bluuebunny/crossref_metadata_2025 huggingface dataset:
Exome sequencing in Asian populations identifies rare deficientSMPD1alleles that increase risk of Parkinson’s disease
Authors: Chew Elaine GY , Liu Zhehao , Li Zheng , Chung Sun Ju , Lian Michelle M , Tandiono Moses , Ng Ebonne Y , Tan Louis CS , Chng Wee Ling , Tan Tiak Ju , Peh Esther KL , Ho Ying Swan , Chen Xiao Yin , Lim Erin YT , Chang Chu Hua , Leong Jonavan J , Heng Yue Jing , Peh Ting Xuan , Chan Ling-Ling , Chao Yinxia , Au Wing-Lok , Prakash Kumar M , Lim Jia Lun , Tay Yi Wen , Mok Vincent , Chan Anne YY , Lin Juei-Jueng , Jeon Beom S , Song Kyuyoung , Tham Clement CY , Pang Chi Pui , Ahn Jeeyun , Park Kyu Hyung , Wiggs Janey L , Aung Tin , Tan Ai-Huey , Annuar Azlina Ahmad , Makarious Mary B. , Blauwendraat Cornelis , Nalls Mike A , Robak Laurie A. , Alcalay Roy N. , Gan-Or Ziv , Lim Shen-Yang , Khor Chiea Chuen , Tan Eng-King , Wang Zhenxun , Foo Jia Nee
Published: August 2023

Parkinson’s disease is an incurable and progressive disease that adversely affects balance, muscle control, and movement. We hypothesized that the landscape of rare, protein-altering genetic variants could provide further mechanistic insights into disease pathogenesis. We performed whole-exome sequencing on 4,298 persons with Parkinson’s disease and 5,512 unaffected controls from Singapore, Malaysia, Hong Kong, South Korea, and Taiwan. We tested for association between gene-based burden of rare, predicted damaging variants and risk of Parkinson’s disease. Genes surpassing exome-wide significance (P<2.5×10-6) were tested for replication in sequencing data from a further 5,585 Parkinson’s disease patients and 5,642 controls of Asian and European ancestry. We observed that carriage of rare, protein-altering variants that were predicted to impair protein function atSMPD1(a gene encoding for acid sphingomyelinase) were significantly associated with increased risk of Parkinson’s disease. Refinement of variant classification using functional acid sphingomyelinase assays suggest that individuals carryingSMPD1variants with less than 44 percent of normal enzymatic activity show the strongest association with Parkinson’s disease risk in both the discovery (odds ratio (OR) = 2.37, 95% CI = 1.68 - 3.35,P= 4.35 × 10-7) and replication collections (OR = 2.18, 95% CI = 1.69 - 2.81,P= 4.80 × 10-10), leading to a significant observation when all data were meta-analyzed (OR = 2.24, 95% CI = 1.83 - 2.76,P= 1.25 × 10-15). Our findings affirm the importance of sphingomyelin metabolism in the pathobiology of neurodegenerative diseases and highlights the utility of functional genomic assays in large-scale exome sequencing studies.
A placebo-controlled clinical study to assess the impact of variable complex weak magnetic fields (VCMF’s) generated by the BeCurie™ (Evolv28) device on the subjects with perceived stress and anxiety
Authors: Jonnalagadda Mohan Krishna , Palle Lalitha , Pasumarthi Shyam Sunder , Gali Chaitanya Chakravarthi
Published: August 2023

Background

Exposure to variable weak magnetic fields, reported to have shown beneficial effects on several neurological illnesses. However, existing therapies are costly, complex, and lack subject ease for frequent follow ups. In the current study, the novel BeCurie™ (Evolv28) wearable neck device that emits variable complex weak magnetic fields (VCMF’s) is evaluated for its positive impact on subjects with perceived stress and anxiety.

Methods

Eighteen participants were enrolled in this study. The primary outcomes of the study were to assess the improvements in perceived stress and anxiety symptoms in the BeCurie™ treated group. Stress and anxiety scores were assessed using DASS-21, HAM-A, and PSS. Quality of life was assessed using the MQoL-R questionnaire. Serum Cortisol and complete blood profile were assessed to understand the safety profile of BeCurie™ treatment.

Results

Participants in the BeCurie™ group showed a significant reduction in stress and anxiety scores compared to the placebo group on Day 30. Furthermore, open label study assessments on Days 60 and 90 revealed improvements in self-reported stress and anxiety scores, significant time dependent improvements in all major domains of quality of life, including physical, psychological, existential, and support-based aspects of life. No adverse events were reported during the study. Comprehensive blood profile assessment showed no significant changes in either the placebo or BeCurie™ groups.

Conclusions

The findings indicate that VCMF’s emitted by the BeCurie™ device can be a supporting non-invasive alternative therapy for managing stress and anxiety. Nonetheless, the limitations of the study, including the small sample size and the lack of a follow-up assessment beyond 90 days, suggest that further investigations are needed to establish the long-term efficacy of BeCurie™ in managing stress and anxiety symptoms.
Spatio-temporal modelling of referrals to outpatient respiratory clinics in the integrated care system of the Morecambe Bay area, England
Authors: Mountain Rachael , Knight Jo , Heys Kelly , Giorgi Emanuele , Gatheral Timothy
Published: August 2023

Background

Promoting integrated care is a key goal of the NHS Long Term Plan to improve population respiratory health, yet there is limited data-driven evidence of its effectiveness. The Morecambe Bay Respiratory Network is an integrated care initiative operating in the North-West of England since 2017. A key target area has been reducing referrals to outpatient respiratory clinics by upskilling primary care teams. This study aims to explore space-time patterns in referrals from general practice in the Morecambe Bay area to evaluate the impact of the initiative.

Methods

Data on referrals to outpatient clinics and chronic respiratory disease patient counts between 2012-2020 were obtained from the Morecambe Bay Community Data Warehouse, a large store of routinely collected healthcare data. For analysis, the data is aggregated by year and small area geography. The methodology comprises of two parts. The first explores the issues that can arise when using routinely collected primary care data for space-time analysis and applies spatio-temporal conditional autoregressive modelling to adjust for data complexities. The second part models the rate of outpatient referral via a Poisson generalised linear mixed model that adjusts for changes in demographic factors and number of respiratory disease patients.

Results

The first year of the Morecambe Bay Respiratory Network was not associated with a significant difference in referral rate. However, the second and third years saw significant reductions in areas that had received intervention, with full intervention associated with a 31.8% (95% CI 17.0-43.9) and 40.5% (95% CI 27.5-50.9) decrease in referral rate, respectively.

Conclusions

Routinely collected data can be used to robustly evaluate key outcome measures of integrated care. The results demonstrate that effective integrated care has real potential to ease the burden on respiratory outpatient services by reducing the need for an onward referral. This is of great relevance given the current pressure on outpatient services globally, particularly long waiting lists following the COVID-19 pandemic and the need for more innovative models of care.
Identification of patients at risk for pancreatic cancer in a 3-year timeframe based on machine learning algorithms
Authors: Zhu Weicheng , Aphinyanaphongs Yindalon , Kastrinos Fay , Simeone Diane M. , Pochapin Mark , Razavian Narges , Gonda Tamas
Published: August 2023

Importance

Early detection of pancreatic cancer (PC) remains challenging largely due to the low population incidence and few known risk factors. However, screening in at-risk populations and detection of early cancer has the potential to significantly alter survival.

Objective

In this study, we aim to develop a predictive model to identify patients at risk for developing new-onset PC at two and a half to three year time frame

Data Sources

We used the Electronic Health Records (EHR) of a large medical system from 2000 to 2021 (N=537,410). The EHR data analyzed in this work consists of patients’ demographic information, diagnosis records, and lab values, which are used to identify patients who were diagnosed with pancreatic cancer and the risk factors used in the machine learning algorithm for prediction.

Results

We identified 73 risk factors of pancreatic cancer with the Phenome-wide Association Study (PheWAS) on a matched case-control cohort. Based on them, we built a large-scale machine learning algorithm based on EHR. A temporally stratified validation based on patients not included in any stage of the training of the model was performed. This model showed an AUROC at 0.742 [0.727, 0.757] which was similar in both the general population and in a subset of the population who has had prior cross-sectional imaging. The prevalence of pancreatic cancer in those in the top 5 percentile of the risk score was 6 folds higher than the general population.

Conclusion

Our model leverages data extracted from a 6-month window of time in the electronic health record to identify patients at nearly 6-fold higher than baseline risk of developing pancreatic cancer 2.5 to 3 years from evaluation. This approach offers an opportunity to define an enriched population entirely based on static data, where current screening may be recommended.
Evidence-Based Practice Competencies among Nutrition Professionals and Students: A Systematic Review
Authors: Ghosh Nirjhar R. , Esmaeilinezhad Zahra , Zając Joanna , Creasy Rebecca A. , Lorenz Saundra G. , Crews Molly , Beathard Karen M. , Bala Malgorzata M. , Klatt Kevin C. , Johnston Bradley C.
Published: August 2023

Background

Evidence-based practice (EBP) promotes shared decision-making between clinicians and patients and has been widely adopted by various health professions including nutrition & dietetics, medicine and nursing.

Objective

To determine evidence-based practice (EBP) competencies among nutrition professionals and students reported in the literature.

Design

Systematic review.

Data sources

Medline, Embase, CINAHL, ERIC, CENTRAL, ProQuest Dissertations and Theses Global, BIOSIS Citation Index, andClinicalTrials.govup to March 2023.

Eligibility criteria for study selection

Eligible primary studies had to objectively or subjectively document the assessment of at least one of six predefined core EBP competencies, including formulating structured clinical questions, searching the literature for best evidence, and assessing studies for methodological quality, magnitude (size) of effects, certainty of evidence for effects, and determining the clinical applicability of study results based on patient values and preferences.

Data extraction and synthesis

Two reviewers independently screened articles and extracted data, including the reporting quality for eligible studies. Results were not amenable to meta-analysis and were thus summarized for each EBP competency.

Results

We identified 12 eligible cross-sectional survey studies, comprised of 1065 participants, primarily registered dietitians, across six countries, with the majority assessed in the United States (n=470). The reporting quality of the survey studies was poor overall, with 43% of items not reported and 22% of items partially reported. Only one study (8%) explicitly used an objective questionnaire to assess EBP competencies. The proportion of studies reporting on each competency were: 17% on the formulation of clinical questions, 83% on searching the literature, 75% on methodological quality or critical appraisal, 58% on interpreting statistical results, and 75% on applying study results. In general, the six competencies were incompletely defined or reported (e.g., it was unclear what ‘applicability’ and ‘critical appraisal’ referred to, and what study designs were appraised by the participants). Two core competencies, the magnitude (size) of effects and the certainty of evidence for effects, were not assessed.

Conclusions

Among 12 included articles the overall quality of study reports was poor, and when EBP competencies were reported they were predominantly self-perceived assessments as opposed to objective assessments. No studies reported on competencies in assessing magnitude of effect or certainty of evidence, skills that are essential for optimizing clinical nutrition decision-making.

Systematic review registration

PROSPERO CRD42022311916.
Machine learning based prediction of recurrence after curative resection for rectal cancer
Authors: Jeon Youngbae , Kim Young-Jae , Jeon Jisoo , Nam Kug-Hyun , Hwang Tae-Sik , Kim Kwang-Gi , Baek Jeong-Heum
Published: August 2023

Purpose

Patients with rectal cancer without distant metastases are typically treated with radical surgery. Post curative resection, several factors can affect tumor recurrence. This study aimed to analyze factors related to rectal cancer recurrence after curative resection using different machine learning techniques.

Methods

Consecutive patients who underwent curative surgery for rectal cancer between 2004 and 2018 at Gil Medical Center were included. Patients with stage IV disease, colon cancer, anal cancer, other recurrent cancer, emergency surgery, or hereditary malignancies were excluded from the study. The SMOTETomek technique was used to compensate for data imbalance between recurrent and no-recurrent groups. Four machine learning methods, logistic regression (LR), support vector machine (SVM), random forest (RF), and XGBoost (XGB), were used to identify significant factors. To overfit and improve the model performance, feature importance was calculated using the permutation importance technique.

Results

A total of 3320 patients were included in the study. However, after exclusion, the total sample size of the study was 961 patients. The median follow-up period was 60.8 months (range:1.2-192.4). The recurrence rate during follow-up was 13.2% (n=127). After applying the SMOTETomek method, the number of patients in both groups, recurrent and non-recurrent group were equalized to 667 patients. After analyzing for 16 variables, the top eight ranked variables (pT, sex, concurrent chemoradiotherapy, pN, age, postoperative chemotherapy, pTNM, and perineural invasion) were selected based on the order of permutational importance. The highest area under the curve (AUC) was for the SVM method (0.831). The sensitivity, specificity, and accuracy were found to be 0.692, 0.814, and 0.798, respectively. The lowest AUC was obtained for the XGBloost method (0.804), with a sensitivity, specificity, and accuracy of 0.308, 0.928, and 0.845, respectively. The variable with highest importance was pT as assessed through SVM, RF, and XGBoost (0.06, 0.12, and 0.13, respectively), whereas pTNM had the highest importance when assessed by LR (0.05).

Conclusions

In the current study, SVM showed the best AUC, and the most influential factor across all machine learning methods except LR was found to be pT. Clinicians should be more alert if patients have a high pT stage during postoperative follow-up in rectal cancer patients.
Forward genetic screening in engineered colorectal cancer organoids identifies novel regulators of metastasis
Authors: Cramer Zvi , Wang Xin , Leu Nicolae Adrian , Monaghan Keara , Rhoades Joshua H. , Tian Yuhua , Rico Joshua , Mendez Diego , Petroni Ricardo , Kim Melissa S. , Matsuda Rina , Carrera Maria F. , Brodsky Igor E. , Li Ning , Lengner Christopher J. , Blanco M. Andrés
Published: August 2023

Cancer is the second leading cause of death globally, due primarily to metastatic dissemination and colonization of distal sites. Recurrent genetic drivers of metastasis are elusive, suggesting that, unlike the stereotyped mutations promoting primary tumor development, drivers of metastasis may be variable. Here, we interrogate pathways governing metastasis through CRISPR/Cas9-based forward genetic screening in a genetically defined colorectal adenocarcinoma tumor organoid (tumoroid) model using ex vivoinvasion screens and orthotopic,in vivoscreens for gain of metastatic potential. We identifyCtnna1andBcl2l13asbona fidemetastasis suppressors. CTNNA1 loss promotes carcinoma cell invasion and migration through an atypical EMT-like mechanism, whereas BCL2L13 loss promotes cell survival after extracellular matrix detachment and non-cell-autonomous macrophage polarization. Ultimately, this study provides a proof-of-principle that high-content forward genetic screening can be performed in tumor-organoid modelsin vivoand identifies novel regulators of colon cancer metastasis.
libpspm: A feature-rich numerical package for solving physiologically structured population models
Authors: Joshi Jaideep , Zhang Lai , Stefaniak Elisa Z. , Dieckmann Ulf , Brännström Åke
Published: August 2023

For a vast majority of organisms, life-history processes depend on their physiological state, such as body size, as well as on their environment. Size-structured population models, or more generally, physiologically structured population models (PSPMs), have emerged as powerful tools for modelling the population dynamics of organisms, as they account for the dependences of growth, mortality, and fecundity rates on an organism’s physiological state and capture feedbacks between a population’s structure and its environment, including all types of density regulation. However, despite their widespread appeal across biological disciplines, few numerical packages exist for solving PSPMs in an accessible and computationally efficient way. The main reason for this is that PSPMs typically involve solving partial differential equations (PDEs), and no single numerical method works universally best, or even at all, for all PDEs. Here, we present libpspm, a general-purpose numerical library for solving user-defined PSPMs. libpspm provides eight different methods for solving the PDEs underlying PSPMs, including four semi-implicit solvers that can be used for solving stiff problems. Users can choose the desired method without changing the code specifying the PSPM. libpspm allows for predicting the dynamics of multiple physiologically structured or unstructured species, each of which can have its own distinct set of physiological states and demographic functions. By separating model definition from model solution, libpspm can make PSPM-based modelling accessible to non-specialists and thus promote the widespread adoption of PSPMs.
Contrastive learning explains the emergence and function of visual category-selective regions
Authors: Prince Jacob S. , Alvarez George A. , Konkle Talia
Published: August 2023

Modular and distributed coding theories of category selectivity along the human ventral visual stream have long existed in tension. Here, we present a reconciling framework –contrastive coding– based on a series of analyses relating category selectivity within biological and artificial neural networks. We discover that, in models trained with contrastive self-supervised objectives over a rich natural image diet, category-selective tuning naturally emerges for faces, bodies, scenes, and words. Further, lesions of these model units lead to selective, dissociable recognition deficits, highlighting their distinct functional roles in information processing. Finally, these pre-identified units can predict neural responses in all corresponding face-, scene-, body-, and word-selective regions of human visual cortex, under a highly constrained sparse-positive encoding procedure. The success of this single model indicates that brain-like functional specialization can emerge without category-specific learning pressures, as the system learns to untangle rich image content. Contrastive coding, therefore, provides a unifying account of object category emergence and representation in the human brain.
Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome
Authors: Pletenev Ilya A. , Bazarevich Maria , Zagirova Diana R. , Kononkova Anna D. , Cherkasov Alexander V. , Efimova Olga I. , Tiukacheva Eugenia A. , Morozov Kirill V. , Ulianov Kirill A. , Komkov Dmitriy , Tvorogova Anna V. , Golimbet Vera E. , Kondratyev Nikolay V. , Razin Sergey V. , Khaitovich Philipp , Ulianov Sergey V. , Khrameeva Ekaterina E.
Published: August 2023

Chromatin architecture regulates gene expression and shapes cellular identity, particularly in neuronal cells. Specifically, polycomb group (PcG) proteins enable establishment and maintenance of neuronal cell type by reorganizing chromatin into repressive domains that limit the expression of fate-determining genes and sustain distinct gene expression patterns in neurons. Here, we map the 3D genome architecture in neuronal and non-neuronal cells isolated from the Wernicke’s area of four human brains and comprehensively analyze neuron-specific aspects of chromatin organization. We find that genome segregation into active and inactive compartments is greatly reduced in neurons compared to other brain cells. Furthermore, neuronal Hi-C maps reveal strong long-range interactions, forming a specific network of PcG-mediated contacts in neurons that is nearly absent in other brain cells. These interacting loci contain developmental transcription factors with repressed expression in neurons and other mature brain cells. But only in neurons, they are rich in bivalent promoters occupied by H3K4me3 histone modification together with H3K27me3, which points to a possible functional role of PcG contacts in neurons. Importantly, other layers of chromatin organization also exhibit a distinct structure in neurons, characterized by an increase in short-range interactions and a decrease in long-range ones.
Do Goats Recognise Humans Cross-Modally?
Authors: Mason Marianne A. , Semple Stuart , Marshall Harry H. , McElligott Alan G.
Published: August 2023

Recognition plays a key role in the social lives of gregarious species, enabling animals to distinguish among social partners and tailor their behaviour accordingly. As domesticated animals regularly interact with humans, as well as members of their own species, we might expect mechanisms used to discriminate between conspecifics to also apply to humans. Given that goats can combine visual and vocal cues to recognize one another, we investigated whether this cross-modal recognition extends to discriminating among familiar humans. We presented 28 goats with facial photographs of familiar people and two repeated playbacks of a voice, either congruent (from the same person) or incongruent with that photograph (from a different person). When cues were incongruent, violating their expectations, we expected goats to respond faster and for longer after playbacks and show increases in physiological arousal (increased heart rate and/or decreased heart rate variability). We found the increase in latency that goats took to respond as the playback series progressed was greater when the face and voice were incongruent. As differences were not as predicted and only observed in one response measured, our evidence is tentative, but the variation in latency to look between congruency conditions suggests goat cross-modal recognition extends to humans. If this is the case, not only would this further demonstrate the flexibility of complex recognition systems to discriminate among members of a very different species, but indicates goats can produce mental representations for familiar people, a key component of individual recognition.
Mice remember experiences via conspecific-context: models of social episodic-like memory
Authors: Ross T. W. , Poulter S. L. , Lever C. , Easton A.
Published: August 2023

The ability to remember unique past events (episodic memory) may be an evolutionarily conserved function, with accumulating evidence of episodic-(like) memory processing in rodents. In humans, it likely contributes to successful complex social networking. Rodents, arguably the most used laboratory models, are also rather social animals. However, many behavioural paradigms are devoid of sociality, and commonly-used social spontaneous recognition tasks (SRTs) are open to non-episodic strategies based upon familiarity. We address this gap by developing new SRT variants. Here, in object-in-context SRTs, we asked if context could be specified by the presence/absence of either a conspecific (experiment 1) or an additional local object (experiment 2). We show that mice readily used the conspecific as contextual information to distinguish unique episodes in memory. In contrast, no coherent behavioural response emerged when an additional object was used as a potential context specifier. Further, in a new social conspecific-in-context SRT (experiment 3) where environment-based change was the context specifier, mice preferably explored a more recently-seen familiar conspecific associated with contextual mismatch, over a less recently-seen familiar conspecific presented in the same context. The results argue that, in incidental SRT conditions, mice readily incorporate conspecific cue information into episodic-like memory. Thus, the tasks offer different ways to assess and further understand the mechanisms at work in social episodic-like memory processing.
Decreased myelin-related gene expression in the nucleus accumbens during spontaneous neonatal opioid withdrawal in the absence of long-term behavioral effects in adult outbred CFW mice
Authors: Borrelli Kristyn N. , Wingfield Kelly K. , Yao Emily J. , Zamorano Catalina A. , Sena Katherine D. , Beierle Jacob A. , Roos Michelle A. , Zhang Huiping , Wachman Elisha M. , Bryant Camron D.
Published: August 2023

Prenatal opioid exposure is a major health concern in the United States, with the incidence of neonatal opioid withdrawal syndrome (NOWS) escalating in recent years. NOWS occurs upon cessation ofin uteroopioid exposure and is characterized by increased irritability, disrupted sleep patterns, high-pitched crying, and dysregulated feeding. The main pharmacological strategy for alleviating symptoms is treatment with replacement opioids. The neural mechanisms mediating NOWS and the long-term neurobehavioral effects are poorly understood. We used a third trimester-approximate model in which neonatal outbred pups (Carworth Farms White; CFW) were administered once-daily morphine (15 mg/kg, s.c.) from postnatal day (P) day 1 through P14 and were then assessed for behavioral and transcriptomic adaptations within the nucleus accumbens (NAc) on P15. We also investigated the long-term effects of perinatal morphine exposure on adult learning and reward sensitivity. We observed significant weight deficits, spontaneous thermal hyperalgesia, and altered ultrasonic vocalization (USV) profiles following repeated morphine and during spontaneous withdrawal. Transcriptome analysis of NAc from opioid-withdrawn P15 neonates via bulk mRNA sequencing identified an enrichment profile consistent with downregulation of myelin-associated transcripts. Despite the neonatal behavioral and molecular effects, there were no significant long-term effects of perinatal morphine exposure on adult spatial memory function in the Barnes Maze, emotional learning in fear conditioning, or in baseline or methamphetamine-potentiated reward sensitivity as measured via intracranial self-stimulation. Thus, the once daily third trimester-approximate exposure regimen, while inducing NOWS model traits and significant transcriptomic effects in neonates, had no significant long-term effects on adult behaviors.

HIGHLIGHTS

We replicated some NOWS model traits via 1x-daily morphine (P1-P14).

We found a downregulation of myelination genes in nucleus accumbens on P15.

There were no effects on learning/memory or reward sensitivity in adults.
Dynamic clustering of genomics cohorts beyond race, ethnicity—and ancestry
Authors: Mohsen Hussein , Blenman Kim , Emani Prashant S. , Morris Quaid , Carrot-Zhang Jian , Pusztai Lajos
Published: August 2023

Background

Recent decades have witnessed a steady decrease in the use of race categories in genomic studies. While studies that still include race categories vary in goal and type, these categories already build on a history during which racial color lines have been enforced and adjusted in the service of social and political systems of power and disenfranchisement. For early modern biological classification systems, data collection was also considerably arbitrary and limited. Fixed, discrete classifications have limited the study of human biodiversity and disrupted widely spread genetic and phenotypic continuums across geographic scales. Relatedly, the use of broad and predefined classification schemes—e.g. continent-based—across traits can risk missing important trait-specific genomic signals.

Results

To address these issues, we introduce a dynamic approach to clustering human genomics cohorts on a trait-specific level and without using a set of predefined categories. We tested the approach on whole-exome sequencing datasets in ten cancer types and partitioned them based on germline variants in cancer-relevant genes that could confer cancer type-specific disease predisposition. Results demonstrate clustering patterns that transcend discrete continent-based categories across cancer types. Functional analysis based on cancer type-specific clusterings also captures the fundamental biological processes underlying cancer, differentiates between dynamic clusters on a functional level, and identifies novel potential drivers overlooked by a continent-based clustering model.

Conclusions

Through a trait-based lens, the dynamic clustering approach reveals genomic patterns that transcend predefined classification categories. We propose that coupled with diverse data collection, new clustering approaches have the potential to draw a more complete portrait of genomic variation and to address, in parallel, technical and social aspects of studying human biodiversity.
Enhancing Opioid Bioactivity Predictions through Integration of Ligand-Based and Structure-Based Drug Discovery Strategies with Transfer and Deep Learning Techniques
Authors: Provasi Davide , Filizola Marta
Published: August 2023

The opioid epidemic has cast a shadow over public health, necessitating immediate action to address its devastating consequences. To effectively combat this crisis, it is crucial to discover better opioid drugs with reduced addiction potential. Artificial intelligence-based and other machine learning tools, particularly deep learning models, have garnered significant attention in recent years for their potential to advance drug discovery. However, utilizing these tools poses challenges, especially when training samples are insufficient to achieve adequate prediction performance. In this study, we investigate the effectiveness of transfer learning using combined ligand-based and structure-based molecular descriptors from the entire opioid receptor (OR) subfamily in building robust deep learning models for enhanced bioactivity prediction of opioid ligands at each individual OR subtype. Our studies hold the potential to greatly advance opioid research by enabling the rapid identification of novel chemical probes with specific bioactivities, which can aid in the study of receptor function and contribute to the future development of improved opioid therapeutics.
Comparison of Screening Guidelines for Cardiovascular disease Prevention and Early Detection:a scoping review
Authors: Darwesh Badawy Mohammed Abd ElFattah Mohammed , Naing Lin , Tuah Nik Ani Afiqah
Published: August 2023

Objective

Globally, cardiovascular disease (CVD) has a significant role in morbidity and early death. This review’s objective is to provide a summary of the strengths and weaknesses in the variety of screening guidelines made by several international organizations for the early identification and prevention of CVD.

Methods

As the reporting guideline for this review, we used Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). We performed a scoping review using a few guideline-specific databases. We tabulated the main key differences between the included screening guidelines for CVD prevention and early detection from different perspectives.

Results

We included a total of 20 unique guidelines that were developed by various organizations throughout the world and focused on screening for CVD prevention and early detection out of the 2,466 guidelines discovered by our search based on our eligibility criteria. We concluded that the target populations, CVD risk assessment techniques, outcomes, and categories of the chosen CVD prevention guidelines widely varied. Additionally, some guidelines adopted no grading scheme for their evidence, while others did not advocate the use of any imaging screening tools in their evaluation of the CVD risk.

Conclusions

This scoping review highlights the areas of each guideline’s strengths and weaknesses and conducts a systematic comparison of a number of worldwide guidelines for CVD prevention and early diagnosis.

What is already known in this review?

Based on the most recent evidence and consensus among experts, each nation creates its own set of guidelines for the early detection and prevention of CVD.

What this review adds

This review conducted a systematic comparison and summarized the strengths and weaknesses of the various screening guidelines made by numerous international organizations for the early detection and prevention of CVD.

• How this review might affect research, practice or policy

This review provided opportunities to improve the future development of the clinical practice guidelines for CVD prevention and early detection.
Divergent warning patterns influence male and female mating behaviours in a tropical butterfly
Authors: Kuo Chi-Yun , Melo-Flóres Lina , Aragón Andrea , Oberweiser Morgan M. , McMillan W. Owen , Pardo-Diaz Carolina , Salazar Camilo , Merrill Richard M.
Published: August 2023

Traits under divergent ecological selection that also function during mating can be important in maintaining species boundaries. Few studies have considered mutual mate choice, where both males and females base mating decisions on the same trait. We investigated the contribution of visual preference to assortative mating between an aposematic butterflyHeliconius cydnoand its sympatric relativeH. melpomene. Wing colouration inHeliconiusbutterflies evolved as a warning signal but also functions as a mating cue. We predicted that both sexes ofH. cydnocontributed to assortative mating by exhibiting visual preference towards conspecific wing colouration. We analysed published and new data from preference experiments, in which males were presented with conspecific andH. melpomenefemales. We also recorded female responses and mating outcomes in choice experiments, involving conspecific males with either the original white or artificially painted red forewing bands. Both sexes ofH. cydnoresponded more positively towards the conspecific colouration, yet male colouration did not predict mating outcomes in female choice experiments. As courtships are initiated by males in butterflies, our findings suggest that female visual preference might be of secondary importance in preventing gene flow betweenH. cydnoandH. melpomene.
Identification of a Novel Hypoxia-induced Inflammatory Cell Death Pathway
Authors: Bhardwaj Abhishek , Antonelli Maria , Ueberheide Beatrix , Neel Benjamin G.
Published: August 2023

Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ∼600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain.CYLD-deleted HER2+ cell-derived xenografts phenocopy the effects of PTP1B deficiency, and reconstitutingRNF213knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning “cold” tumors “hot”. Our findings also reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders.
A Novel Simulation Framework for Validation of Ecological Network Inference
Authors: Kusch Erik , Vinton Anna C.
Published: August 2023

Understanding how the differential magnitude and sign of ecological interactions vary across space is vital to assessing ecosystem resilience to biodiversity loss and predict community assemblies. This necessity for ecological network knowledge and their labour-intensive sampling requirements has spurred the creation of ecological network inference methodology. Recent research has identified inconsistencies in networks inferred using different approaches thus necessitating quantification of inference performance to facilitate choice of network inference approach.

Here we develop a data simulation method to generate data products fit for network inference and subsequently quantify the validity of two well-established ecological interaction network inference methods – HMSC and COOCCUR. The simulation framework we present here can be parameterised using real-world information (e.g., biological interactions observed in-situ and bioclimatic niche preferences) thus representing network inference capabilities in real-world applications. Using this framework, it is thus possible to evaluate the performance of any ecological network inference approach.

We identify a concerningly large range in accuracy of inferred networks as compared to true, realisable association networks. These differences in inference accuracy are governed by a paradigm of input data types and environmental parameter estimation as previously suggested. To establish a workflow for quantification of network inference reliability, we suggest analysis procedures with which to explore inference and detection probabilities of association types of different identity and sign with respect to bioclimatic niche preferences and association strength of association partner-species.

With this study, we provide the groundwork with which to validate and compare ecological network inference methods, and ultimately vastly increase our ability to understand and predict species biodiversity across space and time.
SynGAP regulates synaptic plasticity and cognition independent of its catalytic activity
Authors: Araki Yoichi , Rajkovich Kacey E. , Gerber Elizabeth E. , Gamache Timothy R. , Johnson Richard C. , Tran Thanh Hai , Liu Bian , Hong Ingie , Kirkwood Alfredo , Huganir Richard
Published: August 2023

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations inSYNGAP1in humans result in intellectual disability, autistic-like behaviors, and epilepsy. HeterozygousSyngap1knockout mice display deficits in synaptic plasticity, learning, and memory, and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independent of its GAP activity. Here, we report that inactivating mutations within the SynGAP GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA- receptor-TARP complex, the major excitatory receptor complex in the brain, in the formation of molecular condensates with synaptic scaffolding proteins. These results have significant implications for the development of therapeutic treatments forSYNGAP1- related neurodevelopmental disorders.

One-Sentence Summary

SynGAP regulates synaptic plasticity and cognition due to its phase separation properties instead of its catalytic activity.
Deficiency of Orexin Receptor Type 1 in Dopaminergic Neurons Increases Novelty-Induced Locomotion and Exploration
Authors: Xiao Xing , Yeghiazaryan Gagik , Eggersmann Fynn , Cremer Anna L. , Backes Heiko , Kloppenburg Peter , Hausen A. Christine
Published: August 2023

Orexin signaling in the ventral tegmental area and substantia nigra promotes locomotion and reward processing, but it is not clear whether dopaminergic neurons directly mediate these effects. We show that dopaminergic neurons in these areas mainly express orexin receptor subtype 1 (Ox1R). In contrast, only a minor population in the medial ventral tegmental area express orexin receptor subtype 2 (Ox2R). To analyze the functional role of Ox1R signaling in dopaminergic neurons, we deleted Ox1R specifically in dopamine transporter-expressing neurons of mice and investigated the functional consequences. Deletion of Ox1R increased locomotor activity and exploration during exposure to novel environments or when intracerebroventricularely injected with orexin A. Spontaneous activity in home cages, anxiety, reward processing, and energy metabolism did not change. Positron emission tomography imaging revealed that Ox1R signaling in dopaminergic neurons affected distinct neural circuits depending on the stimulation mode. In line with an increase of neural activity in the lateral paragigantocellular nucleus (LPGi) of Ox1RΔDATmice, we found that dopaminergic projections innervate the LPGi in regions where the inhibitory dopamine receptor subtype D2 but not the excitatory D1 subtype resides. These data suggest a crucial regulatory role of Ox1R signaling in dopaminergic neurons in novelty-induced locomotion and exploration.
Approximating conformational Boltzmann distributions with AlphaFold2 predictions
Authors: Brown Benjamin P. , Stein Richard A. , Meiler Jens , Mchaourab Hassane
Published: August 2023

Protein dynamics are intimately tied to biological function and can enable processes such as signal transduction, enzyme catalysis, and molecular recognition. The relative free energies of conformations that contribute to these functional equilibria are evolved for the physiology of the organism. Despite the importance of these equilibria for understanding biological function and developing treatments for disease, the computational and experimental methods capable of quantifying them are limited to systems of modest size. Here, we demonstrate that AlphaFold2 contact distance distributions can approximate conformational Boltzmann distributions, which we evaluate through examination of the joint probability distributions of inter-residue contact distances along functionally relevant collective variables of several protein systems. Further, we show that contact distance probability distributions generated by AlphaFold2 are sensitive to points mutations thus AF2 can predict the structural effects of mutations in some systems. We anticipate that our approach will be a valuable tool to model the thermodynamics of conformational changes in large biomolecular systems.
Single Cell Transcriptomes, Lineage, and Differentiation of Functional Airway Microfold Cells
Authors: Surve Manalee V. , Lin Brian , Reedy Jennifer L. , Crossen Arianne J. , Xu Anthony , Klein Bruce S. , Vyas Jatin M. , Rajagopal Jayaraj
Published: August 2023

The airway epithelium is frequently exposed to pathogens and allergens, but the cells that are responsible for sampling these inhaled environmental agents have not been fully defined. Thus, there is a critical void in our understanding of how luminal antigens are delivered to the immune cells that drive the appropriate immune defenses against environmental assaults. In this study, we report the first single cell transcriptomes of airway Microfold (M) cells, whose gut counterparts have long been known for their antigen sampling abilities. Given their very recent discovery in the lower respiratory airways, the mechanisms governing the differentiation and functions of airway M cells are largely unknown. Here, we shed light on the pathways of airway M cell differentiation, establish their lineage, and identify a functional M cell-specific endocytic receptor, the complement receptor 2 (CR2). Lastly, we demonstrate that airway M cells can endocytoseAspergillus fumigatusconidia in a CR2-dependent manner. Collectively, this work lays a foundation for deepening our understanding of lung mucosal immunology and the mechanisms that drive lung immunity and tolerance.
Conditional deletion ofCcl2in smooth muscle cells does not reduce early atherosclerosis in mice
Authors: Gunnersen Stine , Shim Jeong Tangkjær , Liu Fan , Tietge Uwe J.F. , Sørensen Charlotte Brandt , Bentzon Jacob Fog
Published: August 2023

Background and aims

C-C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout ofCcl2reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice.

Methods

SMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtypeCcl2alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin /kexin type 9 (PCSK9) and a high-fat diet for 12 weeks.

Results

Unexpectedly, mice with SMC-specificCcl2deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes.

Conclusions

SMC-specific deficiency ofCcl2does not significantly affect plaque development in hypercholesterolemic mice.

Bullet points

SMCs express CCL2 in human plaques and upon inflammatory activation of a murine SMC line in vitro.

Deletion of the Ccl2 gene in SMCs using Cre recombinase does not influence the size or composition of atherosclerotic plaque in mice.

Only by conducting a control study in mice without Cre recombinase was an initially observed difference in atherosclerosis concluded to be a genetic background effect.