bluuebunny/crossref_metadata_2025 huggingface dataset:
Senolytic procyanidin C1 alleviates renal fibrosis by promoting apoptosis of senescent renal tubular epithelial cells
Authors: Gan Yu , Wang Kangning , Chen Xiang , Li Yong , He Yao , Zhou Yan , Zhang Bo
Published: January 2025

Renal fibrosis is a common pathological process in various chronic kidney diseases. The accumulation of senescent renal tubular epithelial cells (TECs) in renal tissues plays an important role in the development of renal fibrosis. Eliminating senescent TECs has been proven to effectively reduce renal fibrosis. Procyanidin C1 (PCC1) plays a senolytic role by specifically eliminating senescent cells and extending its overall lifespan. However, whether PCC1 can alleviate unilateral ureteral obstruction (UUO)‐induced renal fibrosis and the associated therapeutic mechanisms remains unclear. Here, we observed a marked increase in senescent TECs within obstructed human renal tissue and demonstrated the positive correlation between the accumulation of senescent TECs and renal fibrosis in UUO‐induced renal fibrosis in mice. We found that PCC1 reduced the number of senescent TECs, restored the regenerative phenotype in kidneys with reduced fibrosis, and improved tubular repair after UUO‐induced injury. In vitro, PCC1 effectively cleared senescent HK2 cells by inducing apoptosis via ANGPTL4/NOX4 signaling. Incubation with culture medium from senescent HK2 cells promoted fibroblast activation, whereas PCC1 impeded profibrotic effects by downregulating senescence‐associated secretory phenotype (SASP) factors from senescent HK2 cells. Therefore, PCC1 alleviated interstitial renal fibrosis not only by clearing senescent TECs and improving tubular repair but also by indirectly attenuating myofibroblast activation by reducing the level of SASP. In summary, PCC1 may be a novel therapeutic senolytic agent for treating renal fibrosis.
Psychometric Properties of Entrustable Professional Activity–Based Objective Structured Clinical Examinations During Transition From Undergraduate to Graduate Medical Education: A Generalizability Study
Authors: Suneja Manish , Hanrahan Kate DuChene , Kreiter Clarence , Rowat Jane
Published: January 2025

Purpose

The objective structured clinical examination (OSCE) assesses clinical competence in health sciences education. There is little research regarding the reliability and validity of using an OSCE during the transition from undergraduate to graduate medical education. The goal of this study was to measure the reliability of a unique 2-rater Entrustable Professional Activity (EPA)–based OSCE format for transition to internship using generalizability theory for estimating reliability.

Method

During the 2018 to 2022 academic years, 5 cohorts of interns (n = 230) at the University of Iowa Hospital and Clinics participated in a 6-station OSCE assessment delivered during orientation. A univariate and multivariate generalizability study (G study) was conducted on the scores generated by the 3 cases in the orientation OSCE that shared the 2-rater format. This analysis was supplemented with an associated decision study (D study).

Results

The univariate G study for the cases that used a simulated patient and a faculty rater demonstrated that this OSCE generated a moderately reliable score with 3 cases. The D study showed that increasing the OCSE to 12 cases yielded a mean score reliable enough (G = 0.76) for making high-stakes normative decisions regarding remediation and readiness to practice. The universe score correlation between 2 types of raters was 0.398. The faculty ratings displayed a larger proportion of universe (true) score variance and yielded a more reliable (G = 0.433) score compared with the standardized patient ratings (G = 0.337).

Conclusions

This study provides insight into the development of an EPA-based OSCE. The univariate G study demonstrated that when using the 2 rater types, this assessment could generate a moderately reliable score with 3 cases. The multivariate G study showed that the 2 types of raters assessed different aspects of clinical skills, and faculty raters were more reliable.
Direct Neck Skin Excision for Correction of Aging Signs Confined to Skin Laxity and Sagging Skin in the Neck: A Local Anesthesia–Based Day Surgery Optimal for Younger Women
Authors: Okumuş Ayhan
Published: January 2025

BACKGROUND

The removal of excessive neck skin is considered the key parameter in the best postoperative outcome after a neck rejuvenation surgery.

OBJECTIVE

To evaluate the utility of a local anesthesia–based direct neck skin excision surgery in patients with skin laxity and sagging skin in the neck in terms of postoperative aesthetic outcome and patient satisfaction within a 12-month follow-up period.

MATERIALS AND METHODS

A total of 47 female patients who underwent local anesthesia–based direct neck skin excision surgery for the rejuvenation of skin laxity and sagging skin in the cervical neck were included. Data on complications and patient-reported outcomes were recorded at the 12th month postoperatively.

RESULTS

Postoperatively, none of the patients developed suture breakage or loosening, infection, or bleeding, while ecchymosis (21.3%) and hypertrophic scar (17.0%) were manageable. At the 12th postoperative month, 93.6% of patients reported improved appearance and high satisfaction with the postoperative outcome in terms of a sustained tighter appearance in the neck.

CONCLUSION

The local anesthesia–based direct neck skin excision surgery in patients with skin laxity and sagging skin in the neck enables achievement and maintenance of a tighter appearance in the neck, with minor and manageable complications and high patient satisfaction.
HBV and HBsAg strongly reshape the phenotype, function, and metabolism of DCs according to patients’ clinical stage
Authors: Dumolard Lucile , Gerster Theophile , Chuffart Florent , Decaens Thomas , Hilleret Marie-Noelle , Larrat Sylvie , Saas Philippe , Jouvin-Marche Evelyne , Durantel David , Marche Patrice N. , Macek Jilkova Zuzana , Aspord Caroline
Published: January 2025

Background:

Hepatitis B is a liver infection caused by HBV. Infected individuals who fail to control the viral infection develop chronic hepatitis B and are at risk of developing life-threatening liver diseases, such as cirrhosis or liver cancer. Dendritic cells (DCs) play important roles in the immune response against HBV but are functionally impaired in patients with chronic hepatitis B. The underlying mechanisms involved in HBV-induced DC dysfunctions remain to be elucidated.

Methods:

We explored DC modulations by HBV and HBsAg by exposing blood-derived cDC1s, cDC2s, and plasmacytoid DCs from healthy donors to HBV or HBsAg and stimulating them with toll-like receptor ligand. Their phenotypic and functional features, as well as their metabolic profile, were analyzed through multiparametric flow cytometry and multiplex assays and further explored on patients’ samples.

Results:

We found that HBV deeply reshaped the DC secretome in response to toll-like receptor ligand. Strikingly, we observed that HBV-exposed DCs secrete high levels of CX3CL1 (fractalkine), a chemokine responsible for attracting antiviral effectors to the site of infection. HBsAg exposure favored DC activation while drastically altering TRAIL expression in response to toll-like receptor ligand and increasing the secretion of cytokines/chemokines involved in immune tolerance. HBsAg further dampened the metabolism of DC subsets while driving metabolic switches. Notably, the relevance of the CX3CL1/CX3CR1 axis, TGF-β, and metabolic disturbances was demonstrated within intrahepatic DC subsets in patients according to disease stage.

Conclusions:

Our work brings new insights into the immunomodulation induced by HBV on DCs, which contribute to impaired antiviral responses and progression toward chronicity.
Individualizing musical tempo to spontaneous rates maximizes music-induced hypoalgesia
Authors: Yi Wenbo , Palmer Caroline , Serian Angela , Roy Mathieu
Published: January 2025

Music has long been recognized as a noninvasive and cost-effective means of reducing pain. However, the selection of music for pain relief often relies on intuition rather than on a scientific understanding of the impact of basic musical attributes on pain perception. This study examines how a fundamental element of music—tempo—affects its pain-relieving properties. One important finding in research on temporal dynamics of music is that people tend to sing or tap at a characteristic rate when asked to produce a simple melody. This characteristic rate, known as the spontaneous production rate (SPR), is consistent across different rhythm production tasks and may reflect the output of an endogenous oscillator. According to dynamical systems theory, SPRs represent optimal efficiency, minimizing energy expenditure while maximizing behavioral accuracy. This study examined whether aligning music tempo with individual SPRs could enhance the hypoalgesic effects of music. First, participants' SPRs were measured by asking them to produce a familiar melody at a comfortable rate. Next, they were asked to rate painful thermal stimulations under 4 conditions: music modified to match participants' SPR, music modified to be 15% faster or 15% slower than participants' SPR, and silence. Results revealed that musical tempos matching participants' SPR produced stronger reductions in pain compared to faster or slower tempo conditions, supporting the hypothesis that musical tempo aligned with individual rates is optimal for reducing pain. These findings underscore the individual-specific effects of musical tempo on pain perception, offering implications for personalized pain management strategies.
Reimagining Physician Assistant Education: Championing Cognitive Diversity to Promote Inclusivity, Neurodiversity Awareness, and a Sense of Belonging
Authors: George Tonya C. , Hudson Lillie , Brown Sheena D. , Coleman Veronica
Published: January 2025

Neurodiversity, encompassing conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and dyslexia, represents a significant and often under-recognized segment of the population, including within science, technology, engineering, mathematics, and medicine fields like medicine. Neurodiverse individuals possess unique skills, including enhanced creativity, analytical thinking, and meticulous attention to detail, which are valuable in health care professions. However, failure to recognize and support these individuals can result in missed opportunities, social isolation, and mental health challenges. Despite a growing emphasis on diversity, equity, inclusion, and belonging in higher education, neurodiversity is frequently overlooked, particularly in physician assistant (PA) education. This article examines the unique challenges faced by neurodiverse PA student learners and the existing literature gap regarding neurodiversity in PA education. It underscores the need for greater awareness, reduced stigma, and improved support systems. Recommendations include integrating neurodiversity into the PA curriculum, providing faculty training on inclusive teaching practices, and establishing tailored accommodations to foster a sense of belonging. PA programs can foster a more equitable health care system by creating inclusive learning environments that acknowledge and cater to the unique needs of neurodiverse student learners, thereby enhancing student-faculty interactions and promoting academic success. The aim of this article was to facilitate the reimagining of PA education to champion cognitive diversity. By promoting a more inclusive learning environment, PA programs can cultivate future clinicians who are better equipped to serve diverse patient populations.
Bots in white coats: are large language models the future of patient education? a multi-center cross-sectional analysis
Authors: Aghamaliyev Ughur , Karimbayli Javad , Zamparas Athanasios , Bösch Florian , Thomas Michael , Schmidt Thomas , Krautz Christian , Kahlert Christoph , Schölch Sebastian , Angele Martin K. , Niess Hanno , Guba Markus O. , Werner Jens , Ilmer Matthias , Renz Bernhard W.
Published: January 2025

Objectives:

Every year, around 300 million surgeries are conducted worldwide, with an estimated 4.2 million deaths occurring within 30 days after surgery. Adequate patient education is crucial, but often falls short due to the stress patients experience before surgery. Large language models (LLMs) can significantly enhance this process by delivering thorough information and addressing patient concerns that might otherwise go unnoticed.

Material and Methods:

This cross-sectional study evaluated ChatGPT-4o’s audio-based responses to frequently asked questions (FAQs) regarding six general surgical procedures. Three experienced surgeons and two senior residents formulated seven general and three procedure-specific FAQs for both preoperative and postoperative situations, covering six surgical scenarios (major: pancreatic head resection, rectal resection, total gastrectomy; minor: cholecystectomy, Lichtenstein procedure, hemithyroidectomy). In total, 120 audio responses were generated, transcribed, and assessed by 11 surgeons from six different German university hospitals.

Results:

ChatGPT-4o demonstrated strong performance, achieving an average score of 4.12/5 for accuracy, 4.46/5 for relevance, and 0.22/5 for potential harm across 120 questions. Postoperative responses surpassed preoperative ones in both accuracy and relevance, while also exhibiting lower potential for harm. Additionally, responses related to minor surgeries were minimal, but significantly more accurate compared to those for major surgeries.

Conclusion:

This study underscores GPT-4o’s potential to enhance patient education both before and after surgery by delivering accurate and relevant responses to FAQs about various surgical procedures. Responses regarding the postoperative course proved to be more accurate and less harmful than those addressing preoperative ones. Although a few responses carried moderate risks, the overall performance was robust, indicating GPT-4o’s value in patient education. The study suggests the development of hospital-specific applications or the integration of GPT-4o into interactive robotic systems to provide patients with reliable, immediate answers, thereby improving patient satisfaction and informed decision-making.
Performance of sentinel lymph node biopsy after neoadjuvant chemotherapy in clinically node positive breast cancer patients: systematic review and meta-analysis
Authors: Zahwe Mariam , Ghzaiel Abir , Najia Ahmad , Soueid Lara , Asmar Khalil El , Ghezzawi Malak , Iskandarani Sarah El , Diab Marwa , Jibbawi Miryam El , Hoteit Reem , Sbaity Eman
Published: January 2025

Background:

The reliability of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NACT) in patients with initially node-positive breast cancer is still controversial. This meta-analysis is conducted to investigate the feasibility and accuracy of SLNB after NACT in patients with initially positive axillary nodes.

Methods:

We conducted a literature search using Medline, PubMed, Embase, Central, and SCOPUS up until April 2021 for studies on the performance of SLNB following NACT. We included prospective studies including breast cancer patients with positive lymph nodes at diagnosis and received NACT before undergoing SLNB irrespective of their molecular subtypes or stage. Our main outcomes of interest were the identification rate (IR) and the false negative rate (FNR) of SLNB.

Results:

We included an aggregate of 33 studies in this meta-analysis enrolling 4,624 patients. The reported IR ranged from a minimum of 77.6% to a maximum of 100% and resulted in a pooled IR of 88% (95%CI: 86-90, I2:80.9%). The FNR reported in the studies ranged from a minimum of 5.1% to a maximum of 43% and showed a pooled FNR of 13% (95% CI: 11-15, I2: 72.31%). The subgroup analysis demonstrated that the usage of dual mapping technique could decrease the FNR and increase the IR. Moreover, the number of lymph nodes retrieved inversely correlated with FNR (p<0.01).

Conclusion:

Our findings support the feasibility and accuracy of SLNB after NACT in initially node-positive breast cancer patients, that converted to clinically node negative when performed in properly selected cases. SLNB offers a less invasive approach in selected patients sparing them the morbidity associated with ALND. This approach aligns with efforts to de-escalate surgical management in breast cancer and reinforces that SLNB post-NACT should be incorporated into clinical practice, provided that stringent patient selection and procedural standards are maintained.
The Impact of Physical Therapy Postprofessional Education Programs on Productivity in a Large Academic Medical Center
Authors: DeWitt John J. , Weber Mark D. , Tichenor Carol Jo , Farrell Joseph P. , Kidder Melissa S. , Olson-Kellogg Becky J. , Hensley Craig P. , Harrington Kendra L. , Briggs Matthew S.
Published: January 2025

Introduction.

Emerging evidence shows positive impact of postprofessional physical therapy education (residency and fellowship) specific to participants; however, outcomes on organizational impact are largely unknown. The purpose of this project was to describe the impact residency and fellowship training has on financial metrics. A secondary purpose of this case study was to describe trends associated with higher productivity.

Review of Literature.

Previous studies have demonstrated positive professional behavior and generalized operational impact of postprofessional education. No studies have evaluated the impact of residency and fellowship training on individual physical therapist (PT) productivity.

Subjects.

Individual productivity from 191 PTs was collected over a 10-year time frame from a large, ambulatory, rehabilitation department within an academic medical center. Productivity was compared between 4 groups: nonresidency- or fellowship-trained clinicians; residency-trained clinicians; fellowship-trained clinicians; and dual residency and fellowship–trained clinicians.

Methods.

Physical therapists' productivity data were manually extracted retrospectively from operational reports over a 10-year period. Additional data elements extracted included the following: board specialty certification and years employed at the medical center. Data were then categorized as nonresidency/fellowship -trained, residency trained, fellowship trained, or dual residency and fellowship trained. Data were analyzed using descriptive statistics and 1-way analysis of variance (ANOVA).

Results.

Forty-five clinicians with postprofessional training collectively produced $253,617 more in financial annual return to the organization. Fellowship-trained clinicians demonstrated the highest productivity followed by residency-trained and dual residency and fellowship–trained clinicians. Specialty board certification also positively increased productivity regardless of postprofessional training.

Discussion and Conclusion.

Postprofessional training within physical therapy continues to be evaluated in the spectrum of professional development. Evidence supports positive professional behaviors and patient outcomes; however, little is known regarding its impact on productivity metrics. Although no significance was found between the groups with and without postprofessional training, meaningful financial return was demonstrated in clinicians with postprofessional training. The lack of significance may have been influenced by compression because of departmental productivity guidelines. This preliminary data may assist organizations in justifying resources for sustaining and sponsoring future programs.
The disparities of PrEP adherence among men who have sex with men between the Global South and the Global North: An updated determinantal global meta-analysis
Authors: Wang Haoyi , Delnoij Marit , Zimmermann Hanne M.L. , Jonas Kai J.
Published: January 2025

Background:

Suboptimal adherence to PrEP limits its global impact, with current evidence mostly from the Global North and lacking Global South perspectives. This meta-analysis synthesises the rates and determinants of suboptimal adherence to oral PrEP among MSM in both regions.

Methods:

We searched for literature describing PrEP adherence and its determinants among MSM globally up until October 2024 to conduct a meta-analysis on the rate and determinants of suboptimal adherence in both regions. The definition of (sub-)optimal adherence were study-based.

Results:

We included 82 studies in the meta-analysis, with 24, 53, and 5 stemmed from the Global South, North, and global multicentre studies, respectively. Oral PrEP suboptimal adherence is prevalent among MSM PrEP-users globally (rate=0.33, 95%CI:0.28-0.38) with a significantly higher rate (p=0.021) in the Global South (rate=0.41, 95%CI:0.33-0.50) compared to the Global North (rate=0.29, 95%CI:0.23-0.35). In the Global South, older age (OR=0.57, 95%CI:0.37-0.87), alcohol use (OR=1.28, 95%CI:1.02-1.60) and presenting depressive symptoms (OR=1.47, 95%CI:1.01-2.16) were associated with suboptimal adherence. In the Global North, MSM self-identified as Black (OR=2.27, 95%CI:1.31-3.95) or Other (OR=1.36, 95%CI:1.02-1.81), having a university degree (OR=0.50, 95%CI:0.34-0.73), and presenting depressive symptoms (OR=2.26, 95%CI:1.35-3.78) were associated with suboptimal adherence. On-demand PrEP-users globally demonstrated a higher likelihood of suboptimal adherence (OR=1.59, 95%CI:1.18-2.14).

Conclusions:

Suboptimal adherence to oral PrEP is prevalent among MSM globally, particularly higher in the Global South. Regional differences in determinants highlight the need for tailored interventions. Tailored interventions are required to address mental health with tailored efforts to younger MSM in the Global South, while interventions in the Global North should be tailored to specific sub-groups.
Psychosocial Determinants and Outcomes of Expedited Liver Transplant Evaluations: Insights From a Retrospective Cohort Analysis
Authors: Cooper Katherine M. , Srivoleti Padmavathi , Colletta Alessandro , Tripp Doris , Mehta Savant , Movahedi Babak , Devuni Deepika
Published: January 2025

Background.

As the burden of chronic liver disease and the demand for liver transplants (LT) grows, understanding the interplay between access to care and patient outcomes is increasingly important. In this study, we explored patient characteristics and transplant outcomes in patients undergoing LT evaluations, with a focus on identifying risk factors for expedited LT evaluation.

Methods.

This single-center retrospective cohort study included patients who underwent LT evaluation for deceased donor LT between October 2017 and July 2021. Patients were categorized by context: expedited (inpatient) and routine (outpatient) LT evaluation groups. The outcome measures included waitlist status, pre-LT mortality, and post-LT complications.

Results.

Of 602 patients, 26% underwent expedited LT evaluation. Patients who underwent expedited evaluation were more likely to have a history of ascites (P < 0.001), hepatic encephalopathy (P < 0.001), and spontaneous bacterial peritonitis (P < 0.001) and had a higher model for end-stage liver disease sodium scores (P < 0.001). Both mortality (35% versus 17%, P < 0.001) and LT (39% versus 22%, P < 0.001) were more common in the expedited group; post-LT mortality was similar up to 2 y. Perceived financial concerns and social security disability income were risk factors for expedited LT evaluation. In addition, greater proximity to the LT center (95% confidence interval, 1.1-6.3; P = 0.025) and speaking a primary language other than English (95% confidence interval, 1.0-10.7; P = 0.042) were risk factors for expedited LT evaluation in women but not in men.

Conclusions.

Expedited LT evaluations were associated with more severe illness and higher pre-LT mortality; however, post-LT outcomes were comparable with those of routine evaluations. Identifying psychosocial risk factors may enhance equity and access to LT evaluations, particularly for women who face unique challenges in this context.
Prevalence and Clinical Associations of Peripapillary Hyperreflective Ovoid Mass-like Structures in Craniosynostosis
Authors: Jeon-Chapman Jacqueline G. , Estrela Tais , Zurakowski David , Chang Yoon-Hee , Dagi Linda R. , Gise Ryan A.
Published: January 2025

Background:

Patients with craniosynostosis are at high risk of developing elevated intracranial pressure (ICP) causing papilledema and secondary optic atrophy. Diagnosing and monitoring optic neuropathy is challenging because of multiple causes of vision loss including exposure keratopathy, amblyopia, and cognitive delays that limit examination. Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are an optical coherence tomography (OCT) finding reported in association with papilledema and optic neuropathy. We investigated the prevalence of PHOMS in patients with syndromic craniosynostosis and the relationship with known risk factors of optic neuropathy.

Methods:

This was a cross-sectional retrospective study was performed at Boston Children's Hospital and included 118 eyes (60 patients) with syndromic craniosynostosis that had at least one good quality optic nerve OCT volumetry scan between January 2010 and December 2023. Testing was reviewed by 2 neuro-ophthalmologists to determine the presence of PHOMS. Information collected included demographics, and clinical course including possible Chiari malformation, obstructive sleep apnea (OSA), history of elevated ICP, best-corrected visual acuity (VA), spherical equivalent (SE), retinal nerve fiber layer thickness, macular ganglion cell layer volume, and funduscopic examination. Our primary outcome measure was presence of PHOMS, and secondary outcome measure was the relationship between clinical characteristics and the presence of PHOMS.

Results:

Mean age at imaged OCT was 9.8 ± 5.2 years and 41/60 (68.3%) patients were female. The prevalence of PHOMS was 17/60 patients (28.3%) or 26/118 eyes (22.0%), higher than previously reported in children without craniosynostosis (P < 0.001). PHOMS were significantly associated with a history of elevated ICP (odds ratio [OR] 14.4, 95% CI: 1.9–111.0, P < 0.001) and with concurrent papilledema (OR 40.4, 95% CI: 6.6–248.0, P < 0.001). OSA, Chiari malformation, best-corrected VA, craniosynostosis variant, and SE were not independently associated with PHOMS.

Conclusions:

Eyes in children with craniosynostosis had a higher prevalence of PHOMS than reported in children without craniosynostosis. PHOMS were significantly more common with a history of elevated ICP and with concurrent papilledema. PHOMS may serve as a clinically useful indicator of optic neuropathy, and of recurrence of papilledema in patients with craniosynostosis and in other populations characterized by multiple sources of vision loss and cognitive changes that limit evaluation.
Mechanistic models of humoral kinetics following COVID-19 vaccination
Authors: Stocks Daniel , Thomas Amy , Finn Adam , Danon Leon , Brooks-Pollock Ellen
Published: January 2025

COVID-19 vaccine programmes must account for variable immune responses and waning protection. Existing descriptions of antibody responses to COVID-19 vaccination convey limited information about the mechanisms of antibody production and maintenance. We describe antibody dynamics after COVID-19 vaccination with two biologically motivated mathematical models. We fit the models using Markov chain Monte Carlo to seroprevalence data from 14 602 uninfected individuals in England between May 2020 and September 2022. We analyse the effect of age, vaccine type, number of doses and the interval between doses on antibody production and longevity. We find evidence that individuals over 35 years old twice vaccinated with ChAdOx1-S generate a persistent antibody response suggestive of long-lived plasma cell induction. We also find that plasmablast productive capacity is greater in: younger people than older people (≤4.5-fold change in point estimates); people vaccinated with two doses than one dose (≤12-fold change); and people vaccinated with BNT162b2 than ChAdOx1-S (≤440-fold change). We find the half-life of an antibody to be 23–106 days. Routinely collected seroprevalence data are invaluable for characterizing within-host mechanisms of antibody production and persistence. Extended sampling and linking seroprevalence data to outcomes would enable conclusions about how humoral kinetics protect against disease.
The first illustration of an insect brain: Swammerdam on the honeybee (with an unedited autograph)
Authors: Strazzoni Andrea
Published: January 2025

This paper offers an analysis of Johannes Swammerdam’s researches on the brain of the honeybee (
Apis mellifera
), on the basis both of his published texts and of (1) an early, manuscript version of his treatise on bees (broadly intended) (1673), and (2) a hitherto unedited autograph of his, containing the earliest depiction and description of an insect brain (1673–1677). Through a reconstruction of the genesis of Swammerdam’s texts on bees, both the novelty and accuracy of his observations are highlighted, as well as his reliance on a Cartesian physiology in the interpretation and rendering of the observed parts.
The shortest telomere in telomerase-negative cells triggers replicative senescence at a critical threshold length and also fuels genomic instability
Authors: Berardi Prisca , Martinez-Fernandez Veronica , Rat Anaïs , Rosas Bringas Fernando R. , Jolivet Pascale , Langston Rachel , Mattarocci Stefano , Maes Alexandre , Aspert Théo , Zeinoun Bechara , Casier Karine , Kazemier Hinke G. , Charvin Gilles , Doumic Marie , Chang Michael , Teixeira Maria Teresa
Published: January 2025

In the absence of telomerase, telomere shortening triggers the DNA damage checkpoint and replicative senescence, a potent tumor suppressor mechanism. Paradoxically, this same process is also associated with oncogenic genomic instability. Yet, the precise mechanism that connects these seemingly opposing forces remains poorly understood. To directly study the complex interplay between senescence, telomere dynamics and genomic instability, we developed a system inSaccharomyces cerevisiaeto generate and track the dynamics of telomeres of precise length in the absence of telomerase. Using single-telomere and single- cell analyses combined with mathematical modeling, we identify a threshold length at which telomeres switch into dysfunction. A single shortest telomere below the threshold length is necessary and sufficient to trigger the onset of replicative senescence in a majority of cells. At population level, fluctuation assays establish that rare genomic instability arises predominantly incisto the shortest telomere as non-reciprocal translocations that result in re- elongation of the shortest telomere and likely escape from senescence. The switch of the shortest telomere into dysfunction and subsequent processing in telomerase-negative cells thus serves as the mechanistic link between replicative senescence onset, genomic instability and the initiation of post-senescence survival, explaining the contradictory roles of replicative senescence in oncogenesis.
A CD57+ cytotoxic CD8 T cell subset associated with fibrotic lung disease in systemic sclerosis
Authors: Sasaki Takanori , Cao Ye , Marks Kathryne , Higashioka Kazuhiko , Elahee Mehreen , Ainsworth Richard , Taylor Kim , Bottini Nunzio , Wolters Paul , Kamiya Mari , Kim Edy Y. , Boin Francesco , Rao Deepak A.
Published: January 2025

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc); however, the immunopathologic mechanisms driving lung disease in SSc are unclear. T cells have been implicated as a likely driver of lung injury in SSc. Here, we have evaluated T cells in blood and lungs of patients with SSc-ILD and identified a specific population of cytotoxic CD8 T cells that is expanded in SSc-ILD patients. Cytotoxic effector memory CD8 T cells marked by CD57 expression are preferentially expanded in SSc-ILD patients compared to SSc patients without ILD and controls and show prominent clonal expansion. These CD57+ T effector memory (TEM) cells differ from T effector memory cells re-expressing CD45RA (TEMRA) transcriptomically and functionally, with cytotoxic function that is enhanced by CD155 engagement of the costimulatory receptor CD226. Analyses of cells from ILD lungs indicate endothelial cells as a likely source of CD155 to activate CD57+ cytotoxic T cells. Together, the results implicate a CD57+ cytotoxic CD8 T cell population as a potential mediator of lung injury in SSc-ILD.
Xist RNA Dependent and Independent Mechanisms Regulate Dynamic X Chromosome Inactivation in B Lymphocytes
Authors: Toothacre Natalie E. , Rodríguez-Acevedo Kiara L. , Wiggins Keenan J. , Scharer Christopher D. , Anguera Montserrat C.
Published: January 2025

X-Chromosome Inactivation (XCI) involves epigenetic pathways to equalize X-linked gene expression between female and male mammals. XCI is dynamic in female B cells, as cytological enrichment of Xist RNA and heterochromatic marks on the inactive X-chromosome (Xi) are absent in naïve B cells yet return following mitogenic stimulation. Here, we asked whether any heterochromatic histone marks are present on the Xi in naïve B cells, and whether Xist RNA is required for their deposition and retention following stimulation. We find that the Xi in naïve B cells is depleted for H2AK119Ub and H3K9me3 but enriched for DNA methylation and H3K27me3, which maintain an Xist RNA-dependent epigenetic memory of XCI. Upon stimulation, Xist-independent H3K27me3 and Xist-dependent H2AK119Ub modifications accumulate across the Xi with temporal and spatial specificity. Our findings reveal the importance of Xist RNA, H3K27me3, and H2AK119Ub marks for the epigenetic integrity of X-linked genes across the Xi following female B cell stimulation.
JRSeek: Artificial Intelligence Meets Jelly Roll Fold Classification in Viruses
Authors: Sanchez Jason E. , Guo Wenhan , Li Chunqiang , Li Lin , Xiao Chuan
Published: January 2025

The jelly roll (JR) fold is the most common structural motif found in the capsid and nucleocapsid of viruses. Its pervasiveness across many different viral families motives developing a tool to predict its presence from a sequence. In the current work, logistic regression (LR) models trained on six different large language model (LLM) embeddings exhibited over 95% accuracy in differentiating JR from non-JR sequences. The dataset used for training and testing included sequences from single JR viruses, non-JR viruses, and non-virus immunoglobulin-like β-sandwich (IGLBS) proteins which closely resemble the JR fold in structure. The high accuracy is particularly remarkable given the low sequence similarity across viral families and the balanced nature of the dataset. Also, the accuracy of the models was independent of LLM embeddings, suggesting that peak accuracy for predicting viral JR folds hinges more on the data quality and quantity rather than on the specific mathematical models used. Given that many viral capsid and nucleocapsid structures have yet to be resolved, using sequence-based LLMs is a promising strategy that can readily be applied to available data. Principal Component Analysis of the Bert-U100 embeddings demonstrates that most IGLBS sequences and a subset of JR and non-JR sequences are distinguishable even before the application of the LR model, but the LR model is necessary to differentiate a subset of more ambiguous sequences. When applied to double JR folds, the Bert-U100 model was able to assign the JR motif for some viral families, providing evidence for the model’s generalizability. However, for other families, this generalizability was not observed, motivating a future need to develop other models informed by double JR folds. Lastly, the Bert-U100 model was also able to predict whether sequences from a dataset of unclassified viruses produce the JR fold. Two examples are given and the JR predictions are corroborated by AlphaFold3. Altogether, this work demonstrates that JR folds can, in principle, be predicted from their sequences.
Synthetic Mucins as Glycan-Defined Prebiotics
Authors: Alty Jill W , Barnes Carolyn E. , Nicoli Agnese , Turner Bradley , Beneman Ekua A , Dugan Amanda E , Brucks Spencer D , Kruger Austin G , Schrock Richard R , Ribbeck Katharina , Kiessling Laura L
Published: January 2025

The human microbiome contains at least as many bacterial cells as human cells. The mucosal layer that lines all epithelial cells organizes, cultivates, and regulates these bacterial inhabitants. Some commensal bacteria offer benefits, like improving gut barrier function, suppressing pathobiont growth, and modulating host immunity. These health benefits have fueled the popularity of probiotics, but their retention is often hindered by their low colonization efficiency and mucosal adhesion. Mucins, the primary structural components of the mucosal layer, are essential for the organization and regulation of microbial populations, promoting growth and offering sites for adhesion through their multivalent presentation of O–glycosylation. The molecular mechanisms of mucin-probiotic interactions remain understudied due, in part, to the inability to incisively manipulate native mucin sequences or the glycans they bear. In this investigation, we developed synthetic mucins with defined glycan presentations to interrogate glycan–dependent interactions between mucus and probiotic Lactobacillus species. Though synthetic mucins can dampen the effects of pathogens, toxins, and viruses, their impact on probiotic bacteria as prebiotics or binding sites is unclear. We synthesized mucin surrogates that bind to three investigated Lactobacillus species. The nutrient conditions under which bacteria were cultured influenced glycan binding preferences, suggesting mucin–probiotic interactions change with nutrient availability. The addition of synthetic mucins to native mucin increased Lactobacillus fermentum adherence. Additionally, an increase in Lactobacillus glycosidase activity indicated that native and synthetic mucins function as prebiotics, as probiotic bacteria can cleave the displayed O–glycans. Thus, synthetic mucins can cultivate target probiotic bacteria and increase adhesion as binding sites, highlighting their value as tools for elucidating native mucin functions and as promising agents for promoting human health.
Therapeutic ability of extracellular vesicles derived from angio-miRNA-modified mesenchymal stromal cells in ischemic animal models
Authors: Wada Yoshiki , Kudo Toshifumi , Kusakabe Tomomi , Inoue Ayako , Yoshioka Yusuke , Ochiya Takahiro , Fukuda Shoji
Published: January 2025

Background

Regenerative therapy using extracellular vesicles (EVs) is expected to be an option for supportive therapy of chronic limb-threatening ischemia. In this study, we examined the angiogenic potential of EVs derived from genetically modified MSCs, focusing on the angio-miRNAs in these vesicles.

Methods

Bone marrow mesenchymal stromal cells (BM-MSCs) were transfected with a lentiviral vector containing specific angio-miRNAs (miRNA-126, -135b, or -210). EVs were separated from the culture medium of BM-MSCs via ultracentrifugation. The quality and quantity of the EVs were evaluated using nanoparticle tracking analysis, fluorometry, and an ExoScreen assay. Tube formation assays were conducted using human umbilical vein endothelial cells to assess the angiogenic potency of the EVsin vitro. The EVs were injected into the ischemic hind limb muscles of mice. The grades of limb ischemia, blood perfusion, and muscle tissues were analyzed to assess the angiogenic potency of the EVsin vivo.

Results

Angio-miRNAs were overexpressed in MSCs transfected with a lentiviral vector. Tube formation was significantly enhanced when endothelial cells were cultured with the EVs (P < 0.05). Compared to non-contact co-culture with BM-MSCs, EVs derived from modified BM-MSCs significantly promoted tube formation in endothelial cells (P < 0.05). The severity of limb ischemia on day 7 was alleviated when a combination of two or three EVs derived from modified BM-MSCs was injected compared with native EVs. Toe blood perfusion on day 14 significantly recovered when a combination of two or three EVs derived from modified BM-MSCs was injected (P < 0.05). Tissue analysis revealed that the number of newly formed endothelial cells in ischemic muscles increased when a combination of two or three EVs derived from modified BM-MSCs was injected.

Conclusions

The use of a combination of EVs derived from genetically modified MSCs stimulated angiogenesis bothin vitroandin vivo.
Genotype-Dependent Response to Water Deficit: Increases in Maize Cell Wall Digestibility Occurs Through Reducing Both p-Coumaric Acid and Lignification of the Rind
Authors: López-Malvar Ana , Main Oscar , Guillaume Sophie , Jacquemot Marie-Pierre , Meunier Florence , Revilla Pedro , Santiago Rogelio , Mechin Valerie , Reymond Matthieu
Published: January 2025

The compositional dynamics of the cell wall are influenced by drought, and it has been demonstrated that water deficit induces significant changes in its main components. Moreover, changes in cell wall concentration and distribution in response to water deficit affect maize degradability. This study presents a histological and biochemical analysis of thirteen maize inbred lines, evaluated over two years in Pobra de Brollón (Spain) and Mauguio (France) under contrasting water availability conditions. Our aim was to investigate the environmental and genotypic impacts on histological and biochemical profiles, to assess in vitro cell wall digestibility under water deficit, and to explore how these responses relate to changes in cell wall composition and structure. Overall, we observed greater concentrations of p-coumaric acid under control conditions, with significant decreases in stressed conditions at each location. Histologically, we found an increase in non-lignified tissues under water deficit conditions across all tissues and in both locations. In terms of in vitro cell wall digestibility (IVCWRD), significant increases were detected in response to water deficit. Additionally, genotype-dependent response patterns were evident, revealing two distinct behavioural groups. Notably, in plastic genotypes, increases in IVCWRD in response to water deficit were concomitant to reductions in p-coumaric acid content and a decrease in red-stained lignified tissues in the rind. This study emphasizes the complex, genotype-dependent responses to water deficit, underscoring the important roles of plasticity and stability in shaping the impact on maize cell wall digestibility; paving the way to breed for adapted genotypes to face climate changes.

Highlight

Increased digestibility in response to water deficit is genotype-dependent and linked to reductions in p-coumaric acid content and lower lignification of the rind
The spectrum of gene intolerance to variation: Insights from a rare disease cohort
Authors: Cacheiro Pilar , Marengo Gabriel , Gorkin David U. , Peterson Kevin A. , Loskove Yonina , Murray Stephen A. , Smedley Damian
Published: January 2025

Deciphering the spectrum of intolerance to loss-of-function (LoF) variation helps identify genes that are critical at various stages of development and hierarchical levels of organisation. We have previously combined cell and mouse viability screens for single-gene knockouts, to summarise this spectrum into discrete categories, Full Spectrum of Intolerance to Loss-of-function (FUSIL), from genes essential for cell proliferation to those where LoF has no phenotypic impact. Here, we expand on this analysis to uncover distinct patterns in gene expression across developmental stages in both mouse and human within these categories, as well as gene sequence and evolutionary features, protein functional classes, and disease associations. Further, by analysing data from diagnosed patients in a rare disease cohort, we gain insights into the relationships between variant de novo status, molecular consequence, mode of inheritance, and type of disorder in the FUSIL categories. These associations facilitate the identification of predicted pathogenic variants in genes not currently linked to Mendelian conditions.
Long Noncoding RNA Mir17hg and D43Rik Control the Macrophage Response toToxoplasma gondiiInfection
Authors: Doherty Claire M. , Belmares-Ortega Jessica , Haskins Breanne E. , Menard Kayla L.
Published: January 2025

Long noncoding (lnc) RNAs are emerging as imported regulators of immunity but how they impact the host response to infection is still largely unknown. In previous screening studies we identified Mir17hg and D43Rik as host lncRNAs upregulated in mouse bone marrow-derived macrophages regardless of parasite strain type. Here, we examined the impact of Mir17hg and D43Rik during infection of macrophages. Expression of these lncRNAs was transiently increased byT. gondii, peaking 6 hr post infection and falling to background noninfected levels by 18 hrs. Both Mir17hg and D43Rik were predominantly localized to the host cell nucleus, suggesting roles in gene regulation. Using a lncRNA silencing approach mediated by siRNA, we uncovered evidence that both D43Rik and Mir17hg were involved in modulating the host transcriptional response to infection with Type I and Type II strains ofToxoplasma. These effects were most dramatic during infection with the high virulence Type I RH, where Mir17hg silencing resulted in increased expression of a broad panel of immunity-related genes. Our results implicate lncRNAs Mir17hg and D43Rik as important molecular regulators of the macrophage response toToxoplasma.
Heartbeat-like dynamics drives oxygen activation in methane monooxygenase
Authors: Hwang Yunha , Ryu Bumhan , Lee Dong-Heon , Hong Hyo Jin , Na Jeong-Geol , Song Chul Gyu , Kang Hyun Goo , Pozharski Edwin , Lee Seung Jae
Published: January 2025

Soluble methane monooxygenase (sMMO) is an enzyme that hydroxylates methane (CH4), a potent greenhouse gas, at non-heme di-iron active sites under atmospheric conditions. The regulatory component (MMOB) is essential for the catalytic activity of hydroxylase (MMOH) as it induces conformational changes in the active site and facilitating substrate ingress. Recent advances in cryogenic electron microscopy (cryo-EM) have enabled us to elucidate the high resolution picture of sMMO catalytic mechanism. We describe the 2.85 Å cryo-EM structure of MMOH–MMOB, with one equivalent of MMOB bound to MMOH (H-1B), which is in contrast with previously solved crystal structures. MMOB allosterically regulates the MMOH protomer (αβγ) and induces conformational changes that propagate from the surface to the di-iron coordination site. TheN-terminal region of the MMOH β-subunit (NT-Hβ) stabilizes helices essential for iron coordination and oxygen activation. The MMOB-bound protomer (HBA, αβγB) presents the first structural report of a 2.7 Å Fe···Fe distance, while the non-MMOB-bound protomer (HBB, αβγ) and MMOH display a 3.1 Å distance. The coordination of Fe–ligands is maintained by the structural stabilization provided by the β- and γ-subunits of MMOH. This novel cryo-EM structure reveals new coordination environments, offering crucial mechanistic insights into sMMO catalysis.