bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiographic Measurements of Pes Planovalgus Do Not Predict Clinical Outcomes in Tarsal Coalition Excision
Authors: Rushin Claire , Mo Michelle , Miller Patricia E. , Spencer Samantha , Mahan Susan T.
Published: October 2024

Objective:

Many patients who undergo tarsal coalition excision have persistent postoperative pain. Most studies have utilized cat scan (CT) scan parameters of pes planovalgus and heel valgus but have found this to be an inconsistent predictor of outcomes. Plain radiographic parameters have been less utilized in trying to predict outcomes after coalition excision. Radiographic talonavicular coverage angle correlates with pain in patients with flexible pes planovalgus (PPV) but has not been studied in tarsal coalition population. Furthermore, foot alignment is not understood to change after simple coalition excision. The purpose of this study was to compare plain radiographic parameters, including talonavicular coverage angle, with pain after tarsal coalition excision, as well as compare preoperative and postoperative weight-bearing radiographs.

Methods:

Seventy-seven feet that underwent excision of the tarsal coalition had clinical outcomes and radiographic data collected >1 year postoperatively. Measures of PPV on preoperative and postoperative weight-bearing radiographs and CT scans were evaluated.

Results:

Patients were an average of 13 years old at excision. Of the total, 65% had calcaneonavicular (CN) coalitions, whereas the remainder had talocalcaneal coalitions. All patients had significant postoperative improvement in clinical outcomes but 34% (13/38) had continued pain at the most recent follow-up, more so in talocalcaneal than CN coalitions (55% vs 26%, P < 0.001). The subset with CN coalitions had more severe preoperative PPV but greater postoperative PPV improvement. Except for a weak correlation between radiographic weight-bearing (anterior-posterior) talus-first metatarsal angle and pain with activity (r = -0.54), there were no other correlations between preoperative radiographic parameters and clinical outcomes. Heel valgus on CT did not correlate with radiographic measurements of PPV or pain.

Conclusions:

We did not find a correlation of radiographic PPV with persistent pain after tarsal coalition excision. We did find improvement in radiographic PPV in CN coalitions after treatment with simple excision. Heel valgus on CT was not a useful metric for evaluating PPV in the setting of a tarsal coalition.

Level of Evidence:

Level III—prognostic study.
Robot-assisted kidney transplantation: initial experience from a tertiary hospital in China
Authors: Zhang Mingxiao , Ding Zhenshan , Zhao Ying , He Yuhui , Deng Yisen , Zhang Tianyu , Shen Congrong , Cao Chuanzhen , Wang Jianfeng
Published: October 2024

Background

Robot-assisted kidney transplantation (RAKT) has currently become an effective alternative to open kidney transplantation (OKT), which has long been considered the gold standard for kidney transplant surgery. This study aimed to summarize our initial experience with RAKT and explore its safety and feasibility.

Materials and methods

Ten cases of RAKT, including 8 cases of deceased-donor kidney transplantation and 2 cases of living-donor kidney transplantation, were performed at our center from March 2023 to November 2023. Perioperative clinical data and follow-up results of patients were collected and statistically analyzed.

Results

All RAKT surgeries were performed successfully with no complications. The average operative time was 297.90 ± 65.59 minutes, and the median estimated blood loss was 100 mL. The average serum creatinine level decreased from 918.14 ± 166.63 μmol/L preoperatively to 109.89 ± 29.89 μmol/L at discharge. The postoperative outcomes of RAKT from both deceased and living donors were satisfactory during the follow-up period.

Conclusions

RAKT is an effective alternative to OKT and is suitable for both deceased- and living-donor kidney transplantations. The postoperative outcomes were satisfactory, and the postoperative complications were acceptable. RAKT appears to be a safe and feasible procedure for transplantation teams skilled in OKT and robot-assisted surgery.
Updating probability of pathogenicity for RYR1 and CACNA1S exon variants in individuals without malignant hyperthermia after exposure to triggering anesthetics
Authors: Roberts David A. , Bastarache Lisa , He Jing , Lewis Adam , Aka Ida T. , Shotwell Matthew S. , Reddy Srijaya K. , Hogan Kirk J. , Biesecker Leslie G. , Kertai Miklos D.
Published: October 2024

Objectives

We aimed to classify genetic variants in RYR1 and CACNA1S associated with malignant hyperthermia using biobank genotyping data in patients exposed to triggering anesthetics without malignant hyperthermia phenotype.

Methods

We identified individuals who underwent surgery and were exposed to triggering anesthetics without malignant hyperthermia phenotype and who had RYR1 or CACNA1S genotyping data available in our biobank. We classified all variants in the cohort using a Bayesian framework of the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists guidelines for variant classification and updated the posterior probabilities from this model with the new information from our biobank cohort.

Results

We identified 253 patients with 95 RYR1 variants and 12 CACNA1S variants. After applying a Bayesian framework, we classified 17 variants as benign (B), 31 as likely benign (LB), 57 as uncertain (VUS), and 2 as likely pathogenic (LP). When we incorporated evidence about unique exposures to malignant hyperthermia triggering anesthetic agents, 48 of 107 (45%) variants were downgraded (9 to B, 37 to LB, and 2 to VUS). Notably, 41 (72%) of 57 VUSs were downgraded to B or LB. When repeat anesthetics in the same individual were counted as one exposure, 42 of 107 (39%) of variants were downgraded (5 to B, 35 to LB, and 2 to VUS). Specifically, 37 (65%) of 57 VUSs were downgraded to LB.

Conclusion

Deidentified biorepositories linked with anesthetic data offer a new method of integrating clinical evidence into the assessment of variant probability of pathogenicity.
Development of Domains of Competence and Competencies for Physical Therapist Education
Authors: Ambler Steven B. , Burlis Tamara L. , Clark B. Ruth , Holtzman Gregory W. , McGee Patricia Navarro , Frost Jody S. , Randolph Jessica L. , Norton Barbara J. , Holleran Carey L.
Published: October 2024

Background and Purpose.

Competency-based education (CBE) has been gaining widespread acceptance as a viable method for transforming education within health professions. The purpose of this report is to describe the process we used to develop a set of domains of competence and associated competencies for physical therapists. The catalyst for this effort was our desire to implement CBE as part of the major renewal of our Doctor of Physical Therapy curriculum.

Method/Model Description and Evaluation.

We developed a draft set of domains and competencies for physical therapists by considering the future of physical therapy and relevant CBE literature. Next, we used a multistep survey-and-revise process to develop consensus on the appropriateness and clarity of each domain and competency. Surveys were repeated until an 85% threshold level of agreement was achieved for each domain and competency. Between rounds of the surveys, the Competency and Entrustment Writing Team reviewed feedback and edited items accordingly.

Outcomes.

The writing and feedback processes resulted in consensus on a total of 57 competencies, organized into 8 domains of competence.

Discussion and Conclusion.

The development of defined outcomes for physical therapist education (PTE) through domains and competencies provides a framework for a broader effort to re-envision PTE. Careful attention to ensuring that the framework uses shared language across professions has the potential to enhance health care and the health of society.
Safety and Efficacy of Rigid Bronchoscopy-guided Percutaneous Dilational Tracheostomy
Authors: Murn Michael , Burbano Alma V. , Lara Juan C. , Swenson Kai , Beattie Jason , Parikh Mihir , Majid Adnan
Published: October 2024

Background:

Percutaneous dilational tracheostomy (PDT) is commonly performed by a broad spectrum of practitioners. Aside from relative contraindications such as morbid obesity, coagulopathy, and complex airway anatomy, it is preferred over surgical tracheostomy in the critically ill. Rigid bronchoscopy-guided (RBG) PDT provides a secure airway, allows for unobstructed ventilation, protects the posterior membrane from puncture, and increases suction capacity.

Methods:

This is a retrospective case series of patients who underwent RBG-PDT from 2008 to 2023 at Beth Israel Deaconess Medical Center. Electronic medical records were reviewed for preprocedural demographic data, procedural events, and postprocedural outcomes.

Results:

A total of 104 patients underwent RBG-PDT over a 15-year period. Median patient age was 61.95 (95% CI: 59.00-64.90), median BMI was 30.25 kg/m2 (IQR, 23.6 to 37.2) with 41.9% (32.5% to 51.3%) of patients included having a BMI over 30 kg/m2. PDT placement occurred in a mean of 13.7 days after intubation, with 70% due to prolonged mechanical ventilation resulting from ongoing respiratory failure. In all, 51.0% of patients had at least one increased bleeding risk factor, with an increased aPTT >36 seconds being the most common (36.5%). In all, 26.9% of patients underwent tracheostomy with ongoing therapeutic anticoagulation with heparin. In total, 60.6% of patients received concomitant percutaneous endoscopic gastrostomy (PEG) tube placement. No cases of pneumothorax or loss of the airway at the time of exchange of the endotracheal tube for rigid tracheoscopy were reported.

Conclusion:

RBG-PDT is a safe and effective procedure extending the patient population appropriate for PDT when performed by an experienced Interventional Pulmonology team.
Nursing and Volunteerism
Authors: Lal M. Maureen
Published: October 2024

A commitment to community involvement is a fundamental component of the American Nurses Credentialing Center's Magnet Recognition Program®. It reflects the nursing profession's spirit of service to society, as well as the personal ethos of those who pursue a nursing career. As we enter the season of gratitude and giving, we explore the role volunteerism plays in an organization's Magnet® culture, how it contributes to a greater sense of purpose, and how nurses far and wide make an impact when they give back to their local, national, and global communities.
Promoting Nursing Diversity, Equity, and Inclusion Through Virtual Reality Learning
Authors: Nelson Dawn E. , Burkhartzmeyer Holly L. , Kiker Kelly M. , Simiele Kayla C. , Proulx Ashley L. , Arcand Lori L. , Alcock Lynn R. , Frederick Ryannon K. , Phelan Sean , Storsveen Amy S.
Published: October 2024

Nurse leaders are foundational to the success of creating an inclusive culture and climate and responding to situations of discrimination, racism, microaggressions, and bias in healthcare settings. This article describes a leadership education initiative using virtual reality to provide diversity, equity, and inclusion training for nurse leaders. Immersion in a lived experience provides a safe and effective learning environment to promote, improve, and exemplify diversity, equity, and inclusion principles and should be explored for other educational applications.
Mediating Effects of Resilience on the Relationship Between Stress and Professional Commitment Among Nursing Students
Authors: Lin Pao-Chen , Chang Ya-Wen , Chang Yu-Hsuan
Published: October 2024

Background:

Research on the relationship between stress, professional commitment, and resilience among nursing students is lacking.

Purpose:

To examine the mediating effect of resilience on the relationship between stress and professional commitment among nursing students during their fundamental nursing practicum.

Methods:

A cross-sectional design was used. Nursing students who were aged 17 to 20 years and had completed fundamental nursing practicum within 1 week were recruited. The survey covered stress, resilience, and professional commitment. The mediation analysis was conducted using the PROCESS macro with a bootstrap approach.

Results:

This study recruited 485 nursing students. Stress was significantly negatively correlated with resilience and professional commitment, whereas resilience was significantly positively correlated with professional commitment. Furthermore, resilience partially mediated the relationship between stress and professional commitment.

Conclusions:

Appropriate interventions should be implemented to help nursing students reduce stress and improve their resilience, which can thus enhance their professional commitment to the nursing profession.
The Incidence and Severity of Pediatric Injuries Sustained by Electric Bikes and Powered Scooters
Authors: Moati Seraj , Tavor Oren , Capua Tali , Sukhotnik Igor , Glatstein Miguel , Rimon Ayelet , Cohen Neta
Published: October 2024

Objectives

This study aimed to describe the incidence and severity of electrical bicycle (E-bike)– and power scooter (P-scooter)–related injuries and their secular trends among pediatric patients presenting to a pediatric emergency department (ED).

Methods

This retrospective cohort study of patients aged <18 years who sustained E-bike and P-scooter injuries was performed between 2018 and 2023. We explored trends of severe trauma cases, ED visits, hospitalizations, and surgical interventions. Severity of trauma was rated by either an injury severity score (ISS) of >15 or the patient's need for acute care as defined by intensive care unit (ICU) admission, direct disposition to the operating room, acute interventions performed in the trauma room, and in-hospital death.

Results

Of the 1466 pediatric patients who presented to our pediatric ED following P-scooter and E-bike injuries, 216 (14.7%) were hospitalized, with a median age of 14.0 years (interquartile range, 10.5–16.0 years) and male predominance (69.0%). The number of ED visits increased 3.5-fold by study closure, with a parallel increase in hospitalizations, surgical interventions, and severe trauma cases. The relative percentages of severe trauma cases were not significantly different over time. Among hospitalized patients, 3 patients (1.4%) died and 9 (4.1%) required rehabilitation care.

Conclusions

The incidence and severity of E-bike and P-scooter injuries and fatalities continue to increase within the pediatric population. Current personal and road safety regulations are providing inadequate in preventing these injuries, highlighting an urgent need for revision and stricter enforcement.
High-grade Endometrial Carcinomas With Solid Basaloid Morphology and Geographic Necrosis Lacking Definitive Pilomatrix-like Features: Clinicopathologic Characteristics Including Aggressive Behavior and Novel Molecular Events
Authors: Carlson David K. , Painter Cheyenne , Gradecki Sarah E. , Ring Kari L. , Williams Eli S. , Mills Anne M.
Published: October 2024

High-grade endometrioid carcinomas occasionally demonstrate solid basaloid morphology with geographic necrosis (SB-GN). This pattern is among the defining features of pilomatrix-like high-grade endometrioid carcinoma (PiMHEC), a recently proposed tumor type which is additionally characterized by the presence of shadow cells, abnormal beta-catenin/CTNNB1 mutations, strong CDX2 expression, and poor outcomes. Clinicopathologic overlap between PiMHEC and other high-grade endometrial cancers with SB-GN has not been established. We screened 300 endometrial carcinomas on tissue microarray for SB-GN histology and performed a detailed whole-section morphologic review, immunohistochemical analysis, and next-generation sequencing on all cases bearing this pattern. Four (1.3%) demonstrated SB-GN. All 3 with clinical follow-up had extremely aggressive behavior despite being MMR-deficient; in contrast, only 27% of other MMR-deficient high-grade carcinomas recurred. One SB-GN case met most of the previously outlined diagnostic criteria for PiMHEC including abnormal beta-catenin/CTNNB1 (p.S37P variant) and strong CDX2 expression; notably, however, shadow cells were absent. This case also demonstrated a KRAS p.A59T pathogenic variant. The other 3 cases also lacked shadow cells; the 2 with sequencing data bore no CTNNB1 abnormalities but showed likely oncogenic variants involving the pilomatrixoma-associated gene FGFR2. All 3 cases with molecular results also bore somatic Notch pathway (NOTCH1/NOTCH2/NOTCH3) variants. The single case treated with immunotherapy showed complete and sustained response with regression of bone metastases despite abnormal beta-catenin/CTNNB1, which has been associated with immunotherapeutic resistance. These data suggest that the SB-GN pattern may connote a poor prognosis even in the absence of overt pilomatrix-like differentiation, and that novel molecular events may have implications for the treatment of these tumors.
Incidence of high blood pressure among Kenyan adults with HIV
Authors: Suvada Kara , Kocher Erica , Diwan Nazha , Nagy Andrew , Nderitu Mary , Kibaara Charles , Ngomoa Richard , Cagle Tony J. , Kariuki Jacob , Wall Kristin M. , Brunissen Ludivine , Ramireddy Shashank , Johnson Leslie C.M. , Chung Michael H. , Ali Mohammed K.
Published: October 2024

Objective:

People with HIV (PWH) face a heightened risk of cardiovascular diseases, partly because of increased high blood pressure risk. This study assessed high blood pressure burden (i.e. incidence and prevalence) among PWH in Kenya over time.

Design:

Longitudinal, open cohort study.

Methods:

We estimated the incidence and prevalence of high blood pressure in a large sample of Kenyans with HIV from the Coptic Hope Center using electronic medical records from 2004 to 2023. We defined incident high blood pressure as first visit after baseline at which each patient had a SBP at least 140 mmHg and/or a DBP at least 90 mmHg.

Results:

Our sample included 38 709 PWH seeking care at Coptic Hope Center clinics in Kenya (2004–2023). Nearly 40% of patients had high blood pressure at first visit. Among the 60% of patients initially normotensive, almost 40% developed high blood pressure within 20 years. The yearly prevalence of high blood pressure ranged from 8 to 58%. Average SBP was higher among patients who had their first visit from 2019 to 2023 compared with those visiting in the early 2000s and 2010s.

Conclusion:

Our findings reveal a high and rising burden of high blood pressure among PWH in a large, faith-based health system in Kenya. This underscores the need for stronger integration of care for individuals with concurrent HIV, high blood pressure, and other noncommunicable diseases (NCDs). Current systems are insufficient for achieving blood pressure control among PWH. Further research and funding for efforts to address HIV and NCD care in Kenya are warranted.
Development of Worksheets for Immunomodulator Shared Decision-Making to Facilitate Patient-Clinician Communication
Authors: Kumar Bharat , Iftekhar Ayesha , Ni Ruoning , Feng Alick , Gheriani Gatr-alnada , Oke Ibiyemi , Abidov Amir , Moy Lindsay , Morita Craig T. , Cobb Kristina , Sigwarth Erica , Swee Melissa
Published: October 2024

Background

Shared decision-making (SDM) is a principle of humanistic, patient-centered health care within the field of rheumatology. However, clear communication between patients and their clinicians regarding the benefits and risks of immunomodulators may be challenging in a clinical setting. The design-thinking process is a human-centered approach to quality improvement that can help to identify insights to uphold high-quality communication.

Methods

The development process adhered to the Stanford design thinking process framework, encompassing 5 stages: (1) empathize, (2) define, (3) ideate, (4) prototype, and (5) test. During the empathy stage, quality improvement members spent 4 hours immersed in the clinical setting observing how patients and clinicians engage in SDM conversations. These observations were augmented by unstructured debriefing sessions to better understand the needs and drivers of high-quality SDM. Following this, a rapid ideation workshop was convened to generate creative solutions. These led to rapid prototyping and testing, yielding a final product.

Results

The iterative design process identified 4 critical needs: (1) ensuring comprehensibility of materials, (2) upholding accuracy of information, (3) balancing standardization with individualization, and (4) promoting retention of knowledge. During the rapid ideation workshop, the concept of a Worksheet for Immunomodulator Shared Decision-Making (WISDM) was introduced and selected for further elaboration. This led to the creation of 5 prototypes for methotrexate, which were subsequently tested. These were reconciled and modified to make a final product.

Conclusion

The WISDM template contains 7 elements that support SDM. Forty-five WISDMs were created for 23 immunomodulators. Further investigation will focus on how WISDMs exactly impact SDM.
Density-dependent dispersal reduces conflict over the sex ratio
Authors: Chokechaipaisarn Chedhawat , Gardner Andy
Published: October 2024

Haplodiploids—in particular, wasps—are the workhorses of sex-allocation research. This is owing to their unusual system of sex determination, which provides a ready means of sex ratio adjustment. Notably, their sexually asymmetrical mode of genetic inheritance leads mothers and fathers to come into conflict over the sex ratio of their offspring. In the simplest outbreeding scenario, a mother is favoured to employ an even sex ratio while a father prefers that all his mate’s offspring are female. An important modulator of evolutionary conflict between mating partners is genetic relatedness, raising the possibility that this sex ratio conflict is reduced in low-dispersal settings with mating occurring between relatives. However, the impact of population viscosity on sex ratio conflict in haplodiploids remains unknown. Here, we develop and analyse a kin-selection model to investigate how the rate of dispersal modulates sex ratio conflict in a haplodiploid, viscous population setting. We find that population viscosity is associated with a reduction in the extent of sex ratio conflict—the effect being very weak under density-independent dispersal and much stronger under density-dependent dispersal.
Evidence for inbreeding depression in captive Damaraland mole-rats
Authors: Seager David , Leedale Amy E. , Thorley Jack Benjamin , Vullioud Philippe , Zöttl Markus , Clutton-Brock Tim
Published: October 2024

Mating between closely related individuals can result in a reduction in offspring fitness, known as inbreeding depression. Here, we investigate whether breeding with close relatives affects the reproductive output of parents and the development of their offspring in Damaraland mole-rats (
Fukomys damarensis
), a cooperatively breeding species where females avoid mating with familiar individuals. By cross-fostering litters of pups soon after birth, we were able to form breeding pairs from full siblings that were reared apart. We compared the reproductive output of these sibling pairs and the survival and growth of their pups with that of unrelated pairs over a period of 4 years. The litter sizes and interbirth intervals of sibling pairs did not differ from those of unrelated pairs, but the growth and survival of inbred offspring were lower, showing that breeding between close relatives is associated with substantial fitness costs. This study suggests that inbreeding depression is an important driver of the extreme reproductive skew observed in social mole-rats. Studies of the costs of inbred matings are now needed in similar species, such as naked mole-rats (
Heterocephalus glaber
), where captive females more commonly breed with close relatives, to determine whether these costs are lower than in Damaraland mole-rats.
Humphry Davy, transatlantic slavery and his constructions of racial difference in an early notebook
Authors: Bird Eleanor Lucy
Published: October 2024

Humphry Davy was the most celebrated chemist of his day in Britain, but he has been absent from discussions of Romantic-era constructions of race. It is well known that Davy was an experimental chemist, popular lecturer, and, as has been recently explored by the Davy Notebooks Project, a poet; this essay expands this narrative to include his connection to transatlantic slavery and writing about race, which are neglected aspects of his life and writing. In this essay, I examine Davy’s response to the slave-trade debates and for the first time his close family links to transatlantic slavery, focusing on his wife Jane’s stepfather, the major enslaver, Robert Farquhar. I discuss Davy’s writing on the chemical causes of Black skin colour and a draft essay on the climate in notebook 13F in which he constructed the racial difference of Black Africans. I argue that his essay can be understood by recognizing 13F as a school notebook used during his period of self-education and that it reflects the messy and unstable nature of writing about race in the Romantic period. Davy’s racial thinking was influential and he was recognized as an authority on skin colour by his contemporaries, Thomas Beddoes, Johann Friedrich Blumenbach, and Sir Everard Home.
Mycoplasma pneumoniae: not a typical respiratory pathogen
Authors: Rowlands Richard S. , Meyer Sauteur Patrick M. , Beeton Michael L. ,   On behalf of the ESCMID Study Group for Mycoplasma and Chlamydia Infections (ESGMAC)
Published: October 2024

Graphical abstract

(a). The classic ‘fried-egg’ colonies are commonly seen with the growth of Mycoplasma pneumoniae on agar. (b). Scanning electron micrograph of M. pneumoniae demonstrates spindle-shaped cells with attachment organelles. M. pneumoniae is equipped with a repertoire of virulence factors, which include the production of the community-acquired respiratory distress syndrome toxin, formation of H202 and H2S, the immunoglobulin-binding protein of Mycoplasma, adhesion and antigenic variability via the P1 adhesin and associated surface proteins and the ability to form biofilms on surfaces.
Seasonal cycles in a seaweed holobiont: A multiyear time series reveals repetitive microbial shifts and core taxa
Authors: Mudlaff Chantal Marie , Weinberger Florian , Düsedau Luisa , Ghotbi Marjan , Künzel Sven , Bonthond Guido
Published: October 2024

Seasonality is an important natural feature that drives cyclic environmental changes. Seaweed holobionts, inhabiting shallow waters such as rocky shores and mud flats, are subject to seasonal changes in particular, but little is known on the influence of seasonality on their microbial communities.

In this study, we conducted a bi-monthly, three-year time series to assess the seasonality of microbial epibiota in the seaweed holobiontGracilaria vermiculophylla. Our results reveal pronounced seasonal shifts that are both taxonomic and functional, oscillating between late winter and early summer across consecutive years. While epibiota varied taxonomically between populations, they were functionally similar, indicating that seasonal variability drives functional changes, while spatial variability is more redundant.

We also identified seasonal core microbiota that consistently (re)associated with the host at specific times, alongside a permanent core that is present year-round, independent of season or geography. These findings highlight the dynamic yet resilient nature of seaweed holobionts and demonstrate that their epibiota undergo predictable changes. Therewith, the research offers important insights into the temporal dynamics of seaweed-associated microbiota, and demonstrates that the relationship between seaweed host and its epibiota is not static, but naturally subject to an ongoing seasonal succession process.
In vitrometabolic interaction network of a rationally designed nasal microbiota community
Authors: Bonillo-Lopez L. , Rouam-el Khatab O. , Obregon-Gutierrez P. , Florez-Sarasa I. , Correa-Fiz F. , Sibila M. , Aragon V. , Kochanowski K.
Published: October 2024

Mounting evidence suggests that metabolite exchange between microbiota members is a key driver of microbiota composition. However, we still know little about the metabolic interaction networks that occur within many microbiota. This is particularly true for the nasal microbiota, and current efforts towards this end are hampered by a lack of microbial consortia that would enable the mapping of metabolic interactions between nasal microbiota members underin vitroconditions. To tackle these issues, we developed the Porcine Nasal Consortium (PNC8), a rationally designed microbial consortium of eight strains representing the mostin vivoabundant genera in the nasal microbiota of healthy piglets. We used this consortium to systematically examine the metabolic capabilities of nasal microbiota members, as well as the metabolic interactions occurring between them. We found that PNC8 strains differ substantially in their metabolic pathway repertoire and ability to grow across variousin vitroconditions. Nevertheless, spent-media experiments revealed that most metabolic interactions between PNC8 strains are negative, and exometabolomics data pointed to co-depletion of sugars as a key driver of this interaction network. Finally, direct co-cultivation experiments showed that, as a result of this largely negative metabolic interaction network, competition is common among pairs of PNC8 strains and leads to a complex competition hierarchy in which only few strains are able to consistently outcompete all others. Overall, this work provides a valuable resource for studying the nasal microbiota under experimentally tractablein vitroconditions and is a key step towards mapping its metabolic interaction network.
Metabolism-oriented compound screen in physiological culture conditions identifies a NAMPT inhibitor highly effective against drug-naïve and -resistant melanoma cells
Authors: Preis Jasmin Renate , Rolvering Catherine , Kirchmeyer Mélanie , Kreis Stephanie , Behrmann Iris , Haan Claude
Published: October 2024

Many melanoma patients do not respond to therapy or rapidly develop resistance to MAPK pathway inhibitors and immune checkpoint blockade treatments, highlighting the urgent need for additional therapeutic strategies for these patients.

To identify compounds that target drug-naïve and -resistant melanoma cells (Encorafenib/Binimetinib-resistant), we performed a screen using a metabolism-oriented compound library in different cell culture media and growth conditions (2D and 3D).

The efficacy of several compounds varied considerably under changing test conditions, but importantly, we also detected compounds that work across all tested conditions. In general, drug activity was reduced under hypoxia and in 3D spheroids. Thorough validation was performed for drugs showing potency in all conditions with a focus on efficacy in 3D spheroids grown in an in- house physiological culture medium. Using hydrogel matrix-embedded multi-cell type 3D models, we found that FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, is very potently suppressing melanoma cell growth while not affecting the growth of healthy cells such as fibroblasts and endothelial cells.
Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to prevent HER2+ breast cancer
Authors: Sharma Vandana , Fernando Veani , Zheng Xunzhen , Sweef Osama , Choi Eun-Seok , Thomas Venetia , Furuta Saori
Published: October 2024

Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing SEP, the endogenous precursor of BH4(the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we report that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively prevented tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.
Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverseCaenorhabditisnematodes
Authors: Banse Stephen A. , Sedore Christine A. , Coleman-Hulbert Anna L. , Johnson Erik , Onken Brian , Hall David , Segerdell Erik , Jones E. Grace , Song Yuhua , Osman Hadley , Xue Jian , Battistoni Elena , Guo Suzhen , Foulger Anna C. , Achanta Madhuri , Sheikh Mustafa , Fitzgibbon Theresa , Willis John H. , Woodruff Gavin C. , Driscoll Monica , Lithgow Gordon J. , Phillips Patrick C.
Published: October 2024

Aging is a pan-metazoan process with significant consequences for human health and society—discovery of new compounds that ameliorate the negative health impacts of aging promise to be of tremendous benefit across a number of age-based co-morbidities. One method to prioritize a testable subset of the nearly infinite universe of potential compounds is to use computational prediction of their likely anti-aging capacity. Here we present a survey of longevity effects for 16 compounds suggested by a previously published computational prediction set, capitalizing upon the comprehensive, multi-species approach utilized by theCaenorhabditisIntervention Testing Program (CITP). While eleven compounds (aldosterone, arecoline, bortezomib, dasatinib, decitabine, dexamethasone, erlotinib, everolimus, gefitinib, temsirolimus, and thalidomide) either had no effect on median lifespan or were toxic, five compounds (all-trans retinoic acid, berberine, fisetin, propranolol, and ritonavir) extended lifespan inCaenorhabditis elegans. These computer predictions yield a remarkable positive hit rate of 30%. Deeper genetic characterization of the longevity effects of one of the most efficacious compounds, the endogenous signaling ligand all-trans retinoic acid (atRA, designated tretinoin in medical products), which is widely prescribed for treatment of acne, skin photoaging and acute promyelocytic leukemia, demonstrated a requirement for the regulatory kinases AKT-1 and AKT-2. While the canonical Akt-target FOXO/DAF-16 was largely dispensable, other conserved Akt-targets (Nrf2/SKN-1 and HSF1/HSF-1), as well as the conserved catalytic subunit of AMPK AAK-2, were all necessary for longevity extension by atRA. Evolutionary conservation of retinoic acid as a signaling ligand and the structure of the downstream effector network of retinoic acid combine to suggest that the all-trans retinoic acid pathway is an ancient metabolic regulatory system that can modulate lifespan. Our results highlight the potential of combining computational prediction of longevity interventions with the power of nematode functional genetics and underscore that the manipulation of a conserved metabolic regulatory circuit by co-opting endogenous signaling molecules is a powerful approach for discovering aging interventions.
Bystander base editing interferes with visual function restoration in Leber congenital amaurosis
Authors: Lee Seok-Hoon , Wu Jun , Im Dongjoon , Hwang Gue-ho , Jeong You Kyeong , Jiang Hui , Lee Seok Jae , Jo Dong Hyun , Goddard William A. , Kim Jeong Hun , Bae Sangsu
Published: October 2024

Base editors (BEs) have emerged as a powerful tool for gene correction with high activity. However, bystander base editing, a byproduct of BEs, presents challenges for precise editing. Here, we investigated the effects of bystander edits on phenotypic restoration in the context of Leber congenital amaurosis (LCA), a hereditary retinal disorder, as a therapeutic model. We observed that inrd12of LCA model mice, the highest editing activity version of an adenine base editors (ABEs), ABE8e, generated substantial bystander editing, resulting in missense mutations despite RPE65 expression, preventing restoration of visual function. Through AlphaFold-based mutational scanning and molecular dynamics simulations, we identified that the ABE8e-driven L43P mutation disrupts RPE65 structure and function. Our findings underscore the need for more stringent requirements in developing precise BEs for future clinical applications.
Phenotypic impact of individual conserved neuronal microexons and their master regulators in zebrafish
Authors: Lopez-Blanch Laura , Rodríguez-Marin Cristina , Mantica Federica , Iñiguez Luis P. , Permanyer Jon , Kita Elizabeth M. , Mackensen Tahnee , Codina-Tobias Mireia , Romero-Ferrero Francisco , Fernandez-Albert Jordi , Cuadrado Myriam , Bustelo Xosé R. , de Polavieja Gonzalo G. , Irimia Manuel
Published: October 2024

Microexons exhibit striking evolutionary conservation and are subject to precise, switch-like regulation in neurons, orchestrated by the splicing factorsSrrm3andSrrm4. Disruption of these regulators in mice leads to severe neurological phenotypes, and their misregulation is linked to human disease. However, the specific microexons involved in these phenotypes and the effects of individual microexon deletions on neurodevelopment, physiology, and behavior remain poorly understood. To explore this, we generated zebrafish lines with deletions of 18 individual microexons, alongsidesrrm3andsrrm4mutant lines, and conducted comprehensive phenotypic analyses. We discovered that while loss ofsrrm3, alone or together withsrrm4, resulted in significant alterations in neuritogenesis, locomotion, and social behavior, individual microexon deletions typically produced mild or no noticeable effects. Nonetheless, we identified specific microexons associated with defects in neuritogenesis (evi5b,vav2,itsn1,src) and social behavior (vti1a,kif1b). Additionally, microexon deletions triggered coordinated transcriptomic changes in neural pathways, suggesting the presence of molecular compensatory mechanisms. Our findings suggest that the severe phenotypes caused bySrrm3/4depletion arise from the combined effects of multiple subtle disruptions across various cellular pathways, which are individually well-tolerated.
Computational Identification of Migrating T cells in Spatial Transcriptomics Data
Authors: Zhong Lin , Li Bo , Zhang Siyuan , Li Qiwei , Xiao Guanghua
Published: October 2024

T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide novel insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T-cell trafficking display an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix (ECM) remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce a novel approach for studying T cell migration and interactions within the tumor microenvironment (TME), offering valuable insights into tumor-immune dynamics.
Apelin-13 in the paraventricular nucleus protects myocardium from ischemia via V1a receptor of the paraventricular nucleus and GABAA receptor γ2 of the nucleus tractus solitarii in rats
Authors: Yan Wen , Wang Dan , Zhang Xinmin , Xuan Chengluan
Published: October 2024

Background

Apelin system plays a significant role in central blood pressure regulation, but its role in neural control of myocardial injury protection is poorly understood. Thus, this study was undertaken to evaluate the effects of apelin-13 in the paraventricular nucleus (PVN) on myocardial infarction (MI) and ischemia/reperfusion (I/R).

Methods

The cardiac functions were assessed after microinjecting or transferring the apelin-13 gene into the paraventricular nucleus (PVN) of rat models with myocardial infarction (MI) or ischemia/reperfusion (I/R).

Results

In MI rats, we showed that apelin-13 expression decreased in PVN, V1a receptor expression increased in PVN and nucleus tractus solitarii (NTS), and GABAA receptor (GAR) γ2 expression increased in NTS. In primary cultured hypothalamus and medulla oblongata neurons, V1a receptor expression was downregulated by APJ receptor antagonist or GAR agonist, indicating that there are interactions between these receptors in neurons. Apelin-13 overexpression in PVN significantly improved cardiac function of MI and I/R rats, including left-ventricular end-diastolic diameter, left-ventricular end-systolic diameter, left-ventricular ejection fraction, and left-ventricular fractions shortening, accompanied by decreased noradrenaline and increased vasopressin plasma levels. Myocardial ischemia–related apoptotic and inflammatory pathway markers (Bcl-1, Bax, TGF-β1, CCR5, Smad2) were downregulated and four neuropeptides of the parasympathetic endocrine system (somatostatin, cholecystokinin, glucagon-like peptide 1, vasoactive intestinal peptide) were increased in serum correspondingly with cardiac function improving. V1a receptor antagonist in PVN or NTS and GAR agonist in NTS decreased the effects of apelin-13 overexpression on cardiac function of MI and I/R rats.

Conclusions

Overexpression of apelin-13 in PVN leads to cardiac function improvement via V1a receptor in PVN and NTS, and GARγ2 in NTS. Parasympathetic endocrine system and myocardial ischemia–related apoptotic and inflammation signaling pathways are involved in apelin-13 in PVN–mediated cardiac function regulation, which provides evidence for neural regulation of cardiovascular diseases.
Unraveling transposable element-mediated regulatory landscape in diverse human immune cells
Authors: Du Cui , Fan Hairui , Jiang Jiayao , Yang Juan , Chen Shuai , Vorobyeva Nadezhda E , Zhu Congrui , Mao Liming , Li Chenxi , Li Yanhua , Bao Wenbin , Sun Ming-an
Published: October 2024

Transposable elements (TEs) are key contributors to genetic novelty. Despite increasing evidence of their importance, their roles in shaping the regulatory landscape of diverse immune cell populations remain largely unclear. Using single-cell multiome data from human peripheral blood mononuclear cells, we annotated the cell-specific cis-regulatory elements for major immune cell populations and identified a highly cell-specific signature of the overrepresented TE families. Focusing on monocytes that bear fast-evolving transcriptomes, we found that high proportions of their enhancers are TE-derived and bound by multiple pioneer transcription factors. Among them, we confirmed that the core myeloid regulator SPI1 can bind and regulate hundreds of TE-derived enhancers, which further affect the expression of adjacent immune genes. Additionally, interspecies comparison reveals that non-conserved monocyte enhancers are frequently generated by lineage-specific TE insertions, and correlate with the evolved gene expression between human and mouse. Overall, our study supports the importance of TEs in shaping the regulatory landscape of diverse immune cell populations.
Expression pattern of the ST heat-stable enterotoxin gene cassettes inVibriossuperintegrons
Authors: Fonseca Érica L. , Freitas Fernanda S. , Morgado Sérgio M. , Vicente Ana Carolina P.
Published: October 2024

BACKGROUND

Vibrio mimicushas been associated with a cholera-like diarrhea and other gastroenteritis due to the presence of virulence factors such as the heat-stable ST enterotoxin. In spite of its relevant role inVibriopathogenesis, there is still a lack of information concerning ST expression dynamics and associated genomic context.

OBJECTIVE

this study aimed to determine the prevalence, genomic context, and expression of thestgene found inV. choleraeandV. mimicusstrains.

METHODS

genome sequencing, in silico analyses of st promoter region and genomic context, and relative quantification pf st expression by real time RT-PCR were applied.

FINDINGS

Thestgene was found within the SI of bothVibriospecies, presenting variations in their amino acid sequences. Thein silicoanalysis of thest5’UTR identified different promoter versions among them. Significant differences were observed in thestexpression level, which varied from 10X to 640X-fold, correlating with the differences found in the promoter versions.

MAIN CONCLUSIONS

Therefore, the present study highlighted the link between the ST toxin gene and the superintegron, not only forV. cholerae, but also forV. mimicus. The differentialstexpression revealed that it is detrimental to the cognate promoter version, which would impact the toxin production and strain virulence.
Regulation of Sex-biased Gene Expression by the Ancestral X-Y Chromosomal Gene PairKdm5c-Kdm5d
Authors: Malcore Rebecca M. , Samanta Milan Kumar , Kalantry Sundeep , Iwase Shigeki
Published: October 2024

Conventionally, Y-linkedSryis thought to drive sex differences by triggering differential hormone production. Ancestral X-Y gene pairs, however, are hypothesized to drive hormone-independent sex differences. Here, we show that the X-Y gene pairKdm5c-Kdm5dregulates sex-biased gene expression in pluripotent mouse embryonic stem cells (ESCs). Wild-type (WT) XX female ESCs exhibit >2-fold higher expression of 409 genes relative to WT XY male ESCs. Conversely, WT XY male ESCs exhibit >2-fold higher expression of 126 genes compared to WT XX female ESCs. Loss ofKdm5cin female ESCs downregulates female-biased genes. In contrast, loss of eitherKdm5corKdm5din male ESCs upregulates female-biased genes and downregulates male-biased genes, effectively neutralizing sex-biased gene expression. KDM5C promotes the expression ofKdm5dand several other Y-linked genes in male ESCs. Moreover, ectopicKdm5dexpression in female ESCs is sufficient to drive male-biased gene expression. These results establishKdm5c-Kdm5das critical regulators of sex-biased gene expression.