bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Variation in theFAAHGene is Directly Associated with Subjective Well-being and Indirectly Associated with Problematic Alcohol Use
Authors: Bornscheuer Lisa , Lundin Andreas , Forsell Yvonne , Lavebratt Catharina , Melas Philippe A.
Published: August 2023

Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored, particularly with longitudinal data. In our study, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in theFAAHgene (rs324420, Pro129Thr) in a sample of 2,822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points. A subsequent phenome-wide association study (PheWAS) validated our well-being findings in the UK Biobank (N=126,132) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being. We propose that lifelong elevated anandamide levels can disrupt the endocannabinoid system – a biological contributor to well-being – potentially leading to increased alcohol intake. Further genetic studies and mediation analyses are needed to validate and extend these findings.
Endobronchial ultrasound-guided transbronchial mediastinal cryobiopsy: Insights and technical tips from our early experience with 30 patients
Authors: Soo Chun Ian , Kho Sze Shyang
Published: August 2023

Background

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used to diagnose and stage lung cancer. In real-life practice, limitations are seen with cytology samples from EBUS-TBNA. Obtaining adequate samples can be challenging when faced with necrotic lesions with low cellular yield and the evolving landscape of targeted therapy, necessitating additional samples for comprehensive testing. Hence, transbronchial mediastinal cryobiopsy guided by endobronchial ultrasound (EBUS-TBMC) has emerged as a promising approach for obtaining larger tissue samples. In retrospective review, our aim is to present our early experience regarding the feasibility of performing EBUS-TBMC, employing a similar approach to EBUS-TBNA, followed by the outcomes of our procedures. We include a step-by-step explanation and some recommendations to conduct a successful EBUS-TBMC.

Method

Single center retrospective analysis to evaluate the feasibility and utility of EBUS-TBMC cases over six months from July to December 2022.

Results

36 EBUS-TBMC procedures on 30 patients. Moderate sedation was used in 80% of cases. Majority (83.4%) of the patients had biopsy of a single lesion with a median of 3 cryobiopsies (Interquartile range 3-4). The median cryo-activation time was 6 seconds (Interquartile range 6-8). EBUS-TBMC demonstrated a positive yield of 86.1% with an overall diagnostic yield of 83.3%. Mild bleeding occurred in six biopsies (16.7%) which did not required further intervention. No other major complications were observed.

Conclusion

EBUS-TBMC is a safe and effective alternative to EBUS-TBNA. Histology samples obtained through EBUS-TBMC have the potential to increase confidence in diagnosing and staging lung cancer, thereby alleviating concerns about tissue inadequacy.
National Changes in Diabetes Care Practices during the COVID-19 Pandemic: Prospective Study of US Adults
Authors: Vashist Kushagra , Hassan Saria , Weber Mary Beth , Quarells Rakale C. , Patel Shivani A.
Published: August 2023

Background

There is a lack of nationally representative prospective data on the impact of the COVID-19 pandemic on diabetes care and management in adults with type 2 diabetes. We examined changes in diabetes care and management practices before and after the onset of the COVID-19 pandemic.

Methods

Using the National Health Interview Survey, we analyzed data from 870 adults living with type 2 diabetes who were interviewed in 2019 and re-interviewed between August and December 2020. Exposure to the COVID-19 pandemic was defined by year of survey (2019, pre-pandemic; 2020, pandemic). We estimated percent change in past year blood sugar check by a health professional and current use of blood sugar lowering medication overall and by sociodemographic subgroups.

Results

Receiving an annual blood sugar test fell by -3.3 percentage points (pp) (95% CI -5.7, -1.0), from 98.3% in 2019 to 95.0% in late 2020. The reduction in annual blood glucose testing was largely consistent across socio-demographic groups and was particularly pronounced among adults not working and adults aged 65 years and older. In the same time period, current use of diabetes medications increased by +3.8 pp (0.7, 6.9), from 85.9% to 89.7%. The increase in medication use was most pronounced among individuals aged 40-64-year old, employed, and those living in large central metropolitan areas.

Conclusions

Nationally, adults with Type 2 diabetes reported a reduction in annual blood glucose testing by a health professional and an increase in diabetes medication usage during the COVID-19 pandemic. If sustained after the end of the COVID-19 public health emergency, these changes have implications for national diabetes management and care.
Crossover of the dimensions of work-family and family-work conflict in couples: Protocol for a qualitative study
Authors: Smoktunowicz Ewelina , Lesnierowska Magdalena , Ziolkowska Justyna , Roczniewska Marta
Published: August 2023

Conflict between work and non-work is a bidirectional and a multidimensional construct that has garnered much attention from researchers and practitioners alike. Previously, studies with a dyadic design demonstrated that interrole conflict can cross over between partners in romantic relationships. The aim of the present study is to explore—from an individual and dyadic perspective—how partners perceive dimensions of interrole conflict (that is: time, strain, behaviour, and possibly others) and whether crossover between partners is dimension-dependent. This protocol outlines a qualitative interview study. Participants (N= 40) will be dual-earner couples that meet two inclusion criteria: both partners need to be professionally active, and the couples need to have lived together for at least a year. Interviews will be conducted separately with each partner. To analyse the data at the individual level we will use reflexive thematic analysis. To analyse the data at the dyadic level we will apply an adapted version of the framework method. We anticipate that findings of this study will have the potential to advance theoretical models depicting crossover processes and, more generally, the interface between work and family lives. Moreover, insights into how couples experience dimension-based interrole conflict will be important for the development of targeted interventions.
Experiences of psycho-oncological counselling to support mental health in South Australians diagnosed with cancer
Authors: Blunt Jason , Trigg Joshua
Published: August 2023

Background

Effective delivery of psycho-oncological support requires understanding of client perceptions of counselling service effectiveness, psychosocial outcomes, and meeting of client support needs and expectations.

Objective

This study aimed to describe perceptions of clients accessing psycho-oncological counselling for people directly or indirectly affected by cancer, and describe perceived psychological distress, depression, and anxiety from pre-to post-counselling.

Methods

South Australian psycho-oncological counselling service clients were recruited (n=28). Psychological distress, anxiety, and depression were assessed before and after counselling sessions. Client expectations, experiences, and counselling outcomes were examined via pre-post-tests, and thematic analysis.

Results

Clients reported reduced anxiety (t=-2.31,p=.029), depression (t=-2.51,p=.018), distress (t=-4.19,p<.0001), and global mental health symptomology (t=-2.79,p=.009). Four themes were identified: having no expectations, needing help managing emotions, seeking coping strategies, and seeking better understanding of their experience. Client expectations were satisfied (92.8%), regardless of counselling reason.

Conclusion

Benefits of counselling included reduced symptomology, receipt of knowledge and skills, and increased ability to manage everyday life. Supportive counselling significantly reduces distress and symptoms of anxiety and depression while supporting client and family functioning during cancer treatment.

Implications

Individual supportive counselling plays an integral role in lives of cancer patients and family members. Clients face concerns relating to cancer prognosis (e.g., recurrence fear), and to broader related experiences (e.g., social dynamics). Complex needs across cancer experience as a patient, carer, or other family member, requires that psycho-oncological counselling targets major client expectations, promotes benefits of counselling, and strategies for managing daily life events.
iMOUSE - Reforming the Strategy of Refinement and Reduction for indispensable laboratory animal-based studies in translational research
Authors: Łaz Maciej , Lampe Mirko , Connor Isaac , Shestachuk Dmytro , Ludwig Marcel , Müller Ursula , Strauch Oliver F. , Suendermann Nadine , Lüth Stefan , Kah Janine
Published: August 2023

Considering the intricate nature of biological processes within organisms, it is undeniable that relying solely on in vitro-generated primary-cell-like cultures or organ-like products in preclinical and basic research is insufficient to replace animal-based studies fully. This limitation is particularly significant when considering the regulations enforced by legislative assemblies worldwide. The necessity of animal-based studies to approve chemicals and medications. In contradiction, European countries aim to banish animal-based studies. Therefore, we must understand the impact of the data refinement and experiment replacement strategy we will introduce here.

This projectaimedto revolutionize data acquisition in animal-based studies by transforming manual observation into a reliable digital process. Reliable digital data will be generated by having the potential to reduce human bias by simply reducing human interaction. Additionally, reducing human interaction will reduce the severity levels due to stress reduction, fulfilling the 3R principles.

Therefore, the first goal wasto develop and implement a scalable, stable, running, and remotely accessible camera-based monitor system (the iMouse solution). At the same time, the target was to develop a retrofit solution (DigiFrame) for existing home-cage systems, not interfering with the regular workflow in animal facilities.As a result, we developed a digital monitoring system, named iMouseTV platform based on existing open-source software, allowing users to observe, record, share, and review animal-based studies within the home cage anytime from anywhere, reducing the stress level for the animals. Our system’s first Proof of concept ran for over two years at the LIV in Hamburg. We also investigated an effective way to reduce data generation by setting up specific zones for detecting the motion of choice (e.g., drinking, food intake). The data sets can be stored, shared, and reviewed by users and refined by algorithms aiming to recognize the dedicated motions of the animals automatically. The implementation of the ML algorithms allows the iMouse solution to recognize whether an individual mouse was drinking and for how long and store results in the annotated video file and graph format. However, the identification and continuous tracking of the species is still in progress.

In conclusion, we established a scalable human-independent monitoring and recording system, which can be implemented into the existing structures of institutions and companies without changing handling processes, to monitor animals and observe them by getting reliable digital data. Moreover, it is fundamental for automatic recognition within animal-based studies based on Artificial Intelligence.
National Trends in Mortality and Urgent Dialysis after Admission for Acute Hypertension in Japan from 2010 through 2019
Authors: Matsuki Hisazumi , Genma Taku , Mandai Shintaro , Fujiki Tamami , Mori Yutaro , Ando Fumiaki , Mori Takayasu , Susa Koichiro , Iimori Soichiro , Naito Shotaro , Sohara Eisei , Rai Tatemitsu , Fushimi Kiyohide , Uchida Shinichi
Published: August 2023

Background

Despite increasing incidences of hypertension, recent trends in mortality and urgent dialysis following acute hypertension (AHT) remain undetermined.

Methods

This retrospective observational cohort study evaluated 50,316 hospitalized AHT patients from 2010 to 2019, using an administrative claims database in Japan. We examined trends in incidence, urgent dialysis, mortality and its risk factors using logistic regression models. Using ICD-10 codes, AHT was categorized into five spectrums: malignant hypertension (MHT) (n= 1,792), hypertensive emergency (n= 17,907), hypertensive urgency (n= 1,562), hypertensive encephalopathy (n= 6,593), and hypertensive heart failure (HHF) (n= 22,462).

Results

The median age of the patients was 76 years and 54.9% were female. The total AHT incidence was 70 cases per 100,000 admission year. The absolute death rate increased from 1.83% [95% confidence intervals (CI), 1.40–2.40] to 2.88% (95%CI, 2.42–3.41) [Cochran-Armitage trend test (CA),P< 0.0001]. Upward trends were observed in patients aged ≥80, with lean body mass index ≤18.4, and with HHF. Urgent dialysis rates increased from 1.52% (95%CI, 1.12–2.06) to 2.60% (2.17–3.1) (CA,P= 0.0071) in 48,235 patients, excluding maintenance dialysis patients. Older age, male, lean body mass, MHT, HHF, and underlying chronic kidney disease (CKD) correlated with higher mortality risk; greater hospital volume correlated with lower mortality risk; and MHT, HHF, diabetes mellitus, CKD, and scleroderma correlated with a higher risk of urgent dialysis.

Conclusions

Mortality and urgent dialysis rates following AHT have increased. Aging, complex comorbidities, and HHF-type AHT contributed to the rising trend of mortality.
Applying behavioural economics principles to increase demand for free HIV testing services at private doctor-led clinics in Johannesburg, South Africa: A randomised controlled trial
Authors: Bokolo Simamkele , Mabaso Suzanne , Kruger Wentzel , Mistri Preethi , Schmucker Laura , Chetty-Makkan Candice , Pascoe Sophie J S , Buttenheim Alison , Thirumurthy Harsha , Long Lawrence
Published: August 2023

Background

Expanding free HIV testing service (HTS) access to include private clinics could increase testing rates. A donor funded programme, GP Care Cell, offered free HIV testing at selected private doctor-led clinics but uptake was low. We investigated whether HTS demand creation materials that used behavioural economics principles could increase demand for HIV testing at these clinics.

Methods

We conducted a randomised controlled trial in Johannesburg, South Africa (January-April 2022) distributing brochures promoting HTS to adults in five private doctor-led clinic catchment areas. Individuals were randomised to receive three brochure types: (1) “Standard of care” (SOC) advertising a free HIV test and ART; (2) “Healthy lifestyle screening” promoted free low-cost health screenings in addition to HTS; and (3) “Recipient of care voucher” leveraged loss aversion and the endowment effect by highlighting the monetary value of free HTS. The primary outcome was presenting at the clinic following exposure to the brochures. Logistic regression compared outcomes between arms.

Results

Of the 12,129 brochures distributed, 658 were excluded because of errors or duplicates and 11,471 were analysed. About 59% of brochure recipients were male and 50,3% were aged 25-34 years. In total, 448 (3.9%) brochure recipients presented at the private doctor-led clinics of which 50.7% were males. There were no significant differences in clinic presentation between the healthy lifestyle screening and SOC arm (Adjusted Odds Ratio [AOR] 1.02; 95% CI 0.79-1.32), and similarly between the recipient of care voucher and SOC arm (AOR 1.08; 95% CI 0.84-1.39). Individuals were more likely to attend clinics that were centrally located with visible branding for HTS (AOR=5.30; 95% CI: 4.14-6.79).

Conclusion

Brochures that used behavioural insights did not increase demand for HTS at private doctor-led clinics. However, consistent distribution of the brochures may have potential to increase HIV testing uptake at highly visible private doctor-led clinics.

Trial registration

SANCTR registration number: DOH-27-032022-9053
Flexible Bayesian estimation of incubation times
Authors: Gressani Oswaldo , Torneri Andrea , Hens Niel , Faes Christel
Published: August 2023

Motivation

The incubation period is of paramount importance in infectious disease epidemiology as it informs about the transmission potential of a pathogenic organism and helps to plan public health strategies to keep an epidemic outbreak under control. Estimation of the incubation period distribution from reported exposure times and symptom onset times is challenging as the underlying data is coarse.

Methodology

We develop a new Bayesian methodology using Laplacian-P-splines that provides a semi-parametric estimation of the incubation density based on a Langevinized Gibbs sampler. A finite mixture density smoother informs a set of parametric distributions via moment matching and an information criterion arbitrates between competing candidates.

Results

Our method has a natural nest within EpiLPS, a tool originally developed to estimate the time-varying reproduction number. Various simulation scenarios accounting for different levels of data coarseness are considered with encouraging results. Applications to real data on COVID-19, MERS-CoV and Mpox reveal results that are in alignment with what has been obtained in recent studies.

Conclusion

The proposed flexible approach is an interesting alternative to classic Bayesian parametric methods for estimation of the incubation distribution.
Burden of Liver Cancer in China from 1990 to 2019 and projections to 2044: Findings from the Global Burden of Disease Study
Authors: Han Jianglong , Chen Chao , Tang Tian , Liu Wenmin , Chen Ruyan , Li Si , Deng Haiyu , Jian Tingting , Zhao Liang , Fu Zhenming
Published: August 2023

Background

China has the highest liver cancer burden in the world. Prediction and comparison of the future trends of liver cancer in China and some representative areas may guide further control action.

Methods

Using data from the Global Burden of Disease Study, we assessed incidence, mortality, and disability-adjusted life-years of liver cancer in Mainland China, with reference to representative East Asia areas (Taiwan China, Japan, and Korea) and Western areas (the United Kingdom and the United States). The burden of liver cancer was evaluated and predicted using NOREPRED model from 1990 to 2044.

Results

Overall, the liver cancer incidence (28.1 to 10.6 per 100,000) and mortality (27.5 to 9.7 per 100,000) decreased from 1990 to 2015 in Mainland China, which were consistent with the trends of Eastern Asia areas. However, the disease burden in Mainland China were then plateaued and started to increase during 2015-2044 (10.6 to 14.8 per 100,000 for incidence; 9.7 to 14.02 per 100,000 for mortality), including the hepatitis-related liver cancer incidence (increase from 8.6 to 11.7 per 100,000). While the changing patterns of alcohol- and nonalcoholic steatohepatitis (NASH)- related liver cancer incidence were found similar among Mainland China (0.93 to 1.51 per 100,000 for alcohol; 0.5 to 0.73 per 100,000 for NASH) and Western countries in our projection.

Conclusion

The liver cancer burden in Mainland China is unexpectedly predicted to increase again after decades of decline. Future efforts must be made to resolve both the remaining hepatitis-related cancer burden and the changing etiologies.
Immunometabolic effects of lactate on B cell function in healthy individuals of different ages
Authors: Romero Maria , Miller Kate , Gelsomini Andrew , Garcia Denisse , Li Kevin , Suresh Dhananjay , Frasca Daniela
Published: August 2023

Aging is characterized by chronic systemic inflammation and metabolic changes. When we compared B cells from young and elderly donors, we found that aging induces higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects the age-associated expansion of pro-inflammatory B cell subsets, was found associated with higher secretion of lactate and autoimmune antibodies after in vitro stimulation. B cells from elderly individuals, induce in vitro generation of pro-inflammatory CD4+ T cells from young individuals through metabolic pathways mediated by lactate secretion. Lactate also induces immunosenescent B cells that are glycolytic and express transcripts for multiple pro-inflammatory molecules. These results altogether may have relevant clinical implications and suggest novel targets for therapeutic interventions in patients with inflammatory conditions and diseases.
Genetic influences on circulating retinol and its relationship to human health
Authors: Reay William R. , Kiltschewskij Dylan J. , Di Biase Maria A. , Gerring Zachary F. , Kundu Kousik , Surendran Praveen , Greco Laura A. , Clarke Erin D. , Collins Clare E. , Mondul Alison M. , Albanes Demetrius , Cairns Murray J.
Published: August 2023

Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Previous work has characterised genetic influences on circulating retinol; however, small sample sizes have limited our ability to fully appreciate the genetic architecture of this trait. In this study, we performed the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identified eight common variant loci associated with retinol, as well as a rare-variant signal. An integrative gene prioritisation pipeline supported novel retinol-associated genes outside of the main retinol transport complex (RBP4:TTR) related to lipid biology, energy homeostasis, and endocrine signalling. Genetic proxies of circulating retinol were then used to estimate causal relationships with almost 20,000 clinical phenotypes via a phenome-wide Mendelian randomisation study (MR-pheWAS). The MR-pheWAS suggested that retinol may exert causal effects on inflammation, adiposity, ocular measures, the microbiome, and MRI-derived brain phenotypes, amongst several others. Conversely, circulating retinol may be causally influenced by factors including lipids and renal function. Finally, we demonstrated how a retinol polygenic score could identify individuals who are more likely to fall outside of the normative range of circulating retinol for a given age. In summary, this study provides a comprehensive evaluation of the genetics of circulating retinol, as well as revealing traits which should be prioritised for further clinical investigation with respect to retinol related therapies or nutritional intervention.
Connection of brain glymphatic system with circadian rhythm
Authors: Kholmanskiy Alexander
Published: August 2023

To establish the relationship between the glymphatic system of the brain and the circadian rhythm, we analyzed the effect of anomalies in water thermodynamics on the dependence of the dynamic, electrical, and optical characteristics of physiological fluids on temperature. The dynamics of hydrogen bonds in bulk and hydrated water affected the activation energies of ion currents of voltage-dependent channels that regulate signaling and trophic bonds in the neuropil of the cortical parenchyma. The physics of minimizing the of the isobaric heat capacity of water made it possible to explain the stabilization and functional optimization of the thermodynamics of eyeball fluids at 34.5 °C and the human brain during sleep at 36.5 °C. At these temperatures, the thermoreceptors of the cornea and the cells of the ganglionic layer of the retina, through connections with the suprachiasmatic nucleus and the pineal gland, switch the circadian rhythm from daytime to nighttime. The phylogenesis of the circadian rhythm was reflected in the dependence of the duration of the nighttime sleep of mammals on the diameter of the eyeball and the mass of the pineal gland. The activity of all the nerves of the eyeball led to the division of the nocturnal brain metabolism into NREM and REM phases. These phases correspond to two modes of the glymphatic system electrochemical and dynamic. The first is responsible for the relaxation processes of synaptic plasticity and chemical neutralization of toxins with the participation of water and melatonin. Rapid eye movement and an increase in cerebral blood flow in the second mode increase water exchange in the parenchyma and flush out toxins into the venous system. Electrophysics of clearance and conductivity of ionic and water channels of membranes of blood vessels and astrocytes modulate oscillations of polarization potentials of water dipole domains in parietal plasma layers of arterioles and capillaries.
OBMeta: a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases
Authors: Xu Cuifang , Huang Jiating , Gao Yongqiang , Zhao Weixing , Shen Yiqi , Luo Feihong , Yu Gang , Zhu Feng , Ni Yan
Published: August 2023

Gut dysbiosis is closely associated with obesity and related metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). The gut microbial features and biomarkers have been increasingly investigated in recent studies, which require further validation due to the limited sample size and various confounding factors that may affect microbial compositions. So far, it lacks a comprehensive bioinformatics pipeline providing automated statistical analysis and integrating independent studies for cross validation simultaneously. OBMeta aims to streamline the standard metagenomics data analysis from diversity analysis, comparative analysis, functional analysis, to co-abundance network analysis. In addition, a curated database has been established with a total of 88 public research projects, covering three different phenotypes (Obesity, T2D, and NAFLD) and more than five different intervention strategies (exercise, diet, probiotics, medication, and surgery). With OBMeta, users can not only analyze their own research projects, but also search and match public datasets of interest for cross-project validation. Moreover, OBMeta provides cross-phenotype and cross-intervention-based advanced validation that maximally supports preliminary findings from an individual study. To summarize, OBMeta is a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases. OBMeta is freely available at:http://obmeta.met-bioinformatics.cn/.

Abstract Figure
Long-term Prediction of Severe Hypoglycemia in Type 2 Diabetes Based on Multi-view Co-training
Authors: Agraz Melih , Deng Yixiang , Karniadakis George Em , Mantzoros Christos Socrates
Published: August 2023

Background

Patients with type 2 diabetes mellitus (T2DM) who have severe hypoglycemia (SH) poses a considerable risk of long-term death, demanding urgent medical attention. Accurate prediction of SH remains challenging due to its multifactorial nature, contributed from factors such as medications, lifestyle choices, and metabolic measurements.

Method

In this study, we propose a systematic approach to improve the robustness and accuracy of SH predictions using machine learning models, guided by clinical feature selection. Our focus is on developing one-year SH prediction models using both semi-supervised learning and supervised learning algorithms. Utilizing the clinical trial, namely Action to Control Cardiovascular Risk in Diabetes, which involves electronic health records for over 10,000 individuals, we specifically investigate adults with T2DM who are at an increased risk of cardiovascular complications.

Results

Our results indicate that the application of a multi-view co-training method, incorporating the random forest algorithm, improves the specificity of SH prediction, while the same setup with Naive Bayes replacing random forest demonstrates better sensitivity. Our framework also provides interpretability of machine learning (XAI) models by identifying key predictors for hypoglycemia, including fast plasma glucose, hemoglobin A1c, general diabetes education, and NPH or L insulins.

Conclusion

By enhancing prediction accuracy and identifying crucial predictive features, our study contributes to advancing the understanding and management of hypoglycemia in this population.
Developing a male-specific counselling curriculum for HIV treatment in Malawi
Authors: Mphande Misheck , Robson Isabella , Hubbard Julie , Chikuse Elijah , Lungu Eric , Phiri Khumbo , Cornell Morna , Phiri Sam , Coates Thomas J , Dovel Kathryn
Published: August 2023

Men living with HIV in sub-Saharan Africa have sub-optimal engagement in antiretroviral therapy (ART) Programs. Generic ART counselling curriculum in Malawi does not meet men’s needs and should be tailored to men.

We developed a male-specific ART counselling curriculum, adapted from the Malawi Ministry of Health (MOH) curriculum based on literature review of men’s needs and motivations for treatment. The curriculum was piloted through group counselling with men in 6 communities in Malawi, with focus group discussion (FGD) conducted immediately afterward (n=85 men) to assess knowledge of ART, motivators and barriers to care, and perceptions of the male-specific curriculum. Data were analysed in Atlas.ti using grounded theory. We conducted a half-day meeting with MOH and partner stakeholders to finalize the curriculum (n=5).

The male-specific curriculum adapted three existing topics from generic counselling curriculum (status disclosure, treatment as prevention, and ART side effects) and added four new topics (how treatment contributes to men’s goals, feeling healthy on treatment, navigating health systems, and self-compassion for the cyclical nature of lifelong treatment. Key motivators for men were embedded throughout the curriculum and included: family wellbeing, having additional children, financially stability, and earning/keeping respect. During the pilot, men reported having little understanding of how ART contributed to their personal goals prior to the male-specific counselling. Men were most interested in additional information about treatment as prevention, benefits of disclosure/social support beyond their sexual partner, how to navigate health systems, and side effects with new regimens. Respondents stated that the male-specific counselling challenged the idea that men were incapable of overcoming treatment barriers and lifelong medication.

Male-specific ART counselling curriculum is needed to address men’s specific needs. In Malawi context, topics should include: how treatment contributes to men’s goals, navigating health systems, self-compassion/patience for lifelong treatment, and taking treatment while healthy.
Main Manuscript for Microbiome single cell atlases generated with a benchtop instrument
Authors: Li Xiangpeng , Xu Linfeng , Demaree Benjamin , Noecker Cecilia , Bisanz Jordan E. , Weisgerber Daniel W. , Modavi Cyrus , Turnbaugh Peter J. , Abate Adam R.
Published: August 2023

Single cell sequencing is useful for resolving complex systems into their composite cell types and computationally mining them for unique features that are masked in pooled sequencing. However, while commercial instruments have made single cell analysis widespread for mammalian cells, analogous tools for microbes are limited. Here, we present EASi-seq (Easily Accessible Single microbe sequencing). By adapting the single cell workflow of the commercial Mission Bio Tapestri instrument, this method allows for efficient sequencing of individual microbes’ genomes. EASi-seq allows thousands of microbes to be sequenced per run and, as we show, can generate detailed atlases of human and environmental microbiomes. The ability to capture large shotgun genome datasets from thousands of single microbes provides new opportunities in discovering and analyzing species subpopulations. To facilitate this, we develop a companion bioinformatic pipeline that clusters genome by sequence similarity, improving whole genome assembly, strain identification, taxonomic classification, and gene annotation. In addition, we demonstrate integration of metagenomic contigs with the EASi-seq datasets to reduce capture bias and increase coverage. Overall, EASi-seq enables high quality single cell genomic data for microbiome samples using an accessible workflow that can be run on a commercially available platform.
Leveraging fine-scale population structure reveals conservation in genetic effect sizes between human populations across a range of human phenotypes
Authors: Hu Sile , Ferreira Lino A. F. , Shi Sinan , Hellenthal Garrett , Marchini Jonathan , Lawson Daniel J. , Myers Simon R.
Published: August 2023

An understanding of genetic differences between populations is essential for avoiding confounding in genome-wide association studies (GWAS) and understanding the evolution of human traits. Polygenic risk scores constructed in one group perform poorly in highly genetically-differentiated populations, for reasons which remain controversial. We developed a statistical ancestry inference pipeline able to decompose ancestry both within and between countries, and applied it to the UK Biobank data. This identifies fine-scale patterns of genetic relatedness not captured by standard and widely used principal components (PCs), and allows fine-scale population stratification correction that removes both false positive and false negative associations for traits with geographic correlations. We also develop and apply ANCHOR, an approach leveraging segments of distinct ancestries within individuals to estimate similarity in underlying causal effect sizes between groups, using an existing PGS. Applying ANCHOR to >8000 people of mixed African and European ancestry, we demonstrate that estimated causal effect sizes are highly similar across these ancestries for 26 of 29 quantitative molecular and non-molecular phenotypes (mean correlation 0.98 +/-0.08), providing evidence that gene-environment and gene-gene interactions do not play major roles in the poor prediction of European-ancestry PRS scores in African populations for these traits, contradicting previous findings. Instead our results provide optimism that shared causal mutations operate similarly in different groups, focussing the challenge of improving GWAS “portability” between groups on joint fine-mapping.
The stromal side of cytochromeb6fcomplex regulates state transitions
Authors: Riché Alexis , Dumas Louis , Malesinski Soazig , Bossan Guillaume , Madigou Céline , Zito Francesca , Alric Jean
Published: August 2023

In oxygenic photosynthesis, state transitions distribute light energy between Photosystem I and Photosystem II. This regulation involves the reduction of the plastoquinone pool, activation of the STT7 protein kinase by cytochromeb6fcomplex, phosphorylation and migration of Light Harvesting Complexes II (LHCII). Here we show the C-term of cytb6subunit acts on phosphorylation of STT7 and state transitions. We used site-directed mutagenesis of the chloroplastpetBgene to truncate (remove L215b6) or elongate (add G216b6) the cytb6subunit. Modified complexes are devoid of hemeciand degraded by FTSH protease, revealing that salt bridge formation between cytb6(PetB) and subunit IV (PetD) is key to the assembly of the complex. In double mutants where FTSH is inactivated, modified cytb6fare accumulated but the phosphorylation cascade is blocked. We also replaced the arginine interacting with hemecipropionate (R207Kb6). In this modified complex, hemeciis present but the kinetics of phosphorylation are slower. We show that highly phosphorylated forms of STT7 are accumulated transiently after reduction of the PQ pool, and represent the active forms of the protein kinase. 96% protein coverage using phosphoproteomics showed 4 new phosphorylated peptides in the kinase domain of STT7. Phosphorylation of the LHCII targets is favored at the expense of the protein kinase, and the migration of LHCII towards PSI is the limiting step for state transitions.

Significance statement

State transitions are regulatory mechanisms that optimize the quantum yield of photosynthesis.Chlamydomonas reinhardtiiis the choice organism to study this regulation at the molecular level. Our study describes an unprecedented mechanism of stereochemical changes at the Qisite of the cytochromeb6fcomplex that trigger STT7 protein kinase activation through autophosphorylation.
Identifying small-molecules binding sites in RNA conformational ensembles with SHAMAN
Authors: Panei F. P. , Gkeka P. , Bonomi M.
Published: August 2023

The rational targeting of RNA with small molecules is hampered by our still limited understanding of RNA structural and dynamic properties. Mostin silicotools for binding site identification rely on static structures and therefore cannot face the challenges posed by the dynamic nature of RNA molecules. Here, we present SHAMAN, a computational technique to identify potential small-molecule binding sites in RNA structural ensembles. SHAMAN enables exploring the conformational landscape of RNA with atomistic molecular dynamics and at the same time identifying RNA pockets in an efficient way with the aid of probes and enhanced-sampling techniques. In our benchmark composed of large, structured riboswitches as well as small, flexible viral RNAs, SHAMAN successfully identified all the experimentally resolved pockets and ranked them among the most favorite probe hotspots. Overall, SHAMAN sets a solid foundation for future drug design efforts targeting RNA with small molecules, effectively addressing the long-standing challenges in the field.
Whole genome structural predictions reveal hidden diversity in putative oxidative enzymes of the lignocellulose degrading ascomyceteParascedosporium putredinisNO1
Authors: Scott Conor JR , Leadbeater Daniel R , Oates Nicola C , James Sally R , Newling Katherine , Li Yi , McGregor Nicholas GS , Bird Susannah , Bruce Neil C
Published: August 2023

Economic valorisation of lignocellulose is paramount to realising a true circular bioeconomy; however, this requires the development of systems and processes to expand the repertoire of bioproducts beyond current renewable fuels, chemicals, and sustainable materials.Parascedosporium putredinisNO1 is an ascomycete that thrived at the later stages of a wheat- straw composting community culture, indicating a propensity to degrade recalcitrant lignin- enriched biomass, but exists within an underrepresented and underexplored fungal lineage. This strain has proven an exciting candidate for the identification of new enzymes targeting recalcitrant components of lignocellulose following the recent discovery of a new lignin β-ether linkage cleaving enzyme.

The first genome for the genusParascedosporiumforP. putredinisNO1 genome was sequenced, assembled, and annotated. The genome is 39 Mb in size, consisting of 21 contigs annotated to contain 9.998 protein-coding sequences. The carbohydrate-active enzyme (CAZyme) repertoire was compared to 2570 ascomycete genomes and in detail withTrichoderma reesei,Fusarium oxysporum,and sister taxaScedosporium boydii.Significant expansion in the oxidative auxiliary activity class of CAZymes was observed in theP. putredinisNO1 genome resulting from increased sequences encoding putative lytic polysaccharide monooxygenases (LPMOs), oxidative enzymes acting within LPMO redox systems, and lignin-degrading laccases.P. putredinisNO1 scored above the 95thpercentile for AA gene density across the ascomycete phylum, suggesting a primarily oxidative strategy for lignocellulose breakdown. Novel structure-based searching approaches were employed, revealing 17 new sequences with structural similarity to LPMO, laccase, and peroxidase sequences and which are potentially new lignocellulose-degrading enzymes.

Importance

An annotated reference genome has revealedP. putredinisNO1 as a useful resource for the identification of new lignocellulose degrading enzymes for biorefining of woody plant biomass. Utilising a ‘structure-omics’ based searching strategy, new potentially lignocellulose-active sequences were identified that would have been missed by traditional sequence searching methods. These new identifications, alongside the discovery of novel enzymatic functions from this underexplored lineage with the recent discovery of a new phenol oxidase that cleaves the main structural β-O-4 linkage in lignin fromP. putredinisNO1 highlights the underexplored and poorly represented family Microascaceae as particularly interesting candidates worthy of further exploration toward the valorisation of high value biorenewable products.
Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets
Authors: Somuncular Ece , Hauenstein Julia , Su Tsu-Yi , Dumral Özge , Gustafsson Charlotte , Tzortzis Efthymios , Forlani Aurora , Johansson Anne-Sofie , Månsson Robert , Luc Sidinh
Published: August 2023

Age is a risk factor for hematologic malignancies. Attributes of the aging hematopoietic system include increased myelopoiesis, impaired adaptive immunity, and a functional decline of the hematopoietic stem cells (HSCs) that maintain hematopoiesis. Changes in the composition of diverse HSC subsets have been suggested to be responsible for age-related alterations, however, the underlying regulatory mechanisms are incompletely understood in the context of HSC heterogeneity. In this study, we investigated how distinct HSC subsets, separated by CD49b, functionally and molecularly change their behavior with age. We demonstrate that blood lineage differentiation progressively shifts to a higher myeloid cellular output in both lymphoid-biased and myeloid-biased HSC subsets during aging. In parallel, we show that HSCs selectively undergo age-dependent gene expression and gene regulatory molecular changes in a progressive manner, which is initiated already in the pre-adult stage. Overall, our studies suggest that aging intrinsically alters both cellular and molecular properties of HSCs.

Highlights:

With age a gradual shift towards myeloid differentiation occurs in both myeloid-biased and lymphoid-biased enriched HSC subsets.

Age-related molecular changes preferentially occur in HSCs.

Functionally distinct HSC subsets with high transcriptional similarity can be distinguished on the epigenetic level.

HSC aging is associated with a progressive increase in chromatin accessibility.
Development and Analytical Evaluation of a Point-of-Care Electrochemical Biosensor for Rapid and Accurate SARS-CoV-2 Detection
Authors: Meshesha Mesfin , Sardar Anik , Supekar Ruchi , Bhattacharjee Lopamudra , Chatterjee Soumyo , Halder Nyancy , Mohanta Kallol , Pal Biplab
Published: August 2023

The COVID-19 pandemic has underscored the critical need for rapid and accurate screening and diagnostic methods for potential respiratory viruses. Existing COVID-19 diagnostic approaches face limitations either in terms of turnaround time or accuracy. In this study, we present an electrochemical biosensor that offers nearly instantaneous and precise SARS-CoV-2 detection, suitable for point-of-care and environmental monitoring applications. The biosensor employs a stapled hACE-2 N-terminal alpha helix peptide to functionalize an in-situ grown polypyrrole conductive polymer on a nitrocellulose membrane backbone through a chemical process. We assessed the biosensor’s analytical performance using heat-inactivated omicron and delta variants of the SARS-CoV-2 virus in artificial saliva (AS) and nasal swabs (NS) samples diluted in a strong ionic solution. Virus identification was achieved through electrochemical impedance spectroscopy (EIS) and frequency analyses. The assay demonstrated a limit of detection of 40 TCID50/mL, with 95% sensitivity and 100% specificity. Notably, the biosensor exhibited no cross-reactivity when tested against the influenza virus. The entire testing process using the biosensor takes less than a minute. In summary, our biosensor exhibits promising potential in the battle against pandemic respiratory viruses, offering a platform for the creation of rapid, compact, portable, and point-of-care devices capable of multiplexing various viruses. This groundbreaking development has the capacity to significantly bolster our readiness and response to future viral outbreaks.
A novel PEX14/PEX5 interface links peroxisomal protein import and receptor recycling
Authors: Emmanouilidis Leonidas , Sehr Jessica , Reglinski Katharina , Gaussmann Stefan , Goricanec David , Kordon Jonathan , Menezes Filipe , Waithe Dominic , Hublitz Philip , Bader Verian , Winklhofer Konstanze F. , Jung Martin , Schliebs Wolfgang , Eggeling Christian , Erdmann Ralf , Sattler Michael
Published: August 2023

Newly synthesized peroxisomal proteins are recognized in the cytosol by the cycling receptor PEX5 and directed to a docking complex comprising PEX14 and PEX13 at the peroxisomal membrane. After cargo translocation, the unloaded PEX5 is recycled in an ATP-dependent manner. Receptor docking involves the WxxxF-motifs in the N-terminal domain (NTD) of PEX5 that are recognized by the N-terminal domain of PEX14. Here, we combine biochemical methods and NMR spectroscopy to identify a novel binding interface between human PEX5 and PEX14. The interaction involves the PEX5 C-terminal cargo-binding TPR domain and a conserved IPSWQI peptide motif in the C-terminal intrinsically disordered region of PEX14. The three-dimensional structure of the PEX14 IPSWQI peptide bound the PEX5 TPR domain, shows the PEX14 interaction is non-overlapping with PTS1 binding to the TPR domain. Notably, PEX14 IPSWQI motif binding to a hinge region in the TPR domain shows a more open supercoil of the TPR fold that resembles the apo conformation in the absence of PTS1 peptide. Mutation of binding site residues in PEX5 or PEX14 leads to a partial protein import defect and decrease of the steady-state-concentration of PEX5. This resembles the mutant phenotype of cells affected in receptor recycling, suggesting a role in this process.