bluuebunny/crossref_metadata_2025 huggingface dataset:
The Last Straw
Authors: Langford Nolan , Arif Haad , Waldrop Ian , Carpenter Chase , Sheets Nicholas
Published: September 2024

Objectives

With the recent societal push for eco-sustainability, there has been an increase in the prevalence of reusable utensils, particularly multiuse straws. This study is the first to investigate the epidemiology of plastic, glass, and metal straw-related injuries (SRIs) presenting to the emergency department (ED).

Methods

The National Electronic Injury Surveillance System database was examined for SRIs from January 2012 through December 2021. Cases were stratified by sex, age, diagnosis, mechanism of injury, and straw material to monitor epidemiological patterns.

Results

A total of 1,174 SRIs presented to the National Electronic Injury Surveillance System EDs from January 1, 2012 to December 31, 2021. The majority of injuries occurred among males (55.9%) aged 0–3 years old (43.8%). Injuries caused by reusable straws were significantly more common in patients 3 years old or younger (P < 0.001). Injuries most commonly affect the mouth (45.4%), eyes (22%), and internal structures (13.6%). Lacerations and oral injuries were significantly more common among reusable straw materials (P < 0.001). A 46.5% increase in injuries was noted from 2012 to 2021. The most common mechanism of injury was poking injury (53.5%), followed by stationary falls (19.4%), foreign body (18.7%), running and falling (5.9%), and other (2.4%). Of these cases, 46.3% of injuries were due to the improper use of straws. Metal straw injuries increased 12.8% over the study period.

Conclusions

Although most injuries occurred as accidental poking while drinking, nearly half of all injuries were sustained while using straws in an off-label manner. Ensuring the proper use of straws and monitoring children when using a straw may help to decrease the incidence of SRI. Among the options for environmentally friendly straw materials, metal straws pose the greatest risk for injuries requiring ED presentation. Thus, their use should be avoided in the pediatric population.
“Comparative study of adipose-derived stem cells from localized scleroderma patients and healthy donors in treating skin fibrosis”
Authors: Li Zhujun , Xiao Yiding , Kang Lin , Li Yunzhu , Wang Hayson Chenyu , Li Ziming , Yang Yuemei , Huang Jiuzuo , Yu Nanze , Long Xiao
Published: September 2024

Background:

Localized scleroderma (LoS) is an autoimmune disease characterized by fibrosis of the skin and atrophy of the subcutaneous fat tissue. Adipose-derived mesenchymal stem cells (ASCs) is a promising treatment approach for LoS. However, ASCs from scleroderma patients (LoS-ASCs) have been shown to exhibit altered characteristics compared to ASCs from healthy donors (healthy-ASCs). This study aimed to compare the abilities of LoS-ASCs and healthy-ASCs in treating skin fibrosis.

Methods:

The paracrine ability of ASCs was tested with cytokine array. Bleomycin-challenged mice models received subcutaneous injection of LoS-ASCs and healthy-ASCs. Pathological staining and western blotting of COL1, α-SMA was performed. Fibroblasts derived from LoS lesions (LoS-FB) was co-cultured with ASCs, and subjected to RNA sequencing to further explore the similarities and differences in the treatment mechanism.

Results:

In vivo comparison revealed that healthy ASCs had a stronger proliferation ability and secreted higher levels of growth factors and cytokines, including VEGFA, PDGFB, and IL-10. Pathological staining of the skin in mice models treated with ASCs demonstrated that healthy ASCs were more effective in reducing dermal thickness and collagen deposition, while increasing microvessel density and the proportion of M2 macrophages. Co-culture with both healthy-ASCs and LoS-ASCs reduced the proliferation and migration abilities of LoS-FB, as well as the protein expression of α-SMA and COL1. RNA sequencing and validation revealed potential difference in the canonical Wnt pathway.

Conclusions:

Healthy-ASCs exhibited stronger proliferation, paracrine, anti-fibrosis, pro-angiogenesis, and immunomodulation abilities in treating skin fibrosis in scleroderma mouse models.

Clinical Relevance Statement:

Allogenic ASCs obtained from healthy donors are more efficient in treating skin fibrosis, and could serve as a potential alternative for patients who are not suitable candidates for liposuction surgery in the future.
Exploring the Presence of Female Germline Stem Cells in Rats and Mice
Authors: Zhang Jian , Zhang Yu , Luo Jia-Li , Yu Lin , Li Pan-Pan , Wang Xin-Yue , Zhang Ting-Ting , Sun Zhao-Gui
Published: September 2024

Objective:

To determine the presence of female germline stem cells (FGSCs) in postnatal mammals under physiological and pathological conditions.

Methods:

We explored the presence of FGSCs using various models, including mice of different ages, an ovarian mouse model with mechanical injury, and a rat model of endometriosis. Moreover, we investigated the feasibility of inducing FGSCs in vitro using cultured ovarian tissues and employed the differential adhesion method for isolating FGSCs. For labeling FGSCs within the ovary, we employed markers such as MVH/UCHL1 and BrdU.

Results:

Our investigations revealed that FGSCs were not detectable in any of our models, across all conditions tested.

Conclusion:

Our experiments provide evidences for the viewpoint that no FGSC exists in the ovaries of postnatal mice or rats, and then support that mammalian ovaries do not produce new oocytes after birth.
Dynamics and Evolution of Donor-derived Cytomegalovirus Infection in 3 Solid Organ Transplant Recipients With the Same Multiorgan Donor
Authors: Horsten Fien , Chou Sunwen , Gillemot Sarah , Debaveye Yves , Naesens Maarten , Pirenne Jacques , Vanhoutte Thomas , Vanuytsel Tim , Vos Robin , Maes Piet , Snoeck Robert , Andrei Graciela
Published: September 2024

Background.

Cytomegalovirus (CMV) infection poses a significant risk to immunosuppressed transplant recipients, manifesting through primary infection, reinfection, or reactivation.

Methods.

We analyzed the emergence of drug resistance in CMV infection in 3 patients who were later found to have received an allograft from a shared, deceased donor. The seronegative transplant recipients developed symptomatic CMV infections after bowel/pancreas, kidney, or lung transplantation. Prospective Sanger sequencing was used to identify mutations in the viral DNA polymerase (DP) and protein kinase (PK). DP and PK variants were retrospectively quantified by targeted next-generation sequencing. The impact of the novel DP-A505G substitution on drug susceptibility was assessed using a recombinant virus. Whole-genome sequencing of clinical CMV samples was enabled through target DNA enrichment.

Results.

The DP-A505G substitution was found in all patient samples and could be associated with a natural polymorphism. A subsequent review of the patients’ clinical histories revealed that they had all received organs from a single donor. The CMV infection exhibited divergent evolution among the patients: patient 1 developed resistance to ganciclovir and foscarnet because of 2 DP mutations (V715M and V781I), patient 2 showed no genotypic resistance, and patient 3 developed ganciclovir (PK-L595S) and maribavir resistance (PK-T409M). Interpatient variation across the entire CMV genome was minimal, with viral samples clustering in phylogenetic analysis.

Conclusions.

All 3 transplant recipients were infected with the same donor-derived CMV strain and readily developed different drug susceptibility profiles. This underscores the importance of judicious antiviral drug use and surveillance in preventing antiviral resistance emergence.
Incorporation of mpMRI before prostate biopsy shall be universal or selective: A prospective observational study
Authors: Prakash Shashi , Upadhyay Rohit , Mahmood Khalid , Prasad Umakant , Tiwari Rajesh K. , Ahmad Ahsan , Chaudhary Nikhil Ranjan
Published: September 2024

Purpose:

The aim of this study is to evaluate the role of multiparametric magnetic resonance imaging (mpMRI) as a triage workup in the diagnostic pathway of suspected prostate cancer (PCa) in our population.

Material and methods:

This prospective observational study was conducted at lesser than details of site are removed for blinded peer review > on biopsy-naive patients from May 2021 to December 2022. We included patients aged 40 to 80 years with clinical suspicion of PCa, prostate-specific antigen (PSA) level >4 ng/mL, abnormal digital rectal examination (DRE), or all the above. All patients first underwent 1.5-T mpMRI and transrectal ultrasound-guided biopsy using the cognitive biopsy technique.

Results:

A total of 95 patients were included, with the majority of them (64.21%) being ≥66 years old. Of these, 69 patients had abnormal DRE findings, 89 had PSA ≥4 ng/mL, and 64 had both elevated PSA and abnormal DRE findings. PCa was detected in 6.25%, 54.84%, 71.43%, and 96.43% of patients with lesions of Prostate Image Reporting and Data System scores of 2, 3, 4, and 5, respectively. Using Prostate Image Reporting and Data System score of 3 as a biopsy threshold resulted in high sensitivity (98.31%) and low specificity (41.67%) for PCa detection. The proportion of Gleason score of ≥7 cancer-detected cores in the magnetic resonance imaging-guided cognitive biopsy was significantly higher than that in the standard 12-core biopsy (86.54% versus 61.45%; P < 0.001).

Conclusion:

The incorporation of prebiopsy mpMRI could be used as a diagnostic pathway for suspected PCa before transrectal ultrasound-guided biopsy.
The effect of reflexology and pelvic floor muscle (Kegel) exercises on urinary incontinence in people with multiple sclerosis
Authors: Özdelikara Afitap , Alkan Seval Ağaçdiken , Terzi Murat
Published: September 2024

Purpose:

This study was conducted to determine the effects of reflexology and Kegel exercise on urinary incontinence in patients with multiple sclerosis (MS).

Materials and methods:

A single-blind, controlled pretest-posttest study was conducted. The study included 15 patients with MS who presented to the neurology outpatient clinic between March 2020 and February 2022. Patients were assigned to the reflexology, Kegel exercise, or control group using block randomization. Data were collected from all patients using a sociodemographic information form, and quality of life was assessed using the International Consultation on Incontinence Questionnaire–Short Form, Incontinence Quality of Life Scale, and Incontinence Severity Index. The Wilcoxon paired-samples test and Kruskal-Wallis test were used to analyze the data.

Results:

The mean age of the patients was 39.86 ± 9.99 years, and the mean MS duration was 104.46 ± 84.12 months. International Consultation on Incontinence Questionnaire–Short Form scores did not differ significantly between the groups before or after the intervention (P = 0.788). Incontinence Quality of Life Scale total and subscale scores also did not differ between the groups, but significant improvement was noted in the reflexology group between the pretest and posttest assessments (P = 0.970). Incontinence Severity Index scores did not differ between or within the groups (P = 0.193).

Conclusion:

Reflexology and Kegel exercise did not exert different effects on urinary incontinence, whereas reflexology improved incontinence-related quality of life.
Neuropsychiatric Symptoms Cluster and Fluctuate Over Time in Behavioral Variant Frontotemporal Dementia
Authors: Morrow Christopher B. , Kamath Vidyulata , Dickerson Bradford C. , Eldaief Mark , Rezaii Neguine , Wong Bonnie , McGinnis Scott , Darby Ryan , Staffaroni Adam M. , Lapid Maria I. , Pascual Belen , Rojas Julio C. , Masdeu Joseph C. , Tsapkini Kyrana , Huey Edward D. , Fisher Daniel W. , Pantelyat Alexander , Balaji Akshata , Sah Eric , Litvan Irene , Rascovsky Katya , Ghoshal Nupur , Domoto-Reilly Kimiko , Kornak John , Onyike Chiadi U.
Published: September 2024

Objectives

Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may clarify the underlying neurobiology of bvFTD-related NPS and guide development of therapies.

Methodology

Participants (N=354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤ 1) or advanced (CDR® plus NACC FTLD ≥ 1). Baseline and annual follow-up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory-Questionnaire and Clinician Judgement of Symptoms. Polychoric cluster analysis was used to describe NPS clusters.

Results

NPS were highly prevalent (≥ 90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression and anxiety showed the least visit-to-visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit-to-visit in more than 50% of cases.

Conclusion

NPS in bvFTD are frequent and cluster into four discrete groups in bvFTD. These clusters may result from specific neural network disruptions that could serve as targets for future interventions. The fluctuating nature of NPS in bvFTD suggests that they are not reliable markers of disease progression or stage.
Assessing Attitudes and Perceptions of High-risk, Low-resource Communities towards Cardiopulmonary Resuscitation and Public-access Defibrillation
Authors: Hirsch Carolyn , Sachdeva Bhanvi , Roca-Dominguez Dilenny , Foster Jordan , Bryant Kellie , Gautier-Matos Nancy , Minguez Mara , Williams Olajide , Elkind Mitchell S. V. , Homma Shunichi , Lantigua Rafael , Agarwal Sachin
Published: September 2024

Background

Layperson cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) use are vital for improving survival rates after out-of-hospital cardiac arrest (OHCA), yet their application varies by community demographics. We evaluated the concerns and factors influencing willingness to perform CPR and use AEDs among laypersons in high-risk, low-resource communities.

Methods

From April 2022 to March 2024, laypersons in Northern Manhattan’s Community District 12 completed surveys assessing their attitudes toward CPR and AED use before attending Hands-Only CPR training. Fisher’s Exact Test assessed differences in concerns and willingness to perform CPR and AED use across racial-ethnic groups and compared low-resource communities with high-resource groups consisting of non-clinical staff across eight ambulatory sites.

Results

Among 669 respondents, 64% identified as Hispanic, 58% were under 40, and 67% were female. Significant knowledge gaps were identified: 62% had never learned CPR, and 77% were unfamiliar with AEDs. Common concerns included fear of incorrect performance (67%), causing harm (56%), and legal repercussions (53%). Willingness to perform CPR was most influenced by familiarity with the victim (55% family vs. 67% non-family). The main barrier to AED use was a lack of operational knowledge (66%). Non-Hispanic Black participants expressed significantly greater concerns than their non-Hispanic White and Hispanic counterparts. Participants in high-resource settings (n=309) showed higher CPR and AED training rates with similar concerns.

Conclusions

Concerns regarding CPR and AED use stem from a lack of confidence and training. Targeted, culturally sensitive community interventions are essential to address these barriers, enhance preparedness, and improve OHCA survival rates.
Evaluation of HD-sEMG descriptor sensitivity to changes of anatomical and neural properties with aging : A simulation study
Authors: Douania Ines , Laforet Jeremy , Boudaoud Sofiane
Published: September 2024

Background and objectives

A reliable evaluation of anatomical and neural muscle properties and its effects on the electrical signals measured at the skin surface aims to develop a medical non-invasive aid-diagnosis tool assisted by model and personalized to the patient. This tool will be dedicated to understand and evaluate muscle diseases and aging.

Methods

We perform a new Robust Morris Screening Method: RMSM in Douania et al. (2023), to assess the impact of muscle anatomy (model inputs) uncertainties and variations on a simulated HD-sEMG signals (model outputs). The model describes a complex neuromuscular system simulating HD-sEMG (high density surface electromyography) signals generated from motor units electrical sources of a striated muscle: the Biceps Brachii (BB). Two subjects categories and two contractions levels are studied: young men (YM) and old men (OM) at low and high contraction (LC = 20% of MVC and HC = 60% of MVC). A 33 features in time and frequency domains are used as model outputs.

Results

We have demonstrated that the neuromuscular model is able to deliver HD-sEMG signals sensitive to the same anatomical and neural muscle factors as in real cases. Time domain features are mainly sensitive to muscle thickness, conduction velocity of fibers, electrode locations (at HC), number of motor units, and to the number of slow and fast fibers for young and aged categories respectively. Frequency domain feature are sensitive mainly to the conduction velocity of fibers and muscle conductivities (no significant differences between YM and OM are observed).

Conclusion

This result is important, it allows to obtain simulated HD-sEMG signals close to experimental ones with low cost and in reduced time. However, for a reliable evaluation of muscle aging, the neuromuscular model should be enhanced to better describe structural, morphological, and functional age-related phenomena.
Coordinated multi-level adaptations across neocortical areas during task learning
Authors: Han Shuting , Helmchen Fritjof
Published: September 2024

The coordinated changes of neural activity during learning, from single neurons to populations of neurons and their interactions across brain areas, remain poorly understood. To reveal specific learning-related changes, we applied multi-area two-photon calcium imaging in mouse neocortex during training of a sensory discrimination task. We uncovered coordinated adaptations in primary somatosensory area S1 and the anterior (A) and rostrolateral (RL) areas of posterior parietal cortex (PPC). At the single-neuron level, task-learning was marked by increased number and stabilized responses of task neurons. At the population level, responses exhibited increased dimensionality and reduced trial-to-trial variability, paralleled by enhanced encoding of task information. The PPC areas, especially area A, became gradually engaged, opening additional within-area subspaces and inter-area subspaces with S1. Task encoding subspaces gradually aligned with these interaction subspaces. Behavioral errors correlated with reduced neuronal responses, decreased encoding accuracy, and misaligned subspaces. Thus, multi-level adaptations within and across cortical areas contribute to learning-related refinement of sensory processing and decision-making.
Identification of the putative gene encoding the RNA subunit of telomerase inMalasseziaclade species through comparative genomic analysis
Authors: Sanpedro Luna Juan Antonio , Alonso Patricia Sánchez
Published: September 2024

Maintaining telomere length and genomic stability in eukaryotic cells is dependent on telomerase, a ribonucleoprotein with reverse transcriptase activity that counteracts the end replication problem. Its core components include TERT (telomerase reverse transcriptase) and TER (telomerase RNA). This study focused on the identification of the putativeTER1gene that encodes the telomerase RNA subunit in 19Malasseziaspecies via comparative genomics. Unlike the corresponding genes in other yeasts and filamentous fungi, this gene is compact and uniform in length, resembling similar genes in vertebrates, while retaining characteristic elements that are crucial for TER and snRNA biogenesis and activity. These elements include the template domain, pseudoknot domain, CR4/5 domain, and a putative Sm-binding site. Furthermore, transcriptomic analysis confirmed the transcriptional activity of the putativeTER1gene, reinforcing its potential functional significance within theMalasseziaclade. These results establish a robust basis for future experimental investigations to verify the functionality and regulatory mechanisms of this gene, particularly its role in telomere maintenance and broader cellular processes.
Endocrine persistence in ER+ breast cancer is accompanied by metabolic vulnerability in oxidative phosphorylation
Authors: Tau Steven , Chamberlin Mary D. , Yang Huijuan , Marotti Jonathan D. , Roberts Alyssa M. , Carmichael Melissa M. , Cressey Lauren , Dragnev Christo , Demidenko Eugene , Hampsch Riley A. , Soucy Shannon M. , Kolling Fred , Samkoe Kimberley S. , Alvarez James V. , Kettenbach Arminja N. , Miller Todd W.
Published: September 2024

Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2-breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Mice bearing cell line- and patient-derived xenografts were used to measure the anti-tumor effects of mitochondrial complex I inhibition in the context of endocrine therapy. Pharmacological inhibition of complex I suppressed the tumor-forming potential of persisters and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability in the context of endocrine-sensitive disease.

Statement of Significance

Endocrine-tolerant persister cancer cells that survive endocrine therapy can cause recurrent disease. Persister cells exhibit increased energetic dependence upon mitochondria for survival and tumor re-growth potential.
Rationalize the Functional Roles of Protein-Protein Interactions in Targeted Protein Degradation by Kinetic Monte-Carlo Simulations
Authors: Su Zhaoqian , Yin Shanye , Wu Yinghao
Published: September 2024

Targeted protein degradation is a promising therapeutic strategy to tackle disease-causing proteins that lack binding pockets for traditional small-molecule inhibitors. Its first step is to trigger the proximity between a ubiquitin ligase complex and a target protein through a heterobifunctional molecule, such as proteolysis targeting chimeras (PROTACs), leading to the formation of a ternary complex. The properties of protein-protein interactions play an important regulatory role during this process, which can be reflected by binding cooperativity. Unfortunately, although computer-aided drug design has become a cornerstone of modern drug development, the endeavor to model targeted protein degradation is still in its infancy. The development of computational tools to understand the impacts of protein-protein interactions on targeted protein degradation, therefore, is highly demanded. To reach this goal, we constructed a non-redundant structural benchmark of the most updated ternary complexes and applied a kinetic Monte-Carlo method to simulate the association between ligases and PROTAC-targeted proteins in the benchmark. Our results show that proteins in most complexes with positive cooperativity tend to associate into native-like configurations more often. In contrast, proteins very likely failed to associate into native-like configurations in complexes with negative cooperativity. Moreover, we compared the protein-protein association through different interfaces generated from molecular docking. The native-like binding interface shows a higher association probability than all the other alternative interfaces only in the complex with positive cooperativity. These observations support the idea that the formation of ternary complexes is closely regulated by the binary interactions between proteins. Finally, we applied our method to cyclin-dependent kinases 4 and 6 (CDK4/6). We found that their interactions with the ligase are not as similar as their structures. Altogether, our study paves the way for understanding the role of protein-protein interactions in PROTACE-induced ternary complex formation. It can potentially help in searching for degraders that selectively target specific proteins.
Detection of bacteria through taste receptors primes the cellular immune response
Authors: Mazariegos Alix Najera , Manière Gérard , Camp Darius , Kaul Rhea , Duval Carla Jane , Milleville Romane , Berthelot-Grosjean Martine , Alves George , Royet Julien , Grosjean Yaël , Musso Pierre-Yves , Tanentzapf Guy
Published: September 2024

Animals use their sensory system to detect cues in their external environment, then communicate, process, and integrate these cues through the nervous system in order to elicit a specific response. Taste is an important cue used by animals to explore their external environment and can modulate various aspects of animal behavior and physiology. A major ongoing challenge for animals is to detect and respond to the presence of a variety of pathogens in their environment. However, to date, the links between the sensory system and the response to pathogenic threats remain poorly understood. Here we show thatDrosophilalarvae use their taste system to detect bacterial peptidoglycans in their environment and respond by modulating the activity of their cellular immune system. We show that specific PeptidoGlycan Receptor Proteins (PGRPs) act in bitter taste neurons, via the IMmune Deficiency (IMD) pathway. These PGRPs mediate signaling in taste neurons and control immune cells production in the larval hematopoietic organ, the lymph gland. The taste-mediated sensing of bacteria in larvae primes the immune system, and improves survival after infection in adult flies. These results demonstrate that sensory inputs such as taste play an important role in protecting animals from bacterial infection by providing a powerful adaptive response to potential pathogens. Overall, our findings add to the growing list of examples of crosstalk between the nervous and immune systems and provide novel and important mechanisms for linking them.
Identification of genetic variants and their causal association underlying autism spectrum disorder
Authors: Yadav Prashasti , Srivastava Mona , Das Parimal
Published: September 2024

Background

Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder with a complex genetic architecture characterized by persistent deficits in social communication and social interaction along with restricted and repetitive behavior patterns, interests and activities. Over the years its prevalence has increased and affects 1% children globally. Etiology of ASD is remained unclear, but it is well recognized as a complex disorder involving interactions of several genes and environmental risk factors. Studies signify the role of whole exome sequencing in identifying rare genetic variation related to neurodevelopmental disorders and have greatly improved the chance of identifying known as well as novel responsible genes. This study aimed to identify genetic variant in a patient affected with autism spectrum disorder.

Methods

A male patient of age range 0-5 years was investigated and identified according to DSM-5 criteria for autism spectrum disorder. Peripheral blood sample was collected followed by genomic DNA extraction and whole exome sequencing. The functional impact of variant, gene interaction network and pathway enrichment analysis were done usingin silicotools and databases.

Results

Two heterozygous missense variants one inSHANK2(c.401C>G) another inCSNK2A1 (c.572G>A) were identified. Both of these variants were predicted to be deleterious by pathogenicity prediction tool. Gene interaction network and pathway enrichment analysis revealed the involvement ofSHANK2andCSNK2A1in various biological pathways such as protein binging, synaptogenesis, chromosome condensation and cell cycle regulation.

Conclusion

This study revealed a novelSHANK2variant along with a knownCSNK2A1variant that expands the spectrum of genetic variants related to autism spectrum disorder and further enhances the understanding of the molecular mechanism underlyingSHANK2andCSNK2A1pathophysiology.
Cognitively healthy young adults withAPOEe4gene show disrupted functional connectivity of graph properties in multiple resting-state networks
Authors: Kucikova Ludmila , Zeng Jianmin , Brass Adam J. , Muñoz-Neira Carlos , Ritchie Craig W. , Muniz-Terrera Graciela , O’Brien John , Su Li
Published: September 2024

Theapolipoprotein (APOE) e4allele is associated with brain changes in healthy carriers that are similar to changes observed in patients with Alzheimer’s Disease, including abnormalities in functional connectivity. The trajectory of these changes across the lifespan, specifically in early adulthood is still not clear. This study explores the link between theAPOEgenotype and functional connectivity in 129 cognitively healthy Chinese Han college students (aged 17-22 years). By using graph theory, we assessed the connectivity in seven resting-state networks of interest using three different thresholding methods and three different forms of network parcellation. Average Path Length and Closeness Centrality were disrupted ine4carriers in the sensorimotor, visual, salience, and Default Mode salience networks; with effects replicated using different thresholding but not different parcellation methods. This study demonstrated the genetics-related vulnerability in the brain of youngAPOEe4carriers across multiple resting-state networks.
Measuring aversion to health inequality in Canada: an equity-efficiency trade-off experiment
Authors: Iragorri Nicolas , Ali Shehzad , Mishra Sharmistha , Sander Beate
Published: September 2024

OBJECTIVES

To estimate the extent to which Canadians are averse to health inequalities, a critical component for equity-informative economic evaluations but lacking in the Canadian context.

METHODS

We conducted three experiments among a representative sample of adults living in Canada to elicit value judgements about reducing income-related health inequality vs. improving population health. Each experiment compared two programs: (Experiment 1) universal and tailored vaccination; (Experiment 2) non-specific prevention programs; (Experiment 3) generic health care programs. The programs varied in terms of efficiency (additional life years), and income-related health inequality. Preferences were elicited using benefit-trade off analysis and were classified as: pro-rich (maximizing the health of individuals with the highest income); health maximizer (maximizing total health); weighted prioritarian (willing to trade some health to reduce inequalities); maximin (only improving the health of the individuals with the lowest income); and egalitarian (minimizing health inequalities).

RESULTS

We recruited 1,000 participants per experiment. Preferences for the vaccination, prevention, and generic experiments were distributed as follows: pro-rich (Atkinson Index<0): 31%, 22%, and 16% respectively; health maximizers (Atkinson Index=0): 2%, 3%, and 2%, respectively; weighted prioritarians (Atkinson Index>0): 13%, 19%, and 22% respectively; maximins (Atkinson Index=∞): 0%, 1%, and 3%, respectively; egalitarian (Atkinson Index undefined): 54%, 55%, and 57%, respectively. The median responses reflected a preference for minimizing health inequalities across the three experiments.

CONCLUSIONS

Our findings suggest a strong aversion to health inequality among people living in Canada with over half of respondents willing to minimize health inequalities regardless of the impact on efficiency.
Ancestrally diverse genome-wide association analysis highlights ancestry-specific differences in genetic regulation of plasma protein levels
Authors: Sarnowski Chloé , Ma Jianzhong , Nguyen Ngoc Quynh H. , Hoogeveen Ron C , Ballantyne Christie M , Coresh Josef , Morrison Alanna C , Chatterjee Nilanjan , Boerwinkle Eric , Yu Bing
Published: September 2024

Fully characterizing the genetic architecture of circulating proteins in multi-ancestry populations provides an unprecedented opportunity to gain insights into the etiology of complex diseases. We characterized and contrasted the genetic associations of plasma proteomes in 9,455 participants of European and African (19.8%) ancestry from the Atherosclerosis Risk in Communities Study. Of 4,651 proteins, 1,408 and 2,565 proteins had protein-quantitative trait loci (pQTLs) identified in African and European ancestry respectively, and twelve unreported potentially causal protein-disease relationships were identified. Shared pQTLs across the two ancestries were detected in 1,113 aptamer-region pairs pQTLs, where 53 of them were not previously reported (alltranspQTLs). Sixteen unique protein-cardiovascular trait pairs were colocalized in both European and African ancestry with the same candidate causal variants. Our systematic cross-ancestry comparison provided a reliable set of pQTLs, highlighted the shared and distinct genetic architecture of proteome in two ancestries, and demonstrated possible biological mechanisms underlying complex diseases.
Synthetic Data Distillation Enables the Extraction of Clinical Information at Scale
Authors: Woo Elizabeth Geena , Burkhart Michael C. , Alsentzer Emily , Beaulieu-Jones Brett K
Published: September 2024

Large-language models (LLMs) have shown promising potential for extracting information from clinical notes. Deploying these models at scale can be challenging due to high computational costs, regulatory constraints, and privacy concerns. To address these challenges, we used synthetic data distillation to fine-tune smaller, open-source LLMs that achieve performance similar to that of larger models, including the teacher model. These smaller models can be run on less expensive local hardware or at a vastly reduced cost in cloud deployments. In this study, we used Llama-3.1-70B-Instruct to generate synthetic training examples in the form of question-answer pairs along with supporting information and model-assigned difficulty scores. These synthetic examples were used to fine-tune the smaller Llama-3.1-8B-Instruct model. We evaluated the performance of these models on an annotated synthetic dataset resembling clinical trial criteria, the i2b2 2018 Clinical Trial Eligibility Challenge, and clinical notes reflecting the clinical trial for apixaban. The fine-tuned models outperformed the 8B-Instruct model on all tasks and in some cases even exceeded the performance of the larger 70B-Instruct model. This work demonstrates the potential of synthetic data distillation to enable more scalable and efficient clinical information extraction, which could be applied toward improving accuracy and efficiency of patient phenotyping and clinical-trial matching.
Outcome of Graves’ Disease and Associated Genetic Predisposition: A Systematic Review of Literature
Authors: Mokoagow Md. Ikhsan , Manthovani Ahmad Zufar , Epriliawati Marina
Published: September 2024

Background

Graves’ disease (GD) is an autoimmune hyperthyroidism that primarily affects the thyroid gland. The susceptibility, activity, and risk of recurrence of GD may be influenced by various genetic factors, which can interact with environmental triggers to precipitate disease relapse. This review examines the literature on the genetic predisposition to GD recurrence.

Methods

Literature from PubMed, EBSCOhost, and SCOPUS were searched. Three reviewers performed study selection and critical appraisal.

Result

Five studies were selected. The literature indicates a risk of relapse in PTPN22, CTLA-4, TSH-R, IL-21, KREC, and HLA gene abnormalities.

Conclusion

Several genes are associated with GD relapse. However, predicting relapse risk requires consideration of multiple factors beyond genetic predisposition.
Inhibition of FOXM1 synergizes with BCL2 inhibitor Venetoclax in killing non-t(11;14) multiple myeloma cells via repressing MYC pathway
Authors: Wen Zhi , Janz Siegfried , Wang Yidan , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Kim Sung Hoon , Onitilo Adedayo
Published: September 2024

Despite significant improvements in the prognosis of Multiple Myeloma (MM), relapsed/refractory MM remains a major challenge. BCL2 inhibitor Venetoclax induced complete or very good partial responses in 6% of non-t(11;14) MM cases, compared to 27% in t(11;14) cases, when used as monotherapy in relapsed/refractory MM. Though Venetoclax was proposed to treat t(11;14) cases, the resistance became a concern. Furthermore, non-t(11;14) cases account for 80-85% of MM cases, which underscores the value of Venetoclax in non-t(11;14) MM. Here, we report a recently-invented small molecule inhibitor of FOXM1 NB73 synergizing with Venetoclax in killing MM cells. FOXM1, a critical forkhead box transcription factor in high-risk and relapsed/refractory MM, represents a promising therapeutic target of MM. We examined the mechanisms underlying the synergies of Venetoclax and NB73 using multi-omics and molecular and cellular biology tools in non-t(11;14) myeloma cell lines with high FOXM1 expression. NB73 induces immediate loss of FOXM1, decreases BCL2 expression, and increases Puma expression in myeloma cells. Venetoclax enhances NB73-induced FOXM1 ubiquitination and degradation. The NB73-Venetoclax combination abrogates the binding of FOXM1 to the promoters of genes in the MYC pathway, such as PLK1, MYC, CDC20, and CCNA2, leading to the repression of the transcription of these MYC pathway genes. The PLK1-specific inhibitor GSK461364 synergies with NB73 in suppressing myeloma cell growth. Therefore, NB73 synergizes with Venetoclax in killing myeloma cells. Conclusively, the NB73-Venetoclax combination abolishes FOXM1-mediated transcriptional activation of the MYC pathway, resulting in intensive apoptosis of myeloma cells without t(11;14) but with high FOXM1 expression.

Statement of significance

This study implicates that targeting FOXM1 will alleviate resistance to BCL2 inhibitor Venetoclax in non-t(11;14) myeloma cells expressing high FOXM1.
Abundance measurements reveal the balance between lysis and lysogeny in the human gut microbiome
Authors: Lopez Jamie A. , McKeithen-Mead Saria , Shi Handuo , Nguyen Taylor H. , Huang Kerwyn Casey , Good Benjamin H.
Published: September 2024

The human gut contains diverse communities of bacteriophage, whose interactions with the broader microbiome and potential roles in human health are only beginning to be uncovered. Here, we combine multiple types of data to quantitatively estimate gut phage population dynamics and lifestyle characteristics in human subjects. Unifying results from previous studies, we show that an average human gut contains a low ratio of phage particles to bacterial cells (∼1:100), but a much larger ratio of phage genomes to bacterial genomes (∼4:1), implying that most gut phage are effectively temperate (e.g., integrated prophage, phage-plasmids, etc.). By integrating imaging and sequencing data with a generalized model of temperate phage dynamics, we estimate that phage induction and lysis occurs at a low average rate (∼0.001-0.01 per bacterium per day), imposing only a modest fitness burden on their bacterial hosts. Consistent with these estimates, we find that the phage composition of a diverse synthetic community in gnotobiotic mice can be quantitatively predicted from bacterial abundances alone, while still exhibiting phage diversity comparable to native human microbiomes. These results provide a foundation for interpreting existing and future studies on links between the gut virome and human health.
A Novel Mouse Model Demonstrates In Vivo Replenishment of Central Nervous System Pericytes After Successful Acute Ablation
Authors: Atak Dila , Yıldız Erdost , Özkan Esra , Yousefi Mohammadreza , Özkan Ayşe , Yılmaz Aysu Bilge , Kızılırmak Ali Burak , Alnajjar Iman Asaad , Kanar Çiçek , Caan Zeynep Lal , Zeybek Şakir Ümit , Küçükali Cem İsmail , Tüzün Erdem , Gürsoy-Özdemir Yasemin , Vural Atay
Published: September 2024

Central nervous system (CNS) pericytes play crucial roles in vascular development and blood-brain barrier maturation during prenatal development, as well as in regulating cerebral blood flow in adults. They have also been implicated in the pathogenesis of numerous neurological disorders. However, the behavior of pericytes in the adult brain after injury remains poorly understood, partly due to limitations in existing pericyte ablation models. To investigate pericyte responses following acute ablation, we developed a tamoxifen-inducible pericyte ablation model by crossingPDGFRβ-P2A-CreERT2andRosa26-DTA176transgenic mouse lines. Using this model, we studied the effects of different tamoxifen doses and conducted histological examinations 15 and 60 days post-injection to assess both short- and long-term impacts of pericyte ablation. Our results demonstrate that a low dose of tamoxifen effectively ablates CNS pericytes in mice without reducing survival or causing significant systemic side effects, such as weight loss. Additionally, we found that the extent of pericyte depletion varies between the cortex and the spinal cord’s gray and white matter regions. Importantly, both pericyte coverage and numbers increased in the weeks following acute ablation, indicating the regenerative capacity of CNS pericytes in vivo. This model offers a valuable tool for future studies on the role of pericytes in neurological disorders, overcoming the limitations of constitutive pericyte ablation models.
Integral-Omics: serial extraction and profiling of metabolome, lipidome, genome, transcriptome, whole proteome and phosphoproteome using biopsy tissue
Authors: Li Wei , Sun Jing , Sun Rui , Wei Yujuan , Zheng Junke , Zhu Yi , Guo Tiannan
Published: September 2024

The integrative multi-omics characterization of minute amount of clinical tissue specimens has become increasingly important. Here, we present an approach called Integral-Omics, which enables sequential extraction of metabolites, lipids, genomic DNA, total RNA, proteins, and phosphopeptides from a single biopsy-level tissue specimen. We benchmarked this method with various samples and applied the workflow to perform multi-omics profiling of tissues from six patients with colorectal cancer and found that tumor tissues exhibited suppressed ferroptosis pathway at multi-omics levels. Together, this study presents a methodology that enables sequential extraction and profiling of metabolomics, lipidomics, genomics, transcriptomics, proteomics and phosphoproteomics using biopsy tissue specimens.
HEXIM1 is correlated with Alzheimer’s disease pathology and regulates immediate early gene dynamics in neurons
Authors: Htet Myo , Estay-Olmos Camila , Hu Lan , Wu Yiyang , Powers Brian E. , Campbell Clorissa D. , Ahmed M. Rafiuddin , Hohman Timothy J. , Schneider Julie A. , Bennett David A. , Menon Vilas , De Jager Philip L. , Kaas Garrett A. , Colbran Roger J. , Greer Celeste B.
Published: September 2024

Impaired memory formation and recall is a distinguishing feature of Alzheimer’s disease, and memory requires de novo gene transcription in neurons. Rapid and robust transcription of many genes is facilitated by the formation of a poised basal state, in which RNA polymerase II (RNAP2) has initiated transcription, but is paused just downstream of the gene promoter. Neuronal depolarization releases the paused RNAP2 to complete the synthesis of messenger RNA (mRNA) transcripts. Paused RNAP2 release is controlled by positive transcription elongation factor b (P-TEFb), which is sequestered into a larger inactive complex containing Hexamethylene bisacetamide inducible protein 1 (HEXIM1) under basal conditions. In this work, we find that neuronal expression ofHEXIM1mRNA is highly correlated with human Alzheimer’s disease pathologies. Furthermore, P-TEFb regulation by HEXIM1 has a significant impact on the rapid induction of neuronal gene transcription, particularly in response to repeated depolarization. These data indicate that HEXIM1/P-TEFb has an important role in inducible gene transcription in neurons, and for setting and resetting the poised state that allows for the robust activation of genes necessary for synaptic plasticity.

GRAPHICAL ABSTRACT
Investigating Cell Viability under Shear Stress in Complex Microstreaming Flows Generated by Ultrasound-Driven Actuated Microbubbles
Authors: Bakhtiari Amirabas , Schumm Benedikt , Schönfelder Martin , Kähler Christian J.
Published: September 2024

The analysis of rare or specialized cells is often a time-consuming process due to their low concentrations. In this study, we applied, for the first time, a method previously used on polymer particles to manipulate human cells. This technique enables the automatic direction and collection of target cells passing through a microchannel, significantly increasing their concentration for further analysis. The movement of the cells is controlled by an acoustically induced vortex flow generated by a microbubble. By modulating the activation of this microstreaming, the cells are shifted either to the upper or lower regions of the channel and directed into a side channel for collection downstream. The localized stress distribution, along with long-term testing that showed no cell damage, confirmed the biocompatibility of this method, making it a promising tool for lab-on-a-chip systems and biomedical diagnostics.

Impact Statement

This study presents an innovative use of ultrasound-driven microbubble streaming for the precise manipulation and sorting of human cells in microfluidic environments, all while maintaining cell viability. The research shows that the localized shear stress near the microbubble is significantly below the damage threshold for cells, confirming the biocompatibility of this method. The potential impact of this work is considerable for lab-on-a-chip systems and biomedical diagnostics. It offers a reliable, non-invasive solution for the manipulation, sorting, and removal of compromised cells, thus streamlining research and diagnostic procedures. By ensuring the safe and efficient handling of rare or specialized cells, this technique can accelerate various biomedical applications. Additionally, the study’s evidence of sustained cell viability under microstreaming conditions suggests broader applicability in biomedical devices, particularly in automated dead cell removal and selective cell positioning.