still debated, although impaired brain glucose metabolism is taking an increasingly central role. Here we used a rat model of sporadic AD, based on impaired brain glucose metabolism induced by an intracerebroventricular injection of streptozotocin (STZ). We characterized alterations in FC and white matter microstructure longitudinally using functional and diffusion MRI. Those MRI-derived measures were used to classify STZ from control rats using machine learning, and the importance of each individual measure was quantified using explainable artificial intelligence methods.

Results

Overall, combining all the FC and white matter metrics in an ensemble way was the best strategy to discriminate STZ rats, with a consistent accuracy over 0.85. However, the best accuracy early on was achieved using white matter microstructure features, and later on using FC. This suggests that consistent damage in white matter in the STZ group might precede FC. For cross-timepoint prediction, microstructure features also had the highest performance while, in contrast, that of FC was reduced by its dynamic pattern which shifted from early hyperconnectivity to late hypoconnectivity.

Conclusions

Our study highlights the MRI-derived measures that best discriminate STZ vs control rats early in the course of the disease, with potential translation to humans.
Shedding light on human olfaction: electrophysiological recordings from sensory neurons in acute slices of olfactory epithelium
Authors: Hernandez-Clavijo Andres , Sánchez Triviño Cesar Adolfo , Guarneri Giorgia , Ricci Chiara , Mantilla-Esparza Fabian A. , Gonzalez-Velandia Kevin Y. , Boscolo-Rizzo Paolo , Tofanelli Margherita , Bonini Pierluigi , Dibattista Michele , Tirelli Giancarlo , Menini Anna
Published: March 2023

The COVID-19 pandemic brought attention to our limited understanding of human olfactory physiology. While the cellular composition of the human olfactory epithelium is similar to that of other vertebrates, its functional properties are largely unknown. We prepared acute slices of human olfactory epithelium from nasal biopsies and used the whole-cell patch-clamp technique to record electrical properties of cells. We measured voltage-gated currents in human olfactory sensory neurons and supporting cells, and action potentials in neurons. Additionally, inward currents and action potentials responses of neurons to a phosphodiesterase inhibitor indicated that the transduction cascade involves cAMP as a second messenger. Furthermore, responses to odorant mixtures demonstrated that the transduction cascade was intact in this preparation. This study provides the first electrophysiological characterization of olfactory sensory neurons in acute slices of the human olfactory epithelium, paving the way for future research to expand our knowledge of human olfactory physiology.
A dynamic neural resource model bridges sensory and working memory
Authors: Tomić Ivan , Bays Paul M.
Published: March 2023

Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or “iconic” memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these timescales. Here we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.
Simultaneous profiling of host expression and microbial abundance by spatial metatranscriptome sequencing
Authors: Lyu Lin , Li Xue , Feng Ru , Zhou Xin , Guha Tuhin K. , Yu Xiaofei , Chen Guo Qiang , Yao Yufeng , Su Bing , Zou Duowu , Snyder Michael P. , Chen Lei
Published: March 2023

We developed an analysis pipeline that can extract microbial sequences from spatial transcriptomic (ST) data and assign taxonomic labels, generating a spatial microbial abundance matrix in addition to the default host expression matrix, enabling simultaneous analysis of host expression and microbial distribution. We called the pipeline spatial metatranscriptome (SMT) and applied it on both human and murine intestinal sections and validated the spatial microbial abundance information with alternative assays. Biological insights were gained from these novel data that showed host–microbe interaction at various spatial scales. Finally, we tested experimental modification that can increase microbial capture while preserving host spatial expression quality and, by use of positive controls, quantitatively showed the capture efficiency and recall of our methods. This proof-of-concept work shows the feasibility of SMT analysis and paves the way for further experimental optimization and application.