bluuebunny/crossref_metadata_2025 huggingface dataset:
Acceptability of Multilevel Sexual Health Interventions and Sexually Transmitted Infection Screening and Testing Among Persons With HIV Across Three Clinical Sites in Florida
Authors: Manavalan Preeti , Gadkowski L. Beth , Sachdeva Archie , Guha Subharup , Porvasnik Stacy , Nelson John A. , Janelle Jennifer W.
Published: November 2024

Introduction:

The US state of Florida has the third highest rate of HIV and high rates of sexually transmitted infections (STIs) indicating critical HIV and STI prevention needs remain unmet. To address gaps in the STI care continuum in people with HIV (PWH), evidence-based interventions were implemented across 3 Ryan White HIV/AIDS Program (RWHAP)-funded clinics in Florida between August 2020 and August 2021. Interventions included comprehensive sexual health history (SHH) taking using audio computer–assisted self-interview (ACASI) software, self-collected extragenital gonorrhea and chlamydia testing, and the introduction of a lesbian, gay, bisexual, transgender, and queer (LGBTQ+) welcoming environment.

Methods:

We (1) assessed the acceptability of these interventions and examined if acceptability differed among youth and sexual, racial, and ethnic minorities; (2) determined the proportion of appropriate STI testing completed based on the SHH assessment; (3) examined whether STI at-risk individuals underwent STI screening 3–6 months after initial evaluation; and (4) determined the proportion of positive STI test results among priority intervention groups in Florida.

Results:

Acceptability of all interventions was high. Youth, lesbian, gay, and bisexual, and Hispanic individuals were significantly more likely to notice and like LGTBQ+ welcoming measures. The proportion of recommended tests completed was high, although only a subset of at-risk individuals completed rescreening. About 11.9% of rectal samples were positive for chlamydia, and 6.5% of pharyngeal samples were positive for gonorrhea.

Conclusions:

Our study highlights the importance of incorporating comprehensive sexual health care protocols, including extragenital STI testing, into the overall care of PWH.
Influence of Bone Defects After Endoscope-Assisted Suturectomy on Monobloc Advancement in Syndromic Bilateral Coronal Craniosynostosis Patients
Authors: Kamata Masafumi , Hikosaka Makoto , Kaneko Tsuyoshi , Ogiwara Hideki , Usami Kenichi
Published: November 2024

Surgery is performed for craniosynostosis to enlarge intracranial volume and improve cranial morphology. Endoscope-assisted suturectomy is one of the effective treatments. Compared with other techniques, it is reported to be low invasive and enables improvement of cranial volume and morphology at an early age. At the National Center for Child Health and Development (Tokyo, Japan), endoscope-assisted suturectomy is performed for all patients with craniosynostosis under the age of 3 months. Bone defects are sometimes observed several years after endoscope-assisted suturectomy. In syndromic bilateral coronal craniosynostosis patients in whom fused coronal sutures are removed, bone defects often remain in the temporal region. These may cause difficulty in setting the osteotomy line and placing distraction device for later monobloc advancement. In the present study, syndromic bilateral coronal craniosynostosis patients who underwent endoscope-assisted suturectomy between 2017 and 2022 at our hospital were retrospectively reviewed to investigate residual bone defects after the operation. As monobloc advancement, tongue-in-groove technique and placing internal distractors were assumed, and cranial bone defects between the ages of 3 and 5 years were evaluated in 3D by using image processing software. Five patients were included, and in 2 patients, the bone defects in the temporal regions were deemed large enough to interfere with making the bandeau or restrict the use of internal distractors for monobloc advancement. When performing suturectomy for syndromic craniosynostosis patients with midfacial concavity, careful surgical strategies that take into account future monobloc advancement should be considered.
Internally Submerged, Tapered, Bone-level Dental Implants in the Anterior Esthetic Region
Authors: Sodnom-Ish Buyanbileg , Eo Mi Young , Mustakim Kezia Rachellea , Myoung Hoon , Kim Soung Min
Published: November 2024

Background:

Aesthetics is a crucial consideration in the anterior region, alongside dental implant survival and marginal bone loss (MBL). Bone-level implants are advantageous in the esthetic zone as they create a natural emergence profile with the use of customized abutments. This study aimed to assess the esthetic outcomes of internally submerged, tapered, bone-level dental implants and to evaluate associated alveolar bone changes.

Methods:

Patients received Luna implants (Shinhung, Seoul, Korea) from 2012 to 2020. MBL was measured immediately after surgery and at 3-month, 6-month, and 1-year follow-ups. Pink and White Esthetic Scores (PES/WES) were evaluated after final restoration and at 6-month and 12-month follow-ups using standardized photographs.

Results:

Seventy-eight patients (37 males, 41 females) with a mean age of 73.42 years met the study’s inclusion criteria. At the 1-year follow-up, the mean MBL was 0.39 ± 0.74 mm on the mesial aspect and −0.09 ± 0.97 mm on the distal aspect. A statistically significant difference in MBL on the mesial aspect was observed between immediate functional loading and the 12-month follow-up (P = 0.029). All implants achieved PES/WES scores of 6 or higher, meeting the threshold for clinical acceptance.

Conclusions:

Within the study’s limitations, Luna implants demonstrated satisfactory esthetic outcomes and stable bone levels. The results support their use as a viable option for implant placement in the anterior esthetic zone, ensuring both aesthetic and functional success.
Surgeon’s Journey and Pilgrim’s Progress
Authors: Hwang Kun
Published: November 2024

I read “The Pilgrim’s Progress,” by John Bunyan, and this book echoes the journey I have taken from medical school to the present. Christian’s journey symbolizes the spiritual path of a believer in the pursuit of salvation. This narrative serves as an allegory for the Christian life, highlighting themes such as faith, redemption, and perseverance through trials. It includes twelve key stage. Comparing the life of a surgeon, from medical student to master surgeon approaching retirement, to Christian’s journey in “The Pilgrim’s Progress” makes for a fascinating allegory. Both paths involve growth, challenges, and perseverance toward a final goal: (1) Medical Student (City of Destruction), (2) Basic Training (Slough of Despond), (3) Residency (Wicket Gate and Hill of Difficulty), (4) Becoming a Junior Surgeon (Interpreter’s House), (5) First Independent Operations (The Cross and the Burden Lifted), (6) Early Career (Palace Beautiful), (7) Facing Major Challenges (Valley of Humiliation and Shadow of Death), (8) Mid-Career Success and Worldly Temptations (Vanity Fair), (9) Crisis of Confidence (Doubting Castle and Giant Despair), (10) Mastery and Maturity (Delectable Mountains), (11) Facing Retirement (Enchanted Ground), and (12) Retirement and Legacy (Celestial City). In this allegory, the life of a surgeon mirrors Christian’s spiritual journey—a path marked by challenges, doubts, triumphs, and ultimately, the fulfillment of a calling. Both are in pursuit of a final “rest” in their respective fields, whether it be spiritual salvation or the surgeon’s sense of a lasting contribution to humanity. The journey of the surgeon is similar to that of the pilgrim.
The Role of A Beautiful Appearance in the Redemption of Female Ghosts
Authors: Hwang Kun
Published: November 2024

The aim of this study is to analyze the role played by the appearance of female ghosts in their redemption. In the literature on ghosts, entries on female ghosts highlight their “beautiful appearance”: Arang (Korean), Otsuyu (Japanese), The White Lady (Europe), Nie Xiaoqian (Chinese), and Maria Makiling (Filipino). Ghosts are women who died tragically, leaving behind unfulfilled desires-particularly those related to romantic or societal expectations such as marriage, love, and motherhood. In death, they seek out men who might help them resolve these unresolved issues. Their beauty, often used to attract men, is marked by an undertone of sorrow or danger. The ghost’s beauty highlights her humanity and vulnerability, juxtaposing her external allure with her internal suffering. These stories commonly convey that only a virtuous or courageous man can redeem the ghost, implying that moral integrity and kindness are essential to break the curse or free the spirit from its torment. The beauty of a female ghost increases her chances of redemption, serving as a form of social currency even after death. Her attractiveness typically symbolizes her value, prompting men to sympathize with her, fall in love, or attempt to rescue her. Although beauty serves as a device to elicit empathy or offer a pathway to redemption, these tales also highlight broader cultural concerns regarding the objectification of women and the societal focus on physical appearance as an indicator of virtue and value. In this context, plastic surgeons, by enhancing patient’s physical appearance, can be seen as creators of virtue and value.
Small Cell Neuroendocrine Carcinoma of the Nasopharynx
Authors: Li Fengzhen , Cha Xudong , Wang Wenwen , Li Tengfei , Wang Shenglei , Xie Yingqi , Xiong Changhai , Ren Wenwen , Liu Huanhai
Published: November 2024

Background:

Nasopharyngeal malignant tumors were relatively rare head and neck tumors with a low global incidence. There were various pathologic types of nasopharyngeal malignant tumors, and small cell neuroendocrine carcinoma (SCNEC) was a highly malignant subtype with rapid growth and early metastasis. SCNEC was rare in the nasopharynx, and its clinical presentation and treatment strategy were different from other types of nasopharyngeal malignancies, posing a challenge to clinicians. Therefore, a comprehensive analysis of its diagnosis and treatment was essential.

Case presentations:

In February 2024, a 32-year-old male presented with nasal congestion, right ear stuffiness, right ear hearing loss, and right ear pain. Electron nasopharyngoscopy and nasopharyngeal magnetic resonance imaging (MRI) showed a large tumor in the nasopharynx. Pathologic examination confirmed the pathologic type as SCNEC. The patient was finally diagnosed with SCNEC. After chemotherapy, immunotherapy, and radiotherapy, the tumor size was significantly reduced, and the clinical symptoms were significantly improved.

Conclusion:

This case provided insights into the diagnosis and treatment of nasopharyngeal malignancies, particularly for a rare pathologic type (SCNEC), potentially enhancing the overall understanding of the disease.
The atypical faces of optic neuritis: neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease
Authors: Poonja Sabrina , Rattanathamsakul Natthapon , Chen John J.
Published: November 2024

Purpose of review

The purpose of this article is to provide a review of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), with a focus on what renders optic neuritis “atypical” in these two conditions. Clinical features, diagnostic criteria, and epidemiology are outlined. Acute treatments for optic neuritis, as well as immunotherapy for NMOSD and MOGAD are discussed.

Recent findings

Updates in NMOSD and MOGAD are highlighted, with an emphasis on novel work including the new 2023 MOGAD diagnostic criteria, our evolving understanding on the epidemiology of these conditions, and recently FDA-approved NMOSD treatments. Pipeline therapies are also discussed.

A thorough history and examination, supported by ancillary testing, continues to be the mainstay of optic neuritis diagnosis. Stratifying typical versus atypical optic neuritis is paramount. Within the atypical category, NMOSD and MOGAD are important considerations. Clues can point towards these diagnoses and guide steps for treatment, which is increasingly becoming targeted to individual diseases, as the pathophysiology is different for these disorders.
Tickling induces a unique type of spontaneous laughter
Authors: Kamiloğlu Roza G. , Sun Rui , Bos Patrick , Huber Florian , Attema Jisk Jakob , Sauter Disa A.
Published: November 2024

Laughing is ubiquitous in human life, yet what causes it and how it sounds is highly variable. Considering this diversity, we sought to test whether there are fundamentally different kinds of laughter. Here, we sampled spontaneous laughs (
n
= 887) from a wide range of everyday situations (e.g. comedic performances and playful pranks). Machine learning analyses showed that laughs produced during tickling are acoustically distinct from laughs triggered by other kinds of events (verbal jokes, watching something funny or witnessing someone else’s misfortune). In a listening experiment (
n
= 201), participants could accurately identify tickling-induced laughter, validating that such laughter is not only acoustically but also perceptually distinct. A second listening study (
n
= 210) combined with acoustic analyses indicates that tickling-induced laughter involves less vocal control than laughter produced in other contexts. Together, our results reveal a unique acoustic and perceptual profile of laughter induced by tickling, an evolutionarily ancient play behaviour, distinguishing it clearly from laughter caused by other triggers. This study showcases the power of machine learning in uncovering patterns within complex behavioural phenomena, providing a window into the evolutionary significance of ticking-induced laughter.
Character displacement or priority effects: immigration timing can affect community assembly with rapid evolution
Authors: Morita Keiichi , Yamamichi Masato
Published: November 2024

Understanding how biological communities assemble in the presence of rapid evolution is becoming an important topic in ecology. Previous studies demonstrated that community assembly can be affected by two types of eco-evolutionary dynamics: evolution-mediated priority effect (EPE) and ecological character displacement (ECD). In EPE, early-arriving species prevent colonization of late-arriving species via local adaptation (i.e. community monopolization), whereas ECD promotes species coexistence by niche partitioning. Researchers tended to discuss the two processes separately, but it should be possible for those processes to operate in the same system depending on various conditions. Here, we developed a theoretical framework that integrates the two processes by using a simple two-species competition model with eco-evolutionary feedback. We revealed that, when an early-arriving species evolves, the difference in immigration timing between the early-arriving and a late-arriving species can be a key parameter. When the difference is small, ECD occurs because insufficient local adaptation of the early-arriving species allows colonization of the late-arriving species. When the difference is large, however, EPE occurs because niche pre-emption by local adaptation of the early-arriving species prevents colonization of the late-arriving species. Further theoretical and empirical studies will be important to better understand eco-evolutionary community assembly with ECD and EPE.
Whole-genome sequencing of the Streptomyces coelicolor bldA39 mutant (J1700) of reveals hundreds of previously unknown mutations.
Authors: Stone Jack W. , Munnoch John T. , Hoskisson Paul A
Published: November 2024

We report the genome sequence of the bldA39 (J1700) mutant Streptomyces coelicolor, a historically important strain that is deficient in sporulation and antimicrobial production. The S. coelicolor J1700 strain was used extensively from the 1980s onwards to underpin important discoveries in development and antibiotic production in Streptomyces. The bldA gene encodes a leucyl transfer RNA (tRNA), required for the translation of the rare TTA codon found in ~2% of genes in Streptomyces. The whole genome of S. coelicolor J1700 was obtained via Illumina sequencing and mapped to the of S. coelicolor M145 reference genome. Analysis of the genome sequence compared to S. coelicolor M145 identified the known bldA39 mutation (T>C) and revealed more than 300 further mutations, likely associated with the S. coelicolor J1501 genetic background the strain was created in, including the nature of the hisA1 and uraA1 alleles used extensively in genetic mapping experiments and several mutations in natural product biosynthetic gene clusters. This work highlights the importance of whole genome sequencing of historically important strains.
IGHG4Expression in C2 Human Dorsal Root Ganglion Potentially Links B Cells to Spreading Chronic Neck Pain
Authors: Mancilla Moreno Marisol , Payne Cathryn , Mazhar Khadijah , Arendt-Tranholm Asta , Yap Natalie , Chiu Abby P. , Wilde Michael A. , Patel Pooja J. , Yousuf Muhammad Saad , Tavares Ferreira Diana , Jarvik Jeffrey G. , Turner Judith A. , Grace Peter M. , Hofstetter Christoph P. , Price Theodore J. , Curatolo Michele
Published: November 2024

Very little is known about the molecular mechanisms underlying chronic neck pain, a highly prevalent and burdensome condition. We analyzed the C2 dorsal root ganglion (DRG) of patients with neck pain who underwent C1-2 arthrodesis surgery. Using spatial transcriptomics, we provide the first report ofIGHG4expression in a human DRG.IGHG4encodes immunoglobulin G4 (IgG4). Infiltration of IgG4-producing lymphocytes characterizes IgG4-related disease, an immune-mediated inflammatory condition, and IgG4 autoantibodies sensitize DRG sensory neurons. The expression was found only in one of the 8 patients analyzed, was very high, and co-localized with B cells, which have a crucial role in IgG4 production. The findings uncover a molecular mechanism potentially involved in chronic neck pain in patients susceptible to infiltration of IgG4-producing B cells.
Analysis of Curcumin and Piperine for Breast Cancer Prevention and Treatment via Simulation and Artificial Intelligence Methods
Authors: Sivakumar Ashwin , Kumar Rishi Senthil , Pravin Sheena Christabel , Monica P Reena
Published: November 2024

From published literature, the combined properties of Curcumin and Piperine infers that the two molecules are potential preventative agents. The nutraceutical combination of Curcumin and Piperine may aid in breast cancer prevention by enhancing Curcumin’s anti-inflammatory and antioxidant effects. In this paper, we demonstrate the following analysis on these two nutraceutical drug molecules in the effort to replicate these inferences in-silico: Drug Synergy Analysis, Molecular Docking and Simulation of Dose-Response curves. We have predicted the synergy (i.e., the effect of two drug molecules when administered simultaneously) between the two molecules on the basis of the Bliss’ Additivity Score. These scores have been predicted by devising a deep learning model using neural networks to determine that the two molecules of interest are synergetic in nature (i.e., one molecule improves the effectiveness of the other). The data used for this model has been extracted from the DrugComb database and filtered to having drug combinations under the MCF7 cell line. The drug molecules are converted from its original SMILES representation to the ECFP6 molecular fingerprint format prior to training the data with the output feature as the Bliss’ score. In this work we also study the interactions between the molecules of interest and protein targets which are of interest (TRPV1 and STAT3) via Molecular Docking. From this, we have been able to determine the binding affinity of the two ligands of interest by docking simultaneously. We have also identified the coordinates of the binding sites of the respective ligands and other potential binding sites for effective binding. From the binding free energies simulated from molecular docking, we have derived the IC50 values using the Cheng-Prusoff Equation. From these IC50 values we have derived the monotherapy dose-response curves with respect to the activation of each the protein targets and the molecules of interest over a range of molar concentrations (0.01um to 100um) using the 4 – parameter logistic curve equation. Furthermore, we have devised a 3D heatmap indicating the combined effectiveness of Curcumin and Piperine from the 4 – parameter log – logistic curve of the Loewe’s Additivity Model over each of the protein targets in focus.
Reduced prevalence of phage defense systems inPseudomonas aeruginosastrains from Cystic Fibrosis Patients
Authors: van den Berg Daan F. , Brouns Stan J.J.
Published: November 2024

Cystic fibrosis is a genetic disorder that affects mucus clearance, particularly of the lungs. As a result, cystic fibrosis patients often experience infections from bacteria, which contribute to the disease progression.Pseudomonas aeruginosais one of the most common opportunistic pathogens associated with cystic fibrosis. The presence ofP. aeruginosacomplicates the treatment due to its high antibiotic resistance. Thus, research is ongoing to treat these infections with bacterial viruses instead, known as bacteriophages. Notably,P. aeruginosaclinical strains possess a variety of phage defense mechanisms that may limit the effectiveness of phage therapy. In this study, we compared the defense system repertoire ofP. aeruginosastrains isolated from cystic fibrosis patients with those from non-cystic fibrosis patients. Our findings reveal thatP. aeruginosastrains isolated from cystic fibrosis patients have fewer phage defense mechanisms per strain than from non-cystic fibrosis patients, suggesting altered phage selection pressures in strains colonizing CF patient lungs.

Importance

Cystic fibrosis patients often experience chronicPseudomonas aeruginosalung infections, which are challenging to treat with antibiotics and contribute to disease progression and eventual respiratory failure. Phage therapy is being explored as an alternative treatment strategy for these infections. However, assessing strain susceptibility to phage treatment is essential for ensuring efficacy. To address this, we investigated whether CF-associated clinicalP. aeruginosastrains have a distinct phage defense repertoire compared to those isolated from other lung patients. We observedthat CF-associatedP. aeruginosastrains have significantly fewer phage defenses, possibly affecting the susceptibility of these strains to phage infection.
The use of X-ray Computed Tomography revolutionises soil pathogen detection
Authors: Pereira Eric C. , Bell Christopher , Urwin Peter E. , Tracy Saoirse
Published: November 2024

Potato cyst nematodes (PCN), namelyGlobodera pallida, pose a significant threat to potato production worldwide. Accurately quantifying nematode population densities is crucial for effective management strategies. However, traditional detection methods are time-consuming and often imprecise. X-ray computed tomography (CT) offers high-resolution, non-destructive and three-dimensional (3D) imaging frequently used to visualise internal structures of objects, materials or biological tissues, allowing for detailed analysis of their composition, defects, and morphology. Here, we demonstrate the effectiveness of X-ray CT in detecting and quantifying PCN cysts in different soil types. The ability to achieve 3D imaging and volume quantification of PCN cysts from soils allows accurate enumeration of their egg content. To explore future potential, we propose that when integrated with AI-led quantification of X-ray CT-generated cyst counts, this method could evolve into a next-generation technology to accurately and rapidly quantify these damaging pests in agricultural soils. Combined with the potential to co-analyse other organisms within the same sample, we propose X-ray CT as a fundamental tool for comprehensive soil health assessments and sustainable pest management in agriculture.

Author Summary

Potato cyst nematodes are a major threat causing significant crop losses worldwide. Traditionally, detecting this pathogen in soil is challenging, often requiring time-consuming and imprecise. Our study explores a new approach using X-ray computed tomography (CT), a powerful imaging tool that creates detailed 3D imagesin situ. We observed that X-ray CT can effectively detect and measure the cysts nematodes, even within different soil types. This detailed analysis allows us to determine the cyst structures and estimate the eggs contained. In the future, combining X-ray CT with artificial intelligence could make detecting and quantifying these nematodes even faster and more accurate. This method could also be expanded to study other soil organisms, making it a valuable tool for monitoring soil health and improving agricultural pest management.
Centromere-proximal crossovers disrupt proper homologous chromosome disjunction during meiosis
Authors: Sen Sucharita , Sarkar Sneha , Menon Gopika , Nambiar Mridula
Published: November 2024

Centromere-proximal crossovers are repressed during meiosis across all species. However, there is a strong correlation between aberrant centromeric crossovers (C-COs) and the occurrence of meiotic aneuploidy and disorders such as Down syndrome. Despite decades of work in understanding repression of C-COs, the molecular basis of how they cause chromosomal mis-segregation is unknown. Here, we show that increased C-COs result in improper separation of homologs leading to increased meiosis I errors and aneuploidy inSchizosaccharomyces pombe. C-COs cause nondisjunction events that cannot be explained by random segregation of homologs and additionally, may also disrupt mono-orientation of sister chromatids in meiosis I leading to their premature separation. We provide evidence that the protected population of cohesins at centromeres during meiosis I may interfere with timely resolution of C-COs causing homolog nondisjunction. These molecular insights will improve our understanding of infertility and aneuploidy-associated developmental disorders in humans.
RNA editing is a molecular clock in unmodified human cells
Authors: Ghareeb Ali E. , Bayne James , Wagen Aaron Z. , Abdelhafid Alya Masoud , Miller David , Cubitt Laura , Meran Laween , Hill Ciaran , Cribbs Adam P. , Ryten Mina , Gandhi Sonia , Gaffney Eamonn , Coles Mark , Young George , Rodriques Samuel G.
Published: November 2024

Despite major advances in spatial RNA sequencing, the ability to extract temporal information in RNA sequencing experiments is still limited. Here, we describe Transcriptome Timestamping (T2), a system which harnesses naturally occurring A-to-I editing of RNA transcripts in unmodified human cells to infer transcriptional history. T2 provides age estimates for individual RNA transcripts, and serves as an endogenous molecular recorder, differentiating between complex transcriptional programs. We show that T2 can identify transient and transitional transcriptional programs in primary differentiating monocytes that are not apparent from gene expression analysis alone, including a regulatory module in the monocyte-to-macrophage transition that, to our knowledge, has not yet been described in humans. Finally, we show that T2 can also be applied to single cell data, allowing us to identify transcriptional programs in heterogeneous populations, such as asynchronously dividing cells. T2 is a scalable approach to temporal transcriptomics that can be applied to track the activity of thousands of genes in unmodified, primary human cells and tissues, with no genetic engineering.
The Mechanism of Dynamic Steady States in Lamellipodia
Authors: Kim June Hyung , Kim Taeyoon
Published: November 2024

Lamellipodia are quasi-two-dimensional actin projections formed on the leading edge of the cell, playing an important role in sensing surrounding environments by forming focal adhesions. A branched actin network in the lamellipodia exhibits a stable, dynamic steady state characterized by a retrograde flow, which is attributed to a balance between network assembly at the leading edge and disassembly at the rear. Although the molecular players and architecture of the lamellipodia have been investigated extensively during recent decades, it still remains elusive how the dynamic steady state with continuous retrograde flow is achieved and robustly maintained. In this study, using an agent-based computational model, we probed how physical interactions between subcellular components in the lamellipodia lead to the dynamic steady state. We reproduced a steady retrograde flow induced by myosin activity and balance between network assembly and disassembly but hindered by resistances from adhesions formed on the underlying substrate. We demonstrated that different modes of dynamic steady states are possible, and that a network which failed to show the retrograde flow due to perturbations can be rescued by altering other factors. Our study provides insights into understanding how cells maintain the dynamic steady state of the lamellipodia in highly varying microenvironments.
SuperWater: Predicting Water Molecule Positions on Protein Structures by Generative AI
Authors: Kuang Xiaohan , Su Zhaoqian , Liu Yunchao (Lance) , Lin Xiaobo , Spencer-Smith Jesse , Derr Tyler , Wu Yinghao , Meiler Jens
Published: November 2024

Water molecules play a significant role in maintaining protein structural stability and facilitating molecular interactions. Accurate prediction of water molecule positions around protein structures is essential for understanding their biological roles and has significant implications for protein engineering and drug discovery. Here, we introduce SuperWater, a novel generative AI framework that integrates a score-based diffusion model with equivariant graph neural networks to predict water molecule placements around proteins with high accuracy. SuperWater surpasses existing methods, delivering state-of-the-art performance in both crystal water coverage and prediction precision, achieving water localization within 0.3 ± 0.06 °A of experimentally validated positions. We demonstrate the capabilities of SuperWater through case studies involving protein hydration, protein-ligand binding, and protein-protein binding sites. This framework can be adapted for various applications, including structural biology, binding site prediction, multi-body docking, and water-mediated drug design.
A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation
Authors: Wang Yu , Zhang Yunxiao , Leung Verina , Heydari Seradj Saba , Sonmez Utku , Servin-Vences Rocio , Lipomi Darren , Ye Li , Patapoutian Ardem
Published: November 2024

Compared to the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. We found that selective PIEZO2 deletion in fat-innervating neurons phenocopied the molecular alternations in adipose tissue caused by DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as the adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.
Berberine: A dual anti-HIV and anti- cervical cancer compound
Authors: Naushad Wasifa , Okeoma Bryson C. , Islam Humayun K , Wang Zhen Zhen , Yang Nan , Li XiuMin , Okeoma Chioma M.
Published: November 2024

We report the effects of berberine (BBR), a benzylisoquinoline alkaloid small molecule on inhibition of HIV infection of cervical cancer cells. We used HeLa cell-derived TZM-bl cell line as a model of cervical cancer and HIV infection. BBR significantly inhibits viral and cancer processes, including expression of cell-associated HIV RNA, secretion of HIV reverse transcriptase, and HIV Tat-mediated LTR promoter transactivation. BBR significantly inhibits HIV-induced cancer cell viability and cell clustering. Besides its ability to inhibit HIV-induced cancer cell viability, BBR inhibits migration and matrix invasion of cervical cancer cells that are infected with HIV or treated with HIV Tat protein. The ability of BBR to inhibit cell clustering, collective cell migration, and cell invasion may have an effect in controlling progression of cervical cancer and HIV since collective migration and invasion are strategies for local tissue infiltration, as well as metastatic invasion in epithelial cancers. Interestingly, molecular docking and dynamic stimulation show that BBR binds HIVIIIBTat amino acid residues through non-covalent interactions that occurs at multiple sites including LYS71, providing mechanistic insights into BBR regulation HIV infection. The results of the present study suggest that BBR has the potential to inhibit HIV infection and comorbid cervical cancer progression.

Graphical abstract

Berberine (BBR), a benzylisoquinoline alkaloid small molecule, inhibits HIV infection of cervical cancer cells, suppresses HIV-induced migration and invasion of the cancer cells. Mechanistically, BBR interferes with Tat-mediated HIV LTR promoter transactivation and expression of different HIV RNA species, expression of early genes (multiply spliced Tat-Rev) and late genes (unspliced Gag-Pol).
A Realist Evaluation of a Fatigue Risk Management Plan (FRMP) Implementation in Obstetrics and Gynecology Residency: Calls for Systemic, Structural and Cultural Reform
Authors: Kassam Aliya , Antepim Benedicta , Thornton Kimberley , Kumagai Jason , Glaze Sarah
Published: November 2024

Background

Accreditation standards in residency education are calling for initiatives to promote the wellness of resident physicians including the implementation of fatigue risk management plans (FRMPs). We sought to conduct a realist evaluation of a FRMP within a five-year Obstetrics and Gynecology (OBGYN) residency training program in labour and delivery units.

Method

Realist inquiry askes what works, for whom, in what circumstances, and why? through examining contexts, mechanisms, and outcomes. Using a mixed method study design, we collected quantitative and qualitative data from OBGYN residents sequentially across three time points.

Results

There were n=19 unique participants (60% response rate). Most of the participants identified as women (93.7%), single (56.2%) and without children (93.7%). Participants mean age was 28.5 years and ranged from junior to senior residents. We found no significant difference between median sleepiness scores across three timepoints (p=0.17) however 20% of residents reported starting and ending shifts with high sleepiness scores signaling impairment that is hazardous to both residents and patients. The n=6 resident interview participants, reported overlooking patient details (forgetting to order tests, and delaying care) as well as personal safety issues such as driving home whilst fatigued despite FRMP implementation.

Discussion

Specific aspects of the OBGYN FRMP such as the nap model and nutrition could help with decreasing perceptions of fatigue related to lack of sleep and lack of available food. While FRMPs might be helpful in de-stigmatizing fatigue in residency, FRMPs are unlikely to decrease levels of resident fatigue because of systemic, structural, and cultural barriers.
Gal-9 and DCN Serum Expression Reflect Accelerated Brain Aging and Are Attenuated by the Green-Mediterranean Diet: The 18-month DIRECT PLUS Proteomics-Brain MRI Trial
Authors: Pachter Dafna , Yaskolka Meir Anat , Kaplan Alon , Tsaban Gal , Zelicha Hila , Rinott Ehud , Levakov Gidon , Finkelstein Ofek , Shelef Ilan , Salti Moti , Beyer Frauke , Witte Veronica , Klöting Nora , Isermann Berend , Ceglarek Uta , Raviv Tammy Riklin , Blüher Matthias , Stumvoll Michael , Wang Dong D. , Hu Frank B , Stampfer Meir J , Avidan Galia , Shai Iris
Published: November 2024

Background

We recently reported that a green-Mediterranean (green-MED), high-polyphenol diet is potentially neuroprotective for age-related brain atrophy. Here, we explored the interplay between dietary intervention, proteomics profile, and accelerated brain age.

Methods

In the 18-month DIRECT PLUS trial, 294 participants (adherence rate=89%) were randomized to one of three arms: 1) Healthy dietary guidelines (HDG); 2) MED diet; or 3) green-MED diet. Both MED diets included 28g/day of walnuts. Additionally, the low red/processed meat green-MED group received daily supplements of polyphenol-rich green-tea and green Mankai aquatic plant. In this secondary analysis, we measured 87 serum proteins (Olink-CVDII) and conducted Magnetic Resonance Imaging (MRI) to obtain brain 3D-T1-weighted for brain age calculation based on brain convolutional neural network to identify protein markers reflecting the brain age gap (BAG: residual deviation of MRI-assessed brain age from chronological age).

Results

We analyzed eligible brain MRIs (216 at baseline and 18-month) for BAG calculation. At baseline (age=51.3yrs, 90% men), lower weight, waist circumference, diastolic blood pressure, and HbA1c parameters were associated with younger brain age than expected (p<0.05 for all). At baseline, higher levels of two specific proteins: Galectin-9 (Gal-9) and Decorin (DCN), were associated with larger BAG (accelerated brain aging; FDR<0.05). A proteomics principal component analysis (PCA) revealed a significant difference between the 18-month time points among participants who completed the trial with accelerated brain aging (p=0.02). Between baseline and 18 months, Gal-9 significantly decreased (p<0.05) among individuals who completed the intervention with attenuated brain age, and DCN significantly increased (p<0.05) among those who completed the trial with accelerated brain age. A significant interaction was observed between the green-MED diet and proteomics PCA change compared to the HDG (β=-1.7; p-interaction=0.05). Participants in the green-MED diet significantly decreased Gal-9 compared to the HDG diet (p=0.015) and from baseline (p=0.003). DCN levels, however, marginally increased in the HDG diet from baseline (p=0.053).

Conclusion

Higher serum levels of Gal-9 and DCN may indicate an acceleration of brain aging and might be reduced by the green-MED/high-polyphenol diet rich in Mankai and green-tea and low in red/processed meat.

Trial registration number

NCT03020186.
A novel method to assess motor planning deficits in patients with Parkinson’s disease and mild cognitive impairment
Authors: Maffit Natalie J , Banerjee Satwika , Sarkar Subhajit , Majumdar Suchismita , Choudhury Supriyo , Kumar Hrishikesh , Soteropoulos Demetris S , Kraskov Alexander
Published: November 2024

It is well established that patients with Parkinson’s disease (PD) show deficits with movement execution, however experiences of motor planning dysfunction, and how they relate to the severity of motor symptoms, remains unclear. To investigate motor planning in PD, we designed a novel precision-grip task. PD patients showed significantly higher uncertainty in task performance compared to healthy controls, indicative of motor planning deficits. Performance of PD patients did not correlate with indicators of disease severity or subtype, yet patients on a higher daily levodopa dosage showed reduced motor planning deficits. Interestingly, these deficits were present even in recently diagnosed patients, implying that this measure may have potential as an early marker of motor planning impairment. These results suggest that the motor planning deficits revealed by our task may arise from separate pathological processes to that of motor execution dysfunction in PD, though can be alleviated with higher treatment dosages.
Interpretable machine learning classifiers implicate GPC6 in Parkinson's disease from single-nuclei midbrain transcriptomes
Authors: Fiorini Michael R. , Li Jialun , Fon Edward A. , Farhan Sali M.K. , Thomas Rhalena A.
Published: November 2024

Parkinson's disease (PD) is a progressive and devastating neurodegenerative disease. An incomplete understanding of its genetic architecture remains a major barrier to the clinical translation of targeted therapeutics, necessitating novel approaches to uncover elusive genetic determinants. Single-cell and single-nuclear RNA sequencing (scnRNAseq) can help bridge this gap by profiling individual cells for disease-associated differential gene expression and nominating genes for targeted genomic analyses. Here, we introduce a machine learning framework to identify molecular features that characterize post-mortem brain cells from PD patients. We train classifiers to distinguish between PD and healthy cells, then decode the models to unravel the 'reasons' behind the classifications, revealing key genes expression signatures that characterize cells from the parkinsonian brain. Application of this framework to three publicly available snRNAseq datasets characterizing the post-mortem midbrain identified cell-type-specific gene sets that accurately classify PD cells across all datasets, demonstrating our approach's capacity to identify robust molecular markers of disease. Targeted genomic analyses of the key genes characterizing PD cells revealed a previously undescribed association between PD and rare variants in GPC6, a member of the heparan sulfate proteoglycan family, which have been implicated in the intracellular accumulation of alpha-synuclein preformed fibrils. We replicate this association in three separate case-control cohorts. Our method promises to enhance understanding of the genetic architecture in complex diseases like PD, representing a critical step toward targeted therapeutics. Our publicly available framework is readily applicable across diseases.
Risk Prediction for Non-cardiac Surgery Using the 12-Lead Electrocardiogram: An Explainable Deep Learning Approach
Authors: Harris Carl , Pimpalkar Anway , Aggarwal Ataes , Yang Jiyuan , Chen Xiaojian , Schmidgall Samuel , Rapuri Sampath , Greenstein Joseph L. , Taylor Casey Overby , Stevens Robert D.
Published: November 2024

Background

To improve on existing noncardiac surgery risk scores, we propose a novel approach which leverages features of the preoperative 12-lead electrocardiogram (ECG) to predict major adverse postoperative outcomes.

Methods

Data acquired in 37,060 adult patients prior to major noncardiac surgery were used to train a series of convolutional neural network models in the task of predicting in-hospital acute myocardial infarction (MI), in-hospital mortality (IHM), and a composite of in-hospital MI, in-hospital stroke, and 30-day mortality. Preoperative ECG waveform features were first modeled as sole inputs then integrated with clinical variables in fusion models. Model discrimination was evaluated using area under the receiver operating characteristic (AUROC) analysis, and performances were compared with the Revised Cardiac Risk Index (RCRI), a benchmark preoperative risk score To gain interpretable insight, a generative approach using counterfactual ECGs was implemented.

Results

The ECG fusion model had an AUROC of 0.858 (95% CI [0.845, 0.872]), 0.899 (95% CI [0.889, 0.908]), and 0.835 (95% CI [0.827, 0.843]) in predicting MI, IHM, and the composite endpoint, respectively; these AUROC values were significantly higher than in models based on ECG waveforms alone (MI:p= 0.001, IHM:p< 10−4, composite:p< 10−4). All ECG based models had significantly higher discrimination than the RCRI. Counterfactual ECG analysis revealed morphological features relevant to outcome classification.

Conclusion

A deep learning approach integrating preoperative ECG waveform features significantly enhances the ability to predict major outcomes after noncardiac surgery. The use of counterfactual ECGs provides plausible explanations for classifier decisions, increasing the interpretability of the models.

Clinical perspective

What is new?

□ A deep learning approach applied to preoperative 12-lead ECG waveforms accurately predicts major outcomes after noncardiac surgery.

□ This model outperforms the benchmark Revised Cardiac Risk Index (RCRI).

□ The highest predictive performance was obtained with a fusion model that combines preoperative ECG waveforms with routinely collected clinical variables.

□ An exploratory approach in which counterfactual ECGs are generated provides explainability for classifier decisions.

What are the clinical implications?

□ In adults undergoing non-cardiac surgery, ECG waveform features are predictive of postoperative cardiovascular risk

□ Risk models integrating ECG waveforms with clinical variables can serve as the basis for outcome modifying interventions across the surgical continuum.

□ Achieving explainability through counterfactual ECGs represents an important step towards real-world implementation.
Frequency and Longitudinal Course of Autonomic Reflex Testing Abnormalities in Isolated REM Sleep Behavior Disorder
Authors: Taha Hash Brown , Zitser Jennifer , Miglis Mitchell G.
Published: November 2024

Study Objectives

Autonomic dysfunction is common across the α-synucleinopathies including isolated RBD (iRBD), however the presence, severity and distribution of autonomic dysfunction as a risk factor for phenoconversion in iRBD remains unclear. We aimed to characterize autonomic reflex testing (ART) abnormalities in a cohort of participants with iRBD and assess their potential as biomarkers for predicting phenoconversion risk.

Methods

We performed ART on 45 individuals with iRBD and evaluated the ability of individual ART components (sympathetic cholinergic, cardiovagal, sympathetic adrenergic) to predict phenoconversion using univariate and multivariate predictive models, both alone and combined with measures of olfaction, cognition, motor function, and skin biopsy assessment of dermal synuclein.

Results

Forty-one individuals with iRBD were enrolled (age 66.7 ± 7.4 yrs, 27% female), and followed annually for an average of 2.9 ± 2.4 yrs, with four participants lost to follow-up. Eight participants with iRBD phenoconverted during their follow-up period (3 Parkinson’s disease, 4 dementia with Lewy bodies and 1 multiple system atrophy), yielding a phenoconversion rate of 6.6% per year. Eighty seven percent of iRBD participants had an abnormal baseline ART, and 100% had an abnormal follow-up ART. A combination of MDS-UPDRS III score and cardiovagal dysfunction (abnormal heart rate variability with deep breathing) best predicted phenoconversion (AUC = 0.77, 95% CI: 0.59–0.94).

Conclusions

ANS dysfunction was common and spanned all domains of autonomic function. Baseline cardiovagal dysfunction was most affected and predictive of phenoconversion, especially if combined with motor examination. Longitudinal studies with larger sample sizes are needed to confirm these findings.