bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression, anxiety, and stress among USMLE aspirants: a cross-sectional survey
Authors: Khan QaisarAli , Belay NaodF. , Semakieh Bader , Aisha Marium , Khan Fahd Zafar , Wiyarta Elvan , Ain Hoor Ul , Hassan Laila , Khan Hamza Ali , Verma Ravina
Published: February 2025

Background:

The United States Medical Licensure Examination (USMLE) represents a critical step for medical licensure in the United States, requiring extensive preparation that can lead to significant mental health challenges among aspirants. This study aims to explore the prevalence and contributing factors of depression, anxiety, and stress among USMLE aspirants.

Methods:

This cross-sectional survey investigates the prevalence and contributing factors of depression, anxiety, and stress among USMLE aspirants. We deployed a detailed online and paper-based questionnaire targeting a diverse pool of 321 medical students and graduates globally. The survey incorporated validated scales such as the Perceived Stress Scale, Generalized Anxiety Disorder 7-item scale, and Patient Health Questionnaire-9 to evaluate mental health statuses. Data analysis was conducted using SPSS, focusing on demographic correlations and mental health outcomes.

Results:

A total of 321 participant’s data were collected, out of whom 51.1% (n = 164) were male and 48.9% (n = 157) were female. 91.3% (n = 293) were International Medical Graduates (IMG), while 8.7% (n = 28) were American Medical Graduates (AMG), educational status results show undergraduates 38.6% (n = 124) and graduates 61.4% (n = 197). Participants were interviewed through a validated questionnaire, and 75.1% (n = 241) had depression, 71.96 (n = 231) had anxiety, (n = 16) had low stress, (n = 231) had moderate, and (n = 66) had severe perceived stress.

Conclusion:

Our study reveals a high prevalence of depression, anxiety, and stress among USMLE aspirants, with significant variations across demographic subgroups and chosen medical specialities.
Comparing surgical outcomes of subcutaneous-flap vs. subplatysmal-flap techniques in total open thyroidectomy: a cohort study
Authors: Samsami Majid , Nematihonar Behzad , Shafiei Mohammad , Tahmasbi Hamed , Tavakoli Shervin , Kouchak Hosseini Seyed Pedram , Adinevand Ehsan , Toutounchi Alireza Haghbin
Published: February 2025

Introduction:

Various minimally invasive open thyroidectomy techniques have been introduced in surgical centers worldwide, aiming to improve cosmetic outcomes. The conventional open thyroidectomy method involves creating a subplatysmal flap through a horizontal incision, which requires cutting the platysma muscle and anterior jugular veins. This study evaluates a modified open total thyroidectomy technique that uses a subcutaneous flap instead of a subplatysmal flap and compares its outcomes with those of the conventional method.

Methods:

This observational cohort study included 120 patients from 10 years experience of tertiary medical center. Outcomes were compared between the subcutaneous flap (MTT) group and the subplatysmal flap (CTT) group.

Results:

The modified technique increased the duration of surgery, with the flap type significantly affecting operation time (P = 0.016). However, there was no significant difference in hospital stay length between the two groups (P = 0.268). The incidence of hematoma and skin ischemia was lower with the subcutaneous flap. No significant differences were observed between the groups in terms of seroma formation, infection, keloid formation, or hypertrophic scars (P>0.05).

Conclusion:

The findings suggest that the subcutaneous flap technique is safe and does not make additional risks or complications. Additionally, it appears to offer advantages in specific outcomes.
Giant Uterine Leiomyoma Causing Severe Hemodynamic Instability
Authors: Almasarweh Saed , Buderath Paul , Rusch Peter , Ingenwerth Marc , Kimmig Rainer
Published: February 2025

BACKGROUND:

Uterine leiomyomas occasionally manifest as giant leiomyomas, displaying exceptional sizes within the uterus and abdominal cavity. These massive growths, although rare because of increased patient awareness, can severely distort pelvic structures and pose life-threatening complications by compressing adjacent organs. We report a case of a patient who presented with severe hemodynamic instability, cardiac arrest, and multiorgan failure caused by a giant 54.8-kg uterine leiomyoma, representing the heaviest weight ever reported in the literature in surviving patients so far.

CASE:

This article documents a case of a 56-year-old woman with a giant uterine leiomyoma in critical condition characterized by multiorgan failure and acute kidney injury necessitating urgent surgical intervention. A laparotomy and subsequent total abdominal hysterectomy were performed. Histopathologic examination revealed a giant uterine leiomyoma. Postoperatively, the patient underwent intensive care management followed by rehabilitation, exhibiting significant clinical recovery.

CONCLUSION:

Managing giant uterine leiomyomas demands a multidisciplinary approach, emphasizing tailored treatment strategies and specialized surgical expertise. The case report describes one of the largest leiomyomas in the literature, underscoring its rarity, and highlights the significance of timely diagnosis and appropriate interventions.
Posttraumatic Stress Disorder and Pregnancy Outcomes
Authors: Lutgendorf Monica A. , Tyagi Radhika , Edwards Sarah , Deering Shad , Raiciulescu Sorana , Walton Robert B. , Pates Jason A. , Napolitano Peter G. , Ieronimakis Nicholas
Published: February 2025

OBJECTIVE:

To evaluate the prevalence and effect of posttraumatic stress disorder (PTSD) on pregnancy outcomes among individuals with military health care.

METHODS:

This was a prospective cohort study of pregnant individuals receiving care at a military tertiary care center from 2014 to 2018. Participants were screened for PTSD with the PTSD Checklist for civilians and for military service members, as well as for traumatic experiences, combat exposure, risk drinking, and depression. Pregnancy outcomes included preterm birth, fetal growth restriction, preeclampsia, gestational diabetes mellitus, hypertensive disorders of pregnancy, outpatient visits, and neonatal intensive care unit admissions.

RESULTS:

Among 1,467 pregnant individuals, 1,145 were retained: 298 (26.0%) military service members and 847 (73.9%) civilian family members. A total of 108 individuals screened positive for PTSD: 21 (7.0%) military service members and 87 (10.3%) civilians. Individuals who screened positive for PTSD had a 17-fold increased likelihood for depression (50.9% vs 5.5%, odds ratio [OR] 17.84, 95% CI, 11.24–28.33), a fivefold increased likelihood for risk of alcohol use (14.8% vs 3.0%, OR 5.64, 95% CI, 2.97–10.69), and a greater number of outpatient visits (median 18 vs 22.5, P=.007). Pregnancy complications were not different between military service members and civilians or those who screened positive for PTSD.

CONCLUSION:

Screening results positive for PTSD are associated with positive screen results for depression and risk of alcohol use during pregnancy, with no differences in outcomes. Although we identified no differences in pregnancy outcomes based on PTSD screening results, comorbidities of traumatic stress such as depression and alcohol use disorder may have long-term consequences on maternal and fetal health. Further research is warranted to understand the effect of behavioral health disorders on pregnancy.
Impact of fracture type on conversion to total hip arthroplasty following surgical repair of acetabular fractures: a systematic review and meta-analysis
Authors: Collins Andrew P. , Kubsad Sanjay , Firoozabadi Reza
Published: February 2025

Objectives:

The objective of this study was to perform a meta-analysis of risk factors of conversion to total hip arthroplasty (THA) after operative fixation of acetabular fractures.

Methods:

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data sources included PubMed, MEDLINE, EMBASE, and Cochrane Library, which were screened from inception to 2024.

Study Selection:

Inclusion criteria were studies comparing risk factors of conversion to THA following acetabular fracture (OTA/AO 62A, B, C) surgical fixation.

Data Extraction:

Studies were assessed by the risk of bias and methodologic quality of evidence tools designed by the Cochrane Methods Bias Group and Cochrane Statistical Methods Group.

Data Synthesis:

Meta-analyses were conducted with a random-effects model using IBM SPSS Statistics Version 29.0.2.0. One-factor-at-a-time sensitivity analyses were conducted.

Results:

Twelve studies (1951 patients) were included. Based on the Judet and Letournel classification system, patients with associated fracture patterns were more likely to require conversion to THA than those with elementary patterns (risk ratio [RR] = 1.55, P = 0.013). Patients with posterior wall involvement (including posterior wall, posterior column with posterior wall, and transverse with posterior wall patterns) were more likely to require subsequent THA than those without posterior wall involvement (RR = 1.58, P < 0.001). Patients who presented with hip dislocation and acetabular dome impaction and comminution were at higher risk of THA (RR = 1.15 and 1.19, respectively; P < 0.001, both). Owing to heterogeneity in reported findings, there were insufficient data to assess the impact of the quality of reduction, restoration of the articular surface, time since acetabular fixation, and patient demographic factors on conversion to THA.

Conclusions:

This study aids in the identification of patients who may require early THA for posttraumatic arthritis based on fracture and injury patterns at presentation. Acetabular fractures with posterior wall involvement and those with associated fracture patterns are associated with a higher rate of conversion to THA. Injuries with acetabular dome impaction and comminution and hip dislocation are also significantly associated with conversion to THA.

Level of Evidence:

Level III. See Instructions for Authors for a complete description of levels of evidence.
Efficacy, safety, and pharmacokinetics of lenacapavir oral bridging when subcutaneous lenacapavir cannot be administered
Authors: Ogbuagu Onyema E. , Avihingsanon Anchalee , Segal-Maurer Sorana , Wang Hui , Jogiraju Vamshi K. , Singh Renu , Rhee Martin S. , Dvory-Sobol Hadas , Sklar Peter A. , Molina Jean-Michel
Published: February 2025

Objective:

To assess efficacy, safety and pharmacokinetics (PK) of oral lenacapavir (LEN) when used as oral bridging (OB) between delayed subcutaneous (SC) LEN injections.

Design:

Posthoc analysis of participants in two clinical trials of SC LEN for HIV-1 treatment who required OB when LEN SC dosing was interrupted.

Methods:

Oral LEN [300 mg once weekly (QW)] was initiated within 2 weeks of the next scheduled injection (dosing interval: 26 weeks). Efficacy, safety, and PK were assessed every 10–12 weeks.

Results:

Overall, 139 participants received ≥1 dose of oral 300 mg QW LEN plus other antiretrovirals. Median duration of OB was 19 weeks in both clinical trials. By missing = excluded analysis, over 95% of participants maintained virologic suppression (HIV-1 RNA <50 copies/ml) at Weeks 10, 20, and 30. Treatment-emergent AEs (TEAEs) were similar to those with SC LEN (excluding injection site reactions). No Grade ≥3 or serious TEAEs were considered related to oral LEN. Throughout OB, mean LEN plasma concentrations and lower bound 90% confidence intervals (CIs) were consistently above inhibitory quotient 4 (4-fold in-vitro protein binding-adjusted 95% effective concentration). OB adherence (by pill count) was ≥95% in the majority of participants in both clinical trials.

Conclusions:

High rates of virological suppression were maintained during OB. Oral 300 mg QW LEN was well tolerated and provided adequate plasma concentrations to bridge SC LEN dosing. This analysis supports using 300 mg QW LEN for OB when SC LEN treatment is interrupted.
Prognostics Factors to Avoid Eye Injuries in Angle Grinders
Authors: Ke Wang , Gu Kaiming , Zhu Suhui , Wu Jianhao , Dai Yan
Published: February 2025

Objective:

To analyze the clinical characteristics and prognostic factors of eye injuries caused by angle grinders over 2 years.

Methods:

Clinical data from 36 hospitalized patients (36 eyes) with eye injuries caused by angle grinders were collected. The causes of injury, types of trauma, and prognoses were analyzed.

Results:

Among the 36 patients (36 eyes), 34 were male (34 eyes) and 2 were female (2 eyes), with ages ranging from 19 to 66 years. The time from injury to medical consultation was within 12 hours in 29 cases, between 12 and 24 hours in 6 cases, and over 24 hours in 1 case. Primary emergency globe repair surgery was performed within 8 hours of admission in 23 cases, while 29 cases required secondary surgical interventions. Preoperative visual acuity was recorded as no light perception to 0.05 in 13 cases, 0.05 to 0.1 in 10 cases, 0.1 to 0.3 in 9 cases, and >0.3 in 4 cases. Postoperative best-corrected visual acuity was <0.05 in 10 cases, 0.05 to 0.1 in 13 cases, 0.1 to 0.3 in 7 cases, and >0.3 in 6 cases.

Conclusion:

Eye injuries caused by angle grinders are often complex, involving both ocular adnexa and globe injuries, with multiple sites of intraocular trauma. A high proportion of patients require secondary surgical interventions. Factors affecting visual outcomes include the location and type of injury, time to medical consultation, presence of infectious endophthalmitis, and intraocular foreign bodies.
Accessory Infraorbital Foramen: Prevalence in the Mexican Population by Tomographic Study
Authors: Elizarrarás-Alonso Brenda , Malagón-Hidalgo Héctor O. , García-Cano Eugenio , Flores-Hernández José Gabriel , Menéndez-Arzac Rodrigo A. , Lavareda-Santana Marco A.
Published: February 2025

Objective:

The accessory infraorbital foramen (AIOF) has been reported to have a prevalence of up to 47.6% in the global population. Cadaveric studies have observed that components of the infraorbital neurovascular bundle may emerge through the AIOF. The objective of this study was to determine the prevalence of the AIOF in the Mexican population.

Methods:

A cross-sectional, observational, descriptive epidemiological study was conducted, analyzing skull computed tomography (CT) scans with three-dimensional reconstruction from 345 randomly selected Mexican patients performed between 2015 and 2022. The presence of the AIOF was assessed, including its area, location, laterality, and number. Descriptive statistical analysis was performed using IBM SPSS Statistics version 25.0.

Results:

The presence of the AIOF was found in 17.8% (58 cases), with 11% in men and 6.8% in women. The majority of cases (73.9%) had a superomedial location. The AIOF was found bilaterally at 48.3%, on the left side at 41.4%, and on the right side at 10.3%. Of these, 96.6% were single, and 3.4% were double; no triple or quadruple AIOFs were observed. The average area of the AIOF was 2.9 mm².

Conclusions:

Awareness of the presence of the AIOF is crucial for preventing inadvertent injuries to the infraorbital neurovascular bundle during procedures involving the infraorbital area, both medical and surgical, thereby reducing the risk of complications. The use of three-dimensional tomographic reconstruction offers more accurate and precise knowledge when planning these procedures.
Building an inclusive culture at scientific meetings: foundations for future progress
Authors: Maringer Kevin , Cunningham-Oakes Edward , Lane Ffion , Jones Kirsty L. , Rodrigues de Oliveira Bruno Francesco , Baba-Dikwa Aisha , Mitra Arindam , Perez-Sepulveda Blanca , Chappell Callie R. , Macori Guerrino , Donovan-Banfield I’ah , Vohra Prerna , Casey Rowan , Nepal Roshan , Khan C. M. Anjam
Published: February 2025

Scientific meetings and conferences are crucial in knowledge dissemination, fostering collaborations, professional development and inspiring innovative research. However, their traditional structure and organization have remained largely unchanged, perpetuating barriers that continue to exclude scientists from historically marginalized backgrounds. In response, the Microbiology Society has begun its journey to address these longstanding challenges, redesigning its meetings to create a more inclusive culture and a welcoming environment for all participants.
Humanized Bone Marrow-Liver-Thymus Mice for Studying HIV-1 Persistence in Liver and Lung CD4+ T and Myeloid Cell Subsets during Antiretroviral Therapy
Authors: Cattin Amélie , Pham Tram NQ , Dias Jonathan , Do Rosario Natalia Fonseca , Marchand Laurence Raymond , Volodina Olga , Guimond Jean-Victor , Patey Natalie , Li Yuanyi , Béland Kathie , Jenabian Mohammad-Ali , Estaquier Jérôme , Haddad Elie , Cohen Éric A. , Ancuta Petronela
Published: February 2025

Background

While the role of CD4+T-cells in HIV-1 reservoir persistence during antiretroviral therapy (ART) is well-established, studies on tissue-resident macrophages (MΦ) in people with HIV-1 (PWH) are restricted by difficulties in accessing deep tissue samples. Investigations in myeloid-only humanized mouse models demonstrated the contribution of MΦ to viral rebound upon ART interruption. Two distinct MΦ subsets exist in mice and humans: one of embryonic origin and self-renewal capacity generating long-lived tissue-resident MΦ (LL-TRM), and another one of short-lived MΦ (SL-MΦ), constantly replenished by bone marrow monocytes. The relative contribution of LL-TRMversusSL-MΦ to tissue HIV-1 reservoir persistence during ART remains understudied. Here, we used a humanized BM-liver-thymus (hu-BLT) mouse model to quantify integrative HIV-1 infection in liver/lung MΦversusCD4+T-cells before/after ART and document their expression of LL-TRM/SL-MΦ markers.

Results

Lung/liver immune cells were extracted from ART-naive (ART-) and ART-treated (ART+) HIV-infected (HIV+) hu-BLT mice, as well as HIV-uninfected mice (HIV-). MΦ were identified as cells expressing the myeloid markers CD33/HLA-DR and/or CD68 and flow-cytometry sorted based on their differential expression of CD14 and/or CCR2. Matched CD3+CD4+T-cells were sorted in parallel and used as controls. HIV-DNA integration was measured by nested real-time PCR. In contrast to CD4+T-cells that carried the highest levels of proviral HIV-DNA before and after ART, integrative infection in liver/lung MΦ was detected before ART, but was drastically reduced in HIV+ART+ hu-BLT mice, regardless of CD14 or CCR2 expression on MΦ. Markers of LL-TRM (CD163/CX3CR1/Ki67/c-Kit) were expressed on a small fraction of liver but not lung MΦ, indicative of a deficient LL-TRM development in this hu-BLT model.

Conclusions

Together our results demonstrate that lung/liver MΦ in hu-BLT mice support integrative HIV-1 infectionin vivo, but their contribution to viral reservoir persistence during ART is minor when compared to CD4+T-cells. This is consistent with the deficient development of LL-TRM we observed in hu-BLT mice. However, HIV-1 permissive MΦ present in this model likely contribute to viral rebound upon ART interruption. Therefore, HIV-1 cure interventions that are tested in such preclinical models should consider targeting HIV-1 replication in both MΦ and CD4+T-cells.
Swirling motion of breast cancer cells radially aligns collagen fibers to enable collective invasion
Authors: Saraswathibhatla Aashrith , Rabbi Md Foysal , Varma Sushama , Srivastava Vasudha , Ilina Olga , Alyafei Naomi Hassan Kahtan , Hodgson Louis , Gartner Zev , Friedl Peter , West Robert , Kim Taeyoon , Chaudhuri Ovijit
Published: February 2025

In breast cancer (BC), radial alignment of collagen fibers at the tumor-matrix interface facilitates collective invasion of cancer cells into the surrounding stromal matrix, a critical step toward metastasis. Collagen remodeling is driven by proteases and cellular forces, mediated by matrix mechanical plasticity, or irreversible matrix deformation in response to force. However, the specific mechanisms causing collagen radial alignment remain unclear. Here, we study collective invasion of BC tumor spheroids in collagen-rich matrices. Increasing plasticity to BC-relevant ranges facilitates invasion, with increasing stiffness potentiating a transition from single cell to collective invasion. At enhanced plasticity, cells radially align collagen at the tumor-matrix interface prior to invasion. Surprisingly, cells migrate tangentially to the tumor-matrix interface in a swirling-like motion, perpendicular to the direction of alignment. Mechanistically, swirling generates local shear stresses, leading to distally propagating contractile radial stresses due to negative normal stress, an underappreciated property of collagen-rich matrices. These contractile stresses align collagen fibers radially, facilitating collective invasion. The basement membrane (BM), which separates epithelia from stroma in healthy tissues, acts as a mechanical insulator by preventing swirling cells from aligning collagen. Thus, after breaching the BM, swirling of BC cells at the tumor-stroma interface radially aligns collagen to facilitate invasion.
Editing strigolactone biosynthesis genes in tomato reveals novel phenotypic effects and highlightsD27as a key target for parasitic weed resistance
Authors: Nicoliaa A. , Cuccurullo A. , Tamada K. , Yoneyama K. , Rambla J.L. , Granell A. , Camerlengo F. , Festa G. , Francese G. , Contaldi F. , D’Alessandro A. , Rigano M.M. , Principio L. , D’Agostino N. , Cardi T.
Published: February 2025

Parasitic weed infestations pose an increasing threat to agriculture worldwide, especially in the Mediterranean region.Phelipanche ramosaandP. aegyptiaca(broomrapes) cause severe damage to field-grown tomato (Solanum lycopersicum L.). Strigolactones (SLs), apocarotenoid phytohormones, play a critical role in plant physiology and development, and are also the primary signals that trigger the germination of parasitic weed seeds. We generated CRISPR/Cas9 tomato knock-out lines for theSlD27gene, as well as three other key genes involved in SL biosynthesis (SlCCD7,SlCCD8,SlMAX1), all within the same genetic background. The edited lines exhibited a marked reduction in SL content in root exudates, along with impaired broomrape seed germination. A comprehensive analysis of morphological, reproductive, and fruit-related traits revealed gene-specific effects on plant phenotype, including vegetative traits, fruit set, fruit development, and volatilome. Specifically, the knock-out of twoCCDsand theMAX1had a specific impact not only on plant development but also on the production of volatile organic compounds during fruit ripening. In contrast, theSld27lines, produced for the first time in this study, displayed a phenotype similar to the control non-edited plants, suggesting that theD27gene holds promise as a breeding target for enhancing resistance to parasitic weeds in tomato.

Highlight

The characterization of tomato CRISPR/Cas9-edited lines for the four core genes involved in strigolactone biosynthesis revealed gene-specific effects on plant phenotype, withD27emerging as a potential target for resistance to parasitic weeds.
The acidic N-terminus of HHARI and neddylation are essential for the activation and maintenance of RIG-I-mediated type I interferon response
Authors: Kontra Ioanna , Ward Harry , Vinluan Faith , Lau Rachel , Rajeeve Vinothini , Cutillas Pedro , Stieglitz Benjamin , Lewis Myles J.
Published: February 2025

Human homolog of Ariadne (HHARI) is a RING-between-RING ubiquitin E3 ligase which interacts with cullin-RING E3 ligase (CRL) complexes. HHARI has been implicated in the type-I interferon anti-viral response. However, how HHARI drives interferon signalling is not fully understood and the function of the unique, highly conserved acidic N-terminal domain of the protein is unknown. Here, we show that HHARI stimulates interferon-β secretion and autocrine type-I interferon signalling by directly targeting the viral RNA sensor RIG-I (Retinoic Acid-Inducible Gene I) in a neddylation-dependent manner. This suggests that neddylation inhibition could be used to treat interferonopathies and related diseases. Truncated HHARI containing only the N-terminal acidic/UBA-like domains retained the ability to induce interferon signalling in a neddylation-dependent mechanism. HHARI-mediated interferon-β secretion was enhanced by overexpression of cullins 1-5. The N-terminal acidic/UBA-like domain of HHARI is critical for RIG-I activation and interferon signalling, as removal of these domains inactivated the pro-interferon phenotype. We propose a mechanism by which the N-terminus of HHARI interacts with all neddylated cullins leading to endogenous HHARI activation. This suggests a model in which the N-terminus of HHARI ‘unlocks’ and activates neddylated cullins, which in turn are required for activation of HHARI itself. As cullins typically form modular cullin-RING ligase super-assemblies our findings imply that the HHARI N-terminus domain is a critical regulator of the versatile CRL system, which, through widespread protein ubiquitylation, controls many eukaryotic cell functions.
Transcriptional control of T cell tissue adaptation and effector function in infants and adults
Authors: Szabo Peter A. , Levitin Hanna M. , Connors Thomas J. , Chen David , Jin Jenny , Thapa Puspa , Guyer Rebecca , Caron Daniel P. , Gray Joshua I. , Matsumoto Rei , Kubota Masaru , Brusko Maigan , Brusko Todd M. , Farber Donna L. , Sims Peter A.
Published: February 2025

The first years of life are essential for the development of memory T cells, which rapidly populate the body’s diverse tissue sites during infancy. However, the degree to which tissue memory T cell responses in early life reflect those during adulthood is unclear. Here, we use single cell RNA-sequencing of resting andex vivoactivated T cells from lymphoid and mucosal tissues of infant (aged 2-9 months) and adult (aged 40-65 years) human organ donors to dissect the transcriptional programming of memory T cells over age. Infant memory T cells demonstrate a unique stem-like transcriptional profile and tissue adaptation program, yet exhibit reduced activation capacity and effector function relative to adults. Using CRISPR-Cas9 knockdown, we define Helios (IKZF2) as a critical transcriptional regulator of the infant-specific tissue adaptation program and restricted effector state. Our findings reveal key transcriptional mechanisms that control tissue T cell fate and function in early life.
Deciphering DNA’s sequence-dependent structure and deformability with normalizing flows
Authors: Liebl Korbinian
Published: February 2025

The sequence-dependent structure and deformability of double-stranded DNA plays a key role in many cellular processes. Accurate description thereof has thus been a long-standing problem. Previous approaches to this problem assume a specific functional form for the elastic energy in terms of internal coordinates of the DNA double-helix. The conformational flexibility of DNA, however, is strongly impacted by several stereo-chemical effects that complicate the formulation of an accurate functional form. In this work, I propose an entirely new, AI-based method to decipher the sequence-dependent structure and deformability of double-stranded DNA. This method employs normalizing flows that capture multimodal and correlation effects between internal coordinates of the DNA double helix excellently, and hence allows one to accurately quantify deformation energies for any double-stranded DNA structure and sequence. Thus, it offers a wide range of future applications, and speaks in favor of AI-based elasticity-descriptions also for other molecules.
Cutaneous lupus features specialized stromal niches and altered retroelement expression
Authors: Gehlhausen Jeff R. , Kong Yong , Baker Emily , Ramachandran Sarika , Koumpouras Fotios , Ko Christine J. , Vesely Matthew , Little Alicia J. , Damsky William , King Brett , Iwasaki Akiko
Published: February 2025

Cutaneous Lupus is an inflammatory skin disease causing highly morbid inflamed skin and hair loss. In order to investigate the pathophysiology of cutaneous lupus, we performed single-cell RNA and spatial sequencing of lesional and non-lesional cutaneous lupus skin compared to healthy controls. Pathway enrichment analyses of lesional keratinocytes revealed elevated responses to type I interferon, type II interferon, tumor necrosis factor, and apoptotic signaling. Detailed clustering demonstrated unique fibroblasts specific to lupus skin with likely roles in inflammatory cell recruitment and fibrosis. We also evaluated the association of retroelement expression with type I interferons in the skin. We observed increased retroelement expression which correlated with interferon-stimulated genes across multiple cell types. Moreover, we saw elevated expression of genes involved in RIG-I and cGAS-STING pathways, which transduce elevated nucleic acid signals. Treatment of active cutaneous lupus with Anifrolumab reduced RIG-I and cGAS-STING pathways in addition to the most abundant retroelement family, L2b. Our studies better define type I interferon-mediated immunopathology in cutaneous lupus and identify an association between retroelement expression and interferon signatures in cutaneous lupus.
Fast and Scalable Parallel External-Memory Construction of Colored Compacted de Bruijn Graphs with Cuttlefish 3
Authors: Khan Jamshed , Dhulipala Laxman , Patro Rob
Published: February 2025

The rapid growth of genomic data over the past decade has made scalable and efficient sequence analysis algorithms, particularly for constructing de Bruijn graphs and their colored and compacted variants critical components of many bioinformatics pipelines. Colored compacted de Bruijn graphs condense repetitive sequence information, significantly reducing the data burden on downstream analyses like assembly, indexing, and pan-genomics. However, direct construction of these graphs is necessary as constructing the original uncompacted graph is essentially infeasible at large scale. In this paper, we introduce Cuttlefish3, a state-of-the-art parallel, external-memory algorithm for constructing (colored) compacted de Bruijn graphs. Cuttlefish3 introduces novel algorithmic improvements that provide its scalability and speed, including optimizations to significantly speed up local contractions within subgraphs, a parallel algorithm to join local solutions based on parallel list-ranking, and a sparsification method to vastly reduce the amount of data required to compute the colored graph. Leveraging these algorithmic strategies along with algorithm engineering optimizations in parallel and external-memory setting, Cuttlefish3 demonstrates state-of-the-art performance, surpassing existing approaches in speed and scalability across various genomic datasets in both colored and uncolored scenarios.
Implementing long-acting injectable HIV pre-exposure prophylaxis services at private pharmacies in Kenya: Client, pharmacy provider, and key stakeholder perspectives on potential challenges and opportunities
Authors: Roche Stephanie D , Kamolloh Kevin , Thuo Nicholas , Opioyo Maurice , Ogello Vallery , Odira Alfred , Owidi Emmah , Ochwal Perez , Hewa Marion , Adiema Lydia , Mogaka Felix , Omollo Victor O , Malen Rachel C , Harkey Kendall , Stewart Jenell , Ngure Kenneth , Ortblad Katrina F , Bukusi Elizabeth A
Published: February 2025

Introduction: Maximizing the impact of new and forthcoming long-acting injectable HIV pre-exposure prophylaxis (PrEP) products will require novel delivery approaches that widen accessibility and prioritize clients needs and preferences. To understand the potential barriers and facilitators to delivering injectable PrEP via private pharmacies in Kenya, we conducted qualitative formative research. Methods: From July to September 2023, we interviewed pharmacy providers, pharmacy clients, and other key stakeholders of HIV service delivery in Central and Western Kenya. Our purposive sample included some providers and clients with prior experience delivering or obtaining oral PrEP at a pharmacy as part of a pilot study and some without such experience. We analyzed verbatim transcripts thematically using a combination of inductive and deductive approaches, the latter informed by the Consolidated Framework for Implementation Research (CFIR). Results: We interviewed 25 pharmacy clients, 16 pharmacy providers, and 9 key stakeholders. Each group was ~50% female, and median age among clients was 25 (IQR 23-29). Overall, participants supported the idea of pharmacy-based injectable PrEP delivery. Anticipated facilitators included perceived benefits of injectable over oral PrEP; characteristics of pharmacies (e.g., long operating hours) that could fulfill clients need for accessible, fast, and private injectable PrEP services; and existing skillsets of pharmacy providers, especially those already trained on injectable contraception. Anticipated barriers included gaps in enabling policy; pharmacies lack of integration with the public health sector, such as its health information system; low client knowledge of and/or ability to pay for injectable PrEP; and pharmacy staffing and compensation structures that could disincentivize providers. Conclusions: Participants in this study expressed cautious optimism that private pharmacies could be an effective delivery channel for injectable PrEP in Kenya. If private pharmacies facilitate access to and use of injectable PrEP, they could play a pivotal role in ending HIV as a public health threat.
Integrating fossils samples with heterogeneous diversification rates: a combined Multi-Type Fossilized Birth-Death model
Authors: Barido-Sottani Joëlle , Morlon Hélène
Published: February 2025

Birth-death models are widely used to describe the diversification process which leads to the observed species and phylogenies. When integrated into Bayesian phylogenetic inference, birth-death models allow the joint inference of the phylogeny and the diversification parameters from molecular information. Two major classes of extensions of the birth-death process are considered in this article. The first extends the phylogenetic tree to include fossil samples alongside extant species, allowing the inference to integrate information about the past diversity. The second extension models diversification rates which can vary between lineages, and is thus able to infer patterns of variation in speciation or extinction rates. In this work, we combine these two types of extension into a multi-type fossilized birth-death (MTFBD) process, which can perform the joint inference of a phylogeny including extinct and extant samples, and lineage-specific diversification and fossilization rates in a Bayesian framework. The MTFBD model is implemented as part of the phylogenetic inference framework BEAST2. Using simulated and empirical datasets, we demonstrate the performance and accuracy of the new model compared to a model with rate heterogeneity but using only extant samples, and compared to a model without rate variation including fossils. We demonstrate that including fossils improves the accuracy of the phylogeny and diversification rates, especially extinction rates, provided that the inference includes morphological information to accurately place the fossil samples. When this information is not available however, MTFBD estimates are strongly driven by the priors and are thus no better or even worse than estimates obtained only with extant samples. With informative fossil characters, the MTFBD model provides accurate phylogenies, and precisely characterizes how speciation, extinction and fossilization rates vary as diversification proceeds.
Leveraging Pretrained Large Language Model for Prognosis of Type 2 Diabetes Using Longitudinal Medical Records
Authors: Nguyen Phong B.H. , Hungele Andreas , Holl Reinhard W. , Menden Michael P.
Published: February 2025

Timely prognosis of type 2 diabetes (T2D) complications is critical for effective interventions and reducing economic burden. AI-driven large language models (LLMs) offer potential for extracting clinical insights but face challenges due to the sparse, high-dimensional nature of longitudinal medical records. This study demonstrates the utility of LLMs in medical time series prediction by preprocessing data with a missing mask, adding an embedding layer to a pretrained LLM, and fine-tuning both components. The fine-tuned model outperformed baselines in predicting both HbA1c and LDL levels using the DPV registry dataset of 449,185 T2D patients, achieving Pearson’s correlations of 0.749 and 0.754, with a delta improvement of 0.253 and 0.259, respectively. The model also demonstrated robust long-term prediction for HbA1c over 554.3 days (95% CI: [547.0, 561.5]), with a 9% improvement in MSE over last-observation-based methods. Integrated gradient analysis identified significant clinical features and visits, revealing potential biomarkers for early intervention. Overall, the results showed the possibility to leverage the prediction power of LLM in T2D prognosis using sparse medical time series, assisting clinical prognosis and biomarker discovery, ultimately advancing precision medicine.
Unveiling Meropenem Resistance and Co-Resistance Patterns inKlebsiella pneumoniaeandAcinetobacter baumannii: A Global Genome Analysis Using ML/DL and Association Mining
Authors: Ramachandran Srimathy , Deepak K , Shrikumaran M , Mohamed Rasiq R , Ananya S , Aruna V , Derrick Daniel P , Sruthi B , Suma Mohan S
Published: February 2025

Background

The increasing prevalence of meropenem-resistant gram-negative bacteria has significantly undermined its effectiveness and has increased treatment failure and mortality rates. The global availability of bacterial WGS data with antimicrobial resistance phenotypes enables large-scale genome analysis to explore resistance determinants. This study investigated the meropenem resistance mechanism in multidrug-resistant (MDR)Klebsiella pneumoniae(KP) andAcinetobacter baumannii(AB) isolates using advanced data analytics approaches.

Methods

We analysed 2,411 KP and 375 AB isolates with meropenem-resistant and susceptible phenotypes from the BV-BRC database. AMR genes and mutations were identified from the isolates using the CARD database as a reference. Significant AMR genes and missense mutations, determined through chi-square tests, were subsequently used to train ML and DL models. The best-performing SVM model was used for sequential feature selection to identify key features. Additionally, association mining was conducted separately on the selected features and the antibiotics data.

Results

Notable differences were observed in the proportions of genes contributing to the meropenem resistance mechanism categories between KP and AB, including carbapenemases (4% in KP, 23% in AB), antibiotic efflux (30%, 60%), target alteration (23%, 12%), and reduced permeability (18%, 3%). Mutation frequencies also vary, with antibiotic efflux (26%, 67%), target alteration (64%, 5%), and reduced permeability (7%, 15%). A total of 410 significant features in KP and 211 in AB were identified for model building. SVM-based feature selection pinpointed seven key features in KP and 10 in AB, resulting in 95% accuracy for both. Association mining revealedblaKPC-2,blaKPC-3,bleMBL, andaac(6’)-Ib9as key factors in KP, andblaOXA-23, Abau_gyrA_FLO|Ser81Leu, and Abau_OprD_IMP|Asn411Asp in AB associated with meropenem resistance. The observed prevalence of AAC genes and thegyrAmutation, along with insights from association mining, reveals the co-resistance of meropenem with aminoglycosides and fluoroquinolones, whileoprDmutations imply potential shared resistance across antibiotics.

Conclusion

The analysis of AMR genes and mutations based on resistance mechanisms revealed distinct differences in meropenem resistance between KP and AB. The ML/DL models and association mining approaches identified key resistance features and cross-antibiotic resistance insights. These findings deepen our understanding of meropenem resistance, enabling more precise and effective antimicrobial interventions.
Associations of ADHD symptom severity, sleep/circadian factors, depression and quality of life: Secondary analyses of the Netherlands Sleep Registry study
Authors: Nair Siddhi , Deshpande Neha , Hill Catherine M. , Cortese Samuele , Van Someren Eus , Chellappa Sarah L.
Published: February 2025

Study objectives

We investigated whether sleep disruption and circadian preference mediate the associations of ADHD symptom severity with depression symptom severity and quality of life.

Methods

1364 participants (mean: 51.86 [SD= 0.37] years, 75% females) from a large-scale cross-sectional online survey (Netherlands Sleep Registry) completed a sociodemographic questionnaire, the Adult ADHD Rating Scale, Hospital Anxiety and Depression Scale (HADS), Satisfaction With Life Scale (SLS) and Cantril Ladder (CL) (quality of life measures), Insomnia Severity Index, Pittsburgh Sleep Quality Index, and Munich Chronotype Questionnaire.

Results

Higher ADHD symptom severity was significantly associated with depression severity (p= 0.03), lower quality of life (p< 0.001), insomnia severity (p< 0.001), lower sleep quality (p< 0.001), and later circadian preference (p= 0.01). No sleep or circadian factor significantly mediated the association of the severity of symptoms of ADHD and depression (allp> 0.1). Conversely, only insomnia severity significantly mediated the association of the severity of symptoms of ADHD and quality of life (SLS: standardized beta = -0.10, 95% CI = [-0.12, -0.04]; CL: standardized beta = .103, 95% CI = [0.04, 0.16]).

Conclusion

ADHD symptom severity was associated with lower quality of life, primarily mediated by insomnia symptom severity. Future studies targeting insomnia complaints in this population may help mitigate their depression complaints and improve their quality of life.
Effects of One-week Intake of Different Edible Oils on the Urinary Proteome of Rats
Authors: Su Yan , Gao Youhe
Published: February 2025

Objective

To explore the effects of different edible oils on the rat body by analyzing the changes in the urinary proteome and post-translational modifications of rats after one-week intake of olive oil, butter, lard, hydrogenated vegetable oil, and rapeseed oil.

Methods

Six parallel experiments were set up using male Wistar rats. Group A served as the control group, while groups B - F were administered different edible oils. The daily intakes were calculated respectively according to the “2015 - 2020 Dietary Guidelines for Americans” and the “Dietary Guidelines for Chinese Residents”. Urine samples were collected after one week and identified by label - free quantitative proteomics technology of high - performance liquid chromatography - tandem mass spectrometry (LC - MS/MS). Differentially expressed proteins and differential post - translational modifications in the urinary proteome were screened for functional analysis.

Results

After the intake of different types of edible oils, rats produced a large number of proteins and biological pathways related to metabolism, but there were few common differentially expressed proteins among different groups. In addition, the olive oil group and the butter group were enriched with many biological pathways related to the nervous system, and the rapeseed oil group produced more differentially expressed proteins and biological pathways related to immunity.

Conclusion

The urinary proteome of rats showed significant changes after one-week intake of edible oils, and the effects of various edible oils on the rat urinary proteome were different from each other. This effect is comprehensive and multi-dimensional at the level of the rat body. The changes in post-translational modifications of the proteome were relatively small.
A systematic analysis of in-source fragments in LC-MS metabolomics
Authors: Chi Yuanye , Mitchell Joshua M. , Li Shuzhao
Published: February 2025

The “dark matter” of metabolomics refers to the large number of unidentified features in metabolomic studies, mostly from mass spectrometry (MS) based analysis (deSilva2015; David2021; Giera2024). The topic is pertinent to the analytical coverage of small molecules in biomedical research (Kind2009; Uppal2016), approaches to metabolite annotation (Domingo2018; Chaleckis2019; Metz2025), mapping reaction pathways (Zamboni2015) and the promise of applying metabolomics and exposomics to precision medicine (Wishart2016; Vermeulen2020). The number of unidentified features is not a direct account of number of compounds, as a metabolite can have isotopologues, adducts and fragments that are measured in the same data (Mahieu2017; Wang2019; Li2023a). Giera et al (2024) recently reported that in-source fragments (ISFs) accounted for over 70% of MS/MS features in METLIN, one of the leading spectral databases, suggesting that ISFs could be a significant portion of the “dark matter”. Since the reference spectra in METLIN are based on chemical standards, we examine here the LC-MS (liquid chromatography coupled mass spectrometry) metabolomics from biological samples, which are the most relevant in biomedical investigations.
3D-bioprinted marine bacteria for the degradation of bioplastics
Authors: He Luying , Cai Hongyi , Gona Ram S. , Gangan Manasi S. , Lai Timothy , Silberstein Meredith N. , Meyer Anne S.
Published: February 2025

The severe, long-lasting harm caused by plastic pollution to marine ecosystems and coastal economies has led to the development of biodegradable plastics; however, their limited decomposition in cold, dark marine environments remains a challenge. Here, we present our newly developed technologies for creating 3D-bioprinted living materials for bioplastic degradation with specific use in marine environments. Our approach integrates halotolerant bioplastic-degrading bacteriumBacillussp. NRRL B-14911 into alginate-based bio-ink to print an engineered living material (ELM) termed a “bio-sticker.” Quantification of bacteria viability reveals that bioprinted marine bacteria survive within bio-stickers for more than three weeks. The rate at which the bio-stickers degrade the bioplastic polyhydroxybutyrate (PHB) can be tuned by altering bio-sticker biomass concentration, bioplastic concentration, or incubation temperature. Bio-stickers that are transferred to a new PHB sample still retain high biodegradation activity, demonstrating their durability. Strain sweep oscillatory tests demonstrate viscoelastic behavior of the bio-stickers. Monotonic tensile tests indicate that the elastic modulus and the adhesion of the bio-stickers are not negatively impacted by bacteria growth or incubation temperature. Our work paves the way for development of ELMs to facilitate the inclusion of bioplastics within the blue economy, promoting the emergence of more sustainable and eco-friendly materials.