bluuebunny/crossref_metadata_2025 huggingface dataset:
Correction of Brassiere Strap Grooving with Injectable Poly-L-Lactic Acid in Plastic Surgery Resident Filler and Neuromodulator Clinic
Authors: Blanchet Nadia P. , Kelly Brooks B.
Published: February 2024

Poly-L-lactic acid (PLLA) is a biocompatible synthetic polymer that induces neocollagenesis by fibroblasts after placement into the reticular dermis and subcutaneous plane. We present an innovative use of this product to treat brassiere strap grooves. The size and weight of hypertrophied breasts can cause physical and psychological problems that can be corrected with reduction mammaplasty. However, bra strap grooving remains an unsightly consequence of brassiere use with large and heavy breasts. PLLA provides an innovative way to treat this deformity in a minimally invasive way, while maintaining relatively long-term results of two years or more. We studied 10 patients who presented to resident filler and neuromodulator clinic to help improve the bra strap groove deformity. The average number of clinic visits was 3.1. The average total number of vials injected was 2.58 on the right and 2.92 on the left. There were no complications or side effects, apart from one patient who reported injection site bruising. Patient surveys demonstrated 70% satisfied with the results and 30% very satisfied. We also discuss resident filler and neuromodulator clinic as an opportunity for resident research.
Pulmonary Embolism after Botulinum Toxin Treatment for Leg Muscle Hypertrophy
Authors: Wang Xiaoli , Li Xiaofei , Yu Mosheng
Published: February 2024

Leg muscle hypertrophy is a unique physical symptom in East Asian women. Compared with traditional surgical treatment for calf muscle hypertrophy, botulinum toxin is widely favored by East Asian women because of its minimal trauma and significant effects. We describe the case of a 22-year-old woman with pulmonary embolism because of deep vein thrombosis, who presented with hypertrophy of bilateral calf muscles, and was administered 300 U of botulinum toxin A injection in July 2022. On the third day after the injection, she experienced swelling and pain in her left leg, which gradually worsened and made walking difficult. She underwent an ultrasound examination of lower limbs, which revealed several deep and shallow vein thrombi in the left lower limb. Computed tomography arterial imaging indicated multiple embolisms in pulmonary arteries. This study aimed to explore and analyze the causes of pulmonary embolism after botulinum toxin treatment for calf muscle hypertrophy by reviewing and analyzing the patient’s symptoms, diagnosis, and treatment process to provide management strategies for treatment and prevention of this disease.
Teprotumumab for Thyroid Eye Disease-related Strabismus
Authors: Dallalzadeh Liane O. , Villatoro George A. , Chen Lillian , Sim Myung S. , Movaghar Mansoor , Robbins Shira L. , Karlin Justin N. , Khitri Monica R. , Velez Federico G. , Korn Bobby S. , Demer Joseph L. , Rootman Daniel B. , Granet David B. , Kikkawa Don O.
Published: February 2024

Purpose:

To assess and quantify teprotumumab’s effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility.

Methods:

We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab.

Results:

Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation (p < 0.001), without significant change in mean horizontal deviation (p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye (p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion.

Conclusions:

Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.
Bilateral Facial Palsy: A Rare Presenting Symptom for Inclusion Body Myositis
Authors: Meer Elana , Ahmad Meleha , Grob Seanna , Winn Bryan J.
Published: February 2024

Inclusion body myositis is a common type of inflammatory myopathy among populations over the age of 50 years, classically presenting with weakness and atrophy of the forearms and quadriceps. While a third of patients may eventually present with mild facial weakness, findings of ptosis, facial palsy, or involvement of extraocular muscles are rarely, if ever, seen. The authors describe a unique case of inclusion body myositis in which a patient initially presented with bilateral severe facial palsy and exposure keratitis but minimal limb weakness. While midface weakness, unilateral lagophthalmos, and ptosis have been documented in one reported case, key presenting symptoms of bilateral facial palsy and symmetric paralytic lagophthalmos with corneal exposure have not been presented before. Therefore, this case serves as an important reminder to consider the inclusion body myositis in the differential diagnosis of bilateral facial palsy.
Nonsurgical risk factors for marginal ulcer following Roux-en-Y gastric bypass for obesity: a systematic review and meta-analysis of 14 cohort studies
Authors: Liang Yi , Wang Chunyun , Yang Lebin , Yang Kewei , Zhang Shulun , Xie Wenbiao
Published: February 2024

Backgrounds:

Marginal ulcer (MU) is a common complication of Roux-en-Y Gastric Bypass (RYGB). The primary goal of this meta-analysis was to identify potential risk factors for MU post-RYGB.

Methods:

A comprehensive literature search was conducted on four databases (PubMed, Embase, Web of Science, and the Cochrane Library) to identify articles published from inception to 23 May 2023 that reported risk factors linked to ulcer occurrence post-RYGB. Hazard Ratio (HR) and Odds Ratio (OR) with respective 95% CI were calculated to estimate the impact of selected risk factors on MU. The risk factors were evaluated through multivariate analyses. The estimated risk factors were subjected to a random-effects model. Subgroup analysis based on study baseline characteristics and leave-one-out sensitivity analysis were also performed to investigate the potential sources of heterogeneity and assess the robustness of the findings.

Result:

Herein, 14 observational studies involving 77 250 patients were included. Diabetes, smoking, and steroid use were identified to be risk factors of MU, with pooled ORs of (1.812; 95% CI: 1.226–2.676; P=0.003), (3.491; 95% CI: 2.204–5.531; P<0.001), and (2.804; 95% CI: 1.383–5.685; P=0.004), respectively. Other risk factors, such as alcohol consumption, male sex, and PPI use, were deemed not significant due to differences in data acquisition and effect estimates.

Conclusion:

Diabetes, smoking, and steroid use were identified as independent risk factors of MU. Enhancing awareness of these identified risk factors will lead to more effective preoperative prevention and targeted postoperative interventions for patients undergoing RYGB.
Beyond competence and retention: Developing a comprehensive evaluation framework for a rural primary care nurse practitioner residency program
Authors: Hillman JoAnna L. , Gowgiel Janelle C. , Price Paula S. , Robertson Bethany
Published: February 2024

With the rise in nurse practitioner (NP) residency programs, evaluations have largely focused on retention and competency completion for residents. There is a need for expanded evaluation to ensure the sustainability of NP residency programs, to ensure timely adaptations to address resident satisfaction, and to solidify a long-term pathway of NPs well prepared for rural practice. We created a family nurse practitioner (FNP) residency program with a comprehensive evaluation framework to prepare residents for practice in rural settings. The evaluation framework was developed through collaborative engagement of an external evaluation team, program leadership, and clinical site representatives. The evaluation framework of the FNP residency program combined resident assessment and holistic program evaluation, using a rapid continuous quality improvement (QI) approach. The evaluation considered three distinct perspectives: the resident, the peer coach, and the clinical site. The rapid continuous QI approach allowed program leadership to respond swiftly to programmatic challenges, improve the residency program in response to residents' reported experiences, and emphasize sustainability for continued program impact, while assessing residents' learning and performance. The program's data-driven evaluation approach has demonstrated its success in meeting the goals of the Health Resources and Services Administration funding by increasing the number of primary care providers in rural settings. The program's expansion and continued success have further validated the efficacy of this evaluation framework in assessing, improving, and ensuring the sustainability of APRN residency programs. This article calls for the adoption of similar evaluation strategies in future residency programs to promote their long-term success and impact in rural health care settings.
Mapping Cumulative Risk in Delaware: Approach and Implications for Health Equity
Authors: Brooks Madeline M. , Salvatore Alicia L. , Khanal Pragyan , Curriero Frank C.
Published: February 2024

Background:

Addressing health equity requires attention to upstream determinants of health, including environmental and social factors that act in tandem to increase communities' exposure to and vulnerability to toxicants. Cumulative risk assessment, which evaluates combined risks from environmental and social factors, is a useful approach for estimating potential drivers of health disparities. We developed a cumulative risk score of multiple indices of environmental and social conditions and assessed block group–level differences in New Castle County, Delaware.

Methods:

This cross-sectional study used choropleth maps to visualize the distribution of environmental, social, and cumulative risks and Moran's I statistics to assess spatial clustering of cumulative risk across the county and among individual block groups.

Results:

Findings indicate that environmental risk rarely occurs without social risk and that environmental and social risks co-occur in distinct areas, resulting in large-scale clustering of cumulative risk. Areas of higher cumulative risk had more Black residents and people of lower socioeconomic status.

Conclusions:

Replicable measures of cumulative risk can show how environmental and social risks are inequitably distributed by race and socioeconomic status, as seen here in New Castle County. Such measures can support upstream approaches to reduce health disparities resulting from histories of environmental racism.
Effect of Robotic Rehabilitation on Hand Functions and Quality of Life in Children With Cerebral Palsy
Authors: Adar Sevda , Keskin Duygu , Dündar Ümit , Toktaş Hasan , Yeşil Hilal , Eroğlu Selma , Eyvaz Nuran , Beştaş Ersin , Demircan Ali
Published: February 2024

Objective

This study aimed to examine the impact of robotic hand rehabilitation on hand function and quality of life in children with cerebral palsy.

Design

Children with cerebral palsy aged 7–16 yrs were divided into robotic rehabilitation (n = 9) or conventional rehabilitation (n = 10) groups for hand rehabilitation of 30 sessions. The primary outcomes were the Fugl-Meyer Assessment for Upper Extremity and Box and Block Test. The secondary outcomes were the Manual Ability Classification System, modified Ashworth scale, hand grasp and finger strengths, ABILHAND-Kids, Functional Independence Measure for Children, and PedsQL Quality of Life Inventory–CP Module.

Results

In the robotic rehabilitation group, a significant improvement was found in all parameters after treatment (P < 0.05), except for the Functional Independence Measure (P = 0.081). In the conventional rehabilitation group, there was significant improvement after treatment in the modified Ashworth scale, Fugl-Meyer Assessment for Upper Extremity, hand grasp strength, Box and Block Test, ABILHAND-Kids, and PedsQL Quality of Life Inventory–CP Module (P < 0.05). Before and after treatment, all outcome parameters in the groups were similar (P > 0.05).

Conclusions

Robotic hand rehabilitation is effective in improving motor function, manual dexterity, spasticity, and quality of life in children with cerebral palsy. However, it was not demonstrated to be superior to conventional rehabilitation.
Antimicrobial Stewardship and Improved Antibiotic Utilization in the Pediatric Cardiac Intensive Care Unit
Authors: Hillyer Margot M. , Jaggi Preeti , Chanani Nikhil K. , Fernandez Alfred J. , Zaki Hania , Fundora Michael P.
Published: February 2024

Background:

We developed a multidisciplinary antimicrobial stewardship team to optimize antimicrobial use within the Pediatric Cardiac Intensive Care Unit. A quality improvement initiative was conducted to decrease unnecessary broad-spectrum antibiotic use by 20%, with sustained change over 12 months.

Methods:

We conducted this quality improvement initiative within a quaternary care center. PDSA cycles focused on antibiotic overuse, provider education, and practice standardization. The primary outcome measure was days of therapy (DOT)/1000 patient days. Process measures included electronic medical record order-set use. Balancing measures focused on alternative antibiotic use, overall mortality, and sepsis-related mortality. Data were analyzed using statistical process control charts.

Results:

A significant and sustained decrease in DOT was observed for vancomycin and meropenem. Vancomycin use decreased from a baseline of 198 DOT to 137 DOT, a 31% reduction. Meropenem use decreased from 103 DOT to 34 DOT, a 67% reduction. These changes were sustained over 24 months. The collective use of gram-negative antibiotics, including meropenem, cefepime, and piperacillin-tazobactam, decreased from a baseline of 323 DOT to 239 DOT, a reduction of 26%. There was no reciprocal increase in cefepime or piperacillin-tazobactam use. Key interventions involved electronic medical record changes, including automatic stop times and empiric antibiotic standardization. All-cause mortality remained unchanged.

Conclusions:

The initiation of a dedicated antimicrobial stewardship initiative resulted in a sustained reduction in meropenem and vancomycin usage. Interventions did not lead to increased utilization of alternative broad-spectrum antimicrobials or increased mortality. Future interventions will target additional broad-spectrum antimicrobials.
The Effect of Obesity on Vaginoplasty Outcomes
Authors: Berger Lauren E. , Lava Christian X. , Spoer Daisy L. , Huffman Samuel S. , Martin Taylor , Bekeny Jenna C. , Fan Kenneth L. , Lisle David M. , Del Corral Gabriel A.
Published: February 2024

Background

Some surgeons use body mass index criteria within the patient selection processes before vaginoplasty, thereby limiting access to select obese patients. We sought to better characterize the effect of obesity on postoperative outcomes across multiple vaginoplasty techniques.

Methods

A single-center retrospective review of all transfeminine patients undergoing primary vaginoplasty procedures from December 2018 to July 2022 was conducted. Patients were stratified into cohorts according to the World Health Organization Obesity Class criteria. Data regarding demographics, comorbidities, operative details, postoperative complications, and all-cause revision were collected.

Results

A total of 237 patients met the inclusion criteria. Average follow-up duration was 9.1 ± 4.7 months. Multivariate regression revealed that patients with class I and class II/III obesity were associated with higher odds of developing vaginal stenosis (class I: odds ratio [OR], 7.1 [P = 0.003]; class II/III: OR, 3.4 [P = 0.018]) and all-cause revision (class I: OR, 3.7 [P = 0.021]; class II/III: OR, 4.8 [P = 0.027]). Undergoing either robotic peritoneal or robotic intestinal vaginoplasty was associated with lower odds of delayed wound healing (peritoneal: OR, 0.2 [P < 0.001]; intestinal: OR, 0.2 [P = 0.011]). Lastly, adherence to dilation regimen was negatively associated with development of vaginal stenosis (OR, 0.04; P < 0.001).

Conclusions

Patients with obesity may be at a higher risk of developing vaginal stenosis after vaginoplasty, which may ultimately necessitate operative revision. Although patients with obesity may remain surgical candidates, proper preoperative counseling and adherence to postoperative vaginal dilation regimens are critical to optimizing outcomes.
Positional Skull Deformities and Neurodevelopmental Delay: Study on 449 Infants
Authors: Pinyot Joan , Lacambra David , Garriga Maria , Pinyot Maria , Niubó Josep Maria
Published: February 2024

Objective:

Provide data on a cross-sectional study of neurodevelopmental delays (NDD) in patients with positional skull deformities (PSD), based on severity and gender, in early childhood.

Methods:

Neurodevelopment of 449 patients with PSD, with an age range of 3 to 59 months, was assessed with Battelle Developmental Inventory (BDI) tests during and after their cranial orthotic treatment. Data obtained were compared with the anthropometric measurements taken the same day the test was made, and results were grouped by diagnosis and severity, segmented by age group, and split by gender.

Results:

From 3983 patients with PSD and simple craniosynostosis, 526 accepted to participate and took a total of 1261 BDI tests. Premature patients, patients with neurological diseases or congenital malformations, and tests taken when PSD had been corrected were excluded. The resulting study group was 449 children (123 girls and 326 boys) and 972 BDI tests. Ninety-five percent of tests presented significant NDD (median value, expressed in months) in one or more BDI domains; male patients present larger NDD than do female patients; largest delays were found in brachycephaly and plagiocephaly combined (−7 mo at age range 48–59 mo), scaphocephaly (−3.5 mo at age range 12–17 mo), plagiocephaly (−3.2 mo at age range 12–17 mo). No significant NDD were found in the receptive or cognitive domains.

Conclusion:

When evaluating PSD, BDI tests, or similar, as well as mixed PSD classification should be considered. Patients with PSD should be monitored by a coordinated set of medical specialists.
The Patient Perspective on Colectomy for Recurrent Diverticulitis
Authors: Hawkins Alexander T. , Penson David F. , Geiger Timothy M. , Bonnet Kemberlee R. , Mutch Matthew G. , Maguire Lilias H. , Schlundt David G. , Rothman Russell L.
Published: February 2024

Objective:

Understand the patient decision-making process regarding colectomy for recurrent diverticulitis.

Summary Background Data:

The decision to pursue elective colectomy for recurrent diverticulitis is highly preference sensitive. Little is known about the patient perspective in this decision-making process.

Methods:

We performed a qualitative study utilizing focus groups of patients with recurrent diverticulitis at three centers across the United States. Using an iterative inductive/deductive approach, we developed a conceptual framework to capture the major themes identified in the coded data.

Results:

From March 2019-July 2020, 39 patients were enrolled across three sites and participated in six focus groups. After coding the transcripts using a hierarchical coding system, a conceptual framework was developed. Major themes identified included: participants’ beliefs about surgery, such as normative beliefs (e.g., subjective, value placed on surgery), control beliefs (e.g., self-efficacy, stage of change) and anticipated outcomes (e.g., expectations, anticipated regret); the role of behavioral management strategies (e.g., fiber, eliminate bad habits); emotional experiences (e.g., depression, embarrassment); current symptoms (e.g., severity, timing); and quality of life (e.g., cognitive load, psychosocial factors). Three sets of moderating factors influencing patient choice were identified: clinical history (e.g., source of diagnosis, multiple surgeries), clinical protocols (e.g., pre- and post-op education) and provider-specific factors (e.g., specialty, choice of surgeon).

Conclusions:

Patients view the decision to undergo colectomy through three major themes- their beliefs about surgery, their psychosocial context and moderating factors that influence participant choice to undergo surgery. This knowledge is essential both for clinicians counseling patients who are considering colectomy and for researchers studying the process to optimize care for recurrent diverticulitis.
Gamification as a tool to teach key concepts in microbiology to bachelor-level students in biology: a case study using microbial interactions and soil functioning
Authors: Estoppey Aislinn , Tinguely Camille , Cravero Melissa , Blandenier Estelle , Brand Lucie , Court Julien , Zaninetti Marie , Bindschedler Saskia , Junier Pilar
Published: February 2024

Microbiology is a difficult topic to teach given that the objects of study are mostly invisible to the learner. The majority of university students beginning their training in biology are more interested in natural objects that can be seen with the naked eye. Nonetheless, micro-organisms are key components of the biosphere and a good microbiological background is required for a thorough training in natural sciences. Lectures are still a common teaching format in universities. However, it is a passive learning format and no longer considered the most adequate approach in most teaching situations. Instead, alternatives consisting of more active teaching formats have been recognized to better motivate students to acquire and consolidate knowledge. In addition, transferable skills, such as effective communication, critical thinking and time management, are acquired simultaneously. A similar engagement can be obtained using games as part of the teaching experience. In this study, we designed a card game to teach key concepts in basic bacteriology and mycology to bachelor-level students. The first task consists of creating and designing microbial characters based on a list of species. This proved very useful for second-year bachelor students in terms of grasping concepts such as cell morphologies, taxonomy and life cycles. In the second task, third-year students used the characters created in the second-year class to develop a game based on an ecological function, namely forest litter degradation. In addition, they also considered experimental validation of the microbial activities and incorporated knowledge acquired in other fields.
Nanopore sequencing elucidates in vivo development of meropenem resistance by insertion of a mobile genetic element in the porin gene ompC in E. coli
Authors: Matamoros Sébastien , van Hattem Jarne
Published: February 2024

An ESBL-producing

E. coli

isolate recovered from a patient undergoing long-term treatment developed resistance to meropenem without acquiring carbapenem-hydrolysing enzymes. We performed Nanopore and Illumina sequencing and subsequent full hybrid genome assembly of this isolate and the meropenem-susceptible isolate recovered almost 8 weeks prior. Whole genome MLST patterns did not differ between isolates. However, we found the insertion of an IS5-like element in the sequence of the ompC gene and an increase in the number of copies of the CTX-M-15 gene in the resistant isolate. These results show that

E. coli

can develop meropenem resistance under antibiotic pressure by mutations in ompC genes and increasing the copy number of ESBL genes, and the value of next generation sequencing to reveal resistance mechanisms not detected by conventional PCR.
Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer
Authors: Ladaika Christopher A. , Ghobashi Ahmed H. , Boulton William C. , Miller Samuel A. , O’Hagan Heather M.
Published: February 2024

Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.
SEraster: a rasterization preprocessing framework for scalable spatial omics data analysis
Authors: Aihara Gohta , Clifton Kalen , Chen Mayling , Atta Lyla , Miller Brendan F. , Fan Jean
Published: February 2024

Motivation

Spatial omics data demand computational analysis but many analysis tools have computational resource requirements that increase with the number of cells analyzed. This presents scalability challenges as researchers use spatial omics technologies to profile millions of cells.

Results

To enhance the scalability of spatial omics data analysis, we developed a rasterization preprocessing framework called SEraster that aggregates cellular information into spatial pixels. We apply SEraster to both real and simulated spatial omics data prior to spatial variable gene expression analysis to demonstrate that such preprocessing can reduce resource requirements while maintaining high performance. We further integrate SEraster with existing analysis tools to characterize cell-type spatial cooccurrence. Finally, we apply SEraster to enable analysis of a mouse pup spatial omics dataset with over a million cells to identify tissue-level and cell-type-specific spatially variable genes as well as cooccurring cell-types that recapitulate expected organ structures.

Availability and implementation

Source code is available on GitHub (https://github.com/JEFworks-Lab/SEraster) with additional tutorials athttps://JEF.works/SEraster.
Optimal Performance Objectives in the Highly Conserved Bone Morphogenetic Protein Signaling Pathway
Authors: Shaikh Razeen , Larson Nissa J. , Hanjaya-Putra Donny , Zartman Jeremiah , Umulis David M. , Li Linlin , Reeves Gregory T.
Published: February 2024

Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in these cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant. For instance, some cellular systems require a rapid response, while others require high noise filtering. In this paper, we examine how the BMP- Smad pathway balances trade-offs among three such systems-level behaviors, or “Performance Objectives (POs)”: response speed, noise amplification, and the sensitivity of pathway output to receptor input. Using a Smad pathway model fit to human cell data, we show that varying non-conserved parameters (NCPs) such as protein concentrations, the Smad pathway can be tuned to emphasize any of the three POs and that the concentration of nuclear phosphatase has the greatest effect on tuning the POs. However, due to competition among the POs, the pathway cannot simultaneously optimize all three, but at best must balance trade-offs among the POs. We applied the multi-objective optimization concept of the Pareto Front, a widely used concept in economics to identify optimal trade-offs among various requirements. We show that the BMP pathway efficiently balances competing POs across species and is largely Pareto optimal. Our findings reveal that varying the concentration of NCPs allows the Smad signaling pathway to generate a diverse range of POs. This insight identifies how signaling pathways can be optimally tuned for each context.
Defining the mechanisms and properties of post-transcriptional regulatory disordered regions by high-throughput functional profiling
Authors: Lobel Joseph H. , Ingolia Nicholas T.
Published: February 2024

Disordered regions within RNA binding proteins are required to control mRNA decay and protein synthesis. To understand how these disordered regions modulate gene expression, we surveyed regulatory activity across the entire disordered proteome using a high-throughput functional assay. We identified hundreds of regulatory sequences within intrinsically disordered regions and demonstrate how these elements cooperate with core mRNA decay machinery to promote transcript turnover. Coupling high-throughput functional profiling with mutational scanning revealed diverse molecular features, ranging from defined motifs to overall sequence composition, underlying the regulatory effects of disordered peptides. Machine learning analysis implicated aromatic residues in particular contexts as critical determinants of repressor activity, consistent with their roles in forming protein-protein interactions with downstream effectors. Our results define the molecular principles and biochemical mechanisms that govern post-transcriptional gene regulation by disordered regions and exemplify the encoding of diverse yet specific functions in the absence of well-defined structure.
Maximum Likelihood Estimation for Unrooted 3-Leaf Trees: An Analytic Solution for the CFN Model
Authors: Hill Max , Roch Sebastien , Rodriguez Jose Israel
Published: February 2024

Abstract

Maximum likelihood estimation is among the most widely-used methods for inferring phylogenetic trees from sequence data. This paper solves the problem of computing solutions to the maximum likelihood problem for 3-leaf trees under the 2-state symmetric mutation model (CFN model). Our main result is a closed-form solution to the maximum likelihood problem for unrooted 3-leaf trees, given generic data; this result characterizes all of the ways that a maximum likelihood estimate can fail to exist for generic data and provides theoretical validation for predictions made in [28]. Our proof makes use of both classical tools for studying group-based phylogenetic models such as Hadamard conjugation and reparameterization in terms of Fourier coordinates, as well as more recent results concerning the semi-algebraic constraints of the CFN model. To be able to put these into practice, we also give a complete characterization to test genericity.
Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers
Authors: Lin Isabella , Wei Angela , Gebo Tsumugi A , Boutros PC , Flanagan Maeve , Kucine Nicole , Cunniff C , Arboleda VA , Chang VY
Published: February 2024

Background

Bloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants inBLM,which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants inBLM(BLMvariant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients andBLMvariant carriers.

Methods

To determine whetherde novoor somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios.

Results

We discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers ofde novovariants in BSyn probands compared to control probands.

Conclusion

Our findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants inBLMcould be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.
Capture and Release of Minke Whales Offers New Research Opportunities Including Measurements of Mysticete Hearing
Authors: Kleivane Lars , Kvadsheim Petter H , Vinje Anna Victoria Pyne , Mulsow Jason , Ølberg Rolf Arne , Teilmann Jonas , Harms Craig , Houser Dorian
Published: February 2024

Knowledge about species-specific hearing is vital to assessing how anthropogenic noise impacts marine mammals. Unfortunately, no empirical audiogram exists for any mysticete whale. We therefore developed a catch-and-release method to assess hearing in a small mysticete, the minke whale (Balaenoptera acutorostrata). Stationary lead nets were placed to intercept migratory routes and direct animals into an ocean basin enclosed by nets and islets, while another net was pulled across the entrance once a whale entered the basin. The whales were then slowly corralled into a modified aquaculture pen using a net suspended between two boats. Subsequently, the water volume available to the whales was gradually reduced by raising the pen net by hand until the whales were secured in a “hammock” between the floating pen ring and a raft. From the raft, researchers could access the whales to monitor their health, apply instruments for hearing tests, or other research objectives, and attach tags to monitor the movements and diving behavior of the whale post-release. The method is a slow and controlled procedure, allowing continuous monitoring, and quick release of the whales, if needed. In the first three field seasons employing the method, three animals were caught for research procedures. Initial hearing measurements using auditory evoked potentials were successfully completed. After release the animals resumed migration and dive behavior were considered normal. Our observations demonstrate that minke whales can be safely guided via moored net barriers, corralled into an aquaculture pen, and safely handled for research purposes, before being released back into the wild.
Decoding the Impact of Neighboring Amino Acid on ESI-MS Intensity Output through Deep Learning
Authors: Abdul-Khalek Naim , Wimmer Reinhard , Overgaard Michael Toft , Echers Simon Gregersen
Published: February 2024

Peptide-level quantification using mass spectrometry (MS) is no trivial task as the physicochemical properties affect both response and detectability. The specific amino acid (AA) sequence affects these properties, however the link from sequence to intensity output remains poorly understood. In this work, we explore combinations of amino acid pairs (i.e., dimer motifs) to determine a potential relationship between the local amino acid environment and MS1 intensity. For this purpose, a deep learning (DL) model, consisting of an encoder-decoder with an attention mechanism, was built. The attention mechanism allowed to identify the most relevant motifs. Specific patterns were consistently observed where a bulky/aromatic and hydrophobic AA followed by a cationic AA as well as consecutive bulky/aromatic and hydrophobic AAs were found important for the MS1 intensity. Correlating attention weights to mean MS1 intensities revealed that some important motifs, particularly containing Trp, His, and Cys, were linked with low responding peptides whereas motifs containing Lys and most bulky hydrophobic AAs were often associated with high responding peptides. Moreover, Asn–Gly was associated with low MS1 response. The model could predict MS1 response with a mean average percentage error of ∼11% and a Pearson correlation coefficient of ∼0.68.
Metagenomic estimation of dietary intake from human stool
Authors: Diener Christian , Gibbons Sean M.
Published: February 2024

Dietary intake is tightly coupled to gut microbiota composition, human metabolism, and to the incidence of virtually all major chronic diseases. Dietary and nutrient intake are usually quantified using dietary questionnaires, which tend to focus on broad food categories, suffer from self-reporting biases, and require strong compliance from study participants. Here, we present MEDI (Metagenomic Estimation of Dietary Intake): a method for quantifying dietary intake using food-derived DNA in stool metagenomes. We show that food items can be accurately detected in metagenomic shotgun sequencing data, even when present at low abundances (>10 reads). Furthermore, we show how dietary intake, in terms of DNA abundance from specific organisms, can be converted into a detailed metabolic representation of nutrient intake. MEDI could identify the onset of solid food consumption in infants and it accurately predicted food questionnaire responses in an adult population. Additionally, we were able to identify specific dietary features associated with metabolic syndrome in a large clinical cohort, providing a proof-of-concept for detailed quantification of individual-specific dietary patterns without the need for questionnaires.
BMI1 regulates human erythroid self-renewal through both gene repression and gene activation
Authors: McGrath Kathleen E. , Koniski Anne D. , Murphy Kristin , Getman Michael , An Hyun Hyung , Schulz Vincent P. , Kim Ah Ram , Zhang Bin , Schofield Taylor L. , Papoin Julien , Blanc Lionel , Kingsley Paul D. , Westhoff Connie M. , Gallagher Patrick G. , Chou Stella T. , Steiner Laurie A. , Palis James
Published: February 2024

The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.
Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer
Authors: Gu Langyu , He Shasha , Wu Linxiang , Zeng Yu , Zhang Yang , Zheng Chenqing , Wu Chuling , Xu Huishan , Zhang Xiaoyan , Shen Hongwei , Yao Shuzhong , Ren Yufeng , Yang Guofen
Published: February 2024

Chemoresistance has long been a significant but unresolved issue in the treatment of various cancers, including the most deadly gynecological cancer, the high-grade serous ovary cancer (HGSOC). In this study, single nuclei transcriptome analyses were utilized to identify key cells and core networks for chemoresistance in HGSOC patients with different early responses to platinum-based chemotherapy at the single-cell level. Biomarkers for chemoresistance were also screened using bulk transcriptome data from independent cohorts with larger sample sizes. A total of 62,482 single cells from six samples were analyzed, revealing that chemoresistant cancer cells (Epithelial cells_0) pre-existed within individual patient before treatment. Two network modules formed with hub genes such as hormone-related genes (ESR1 and AR), insulin-related genes (INSR and IGF1R), and CTNNB1, were significantly overexpressed in these cells in the chemoresistant patient. BMP1 and TPM2 could be promise biomarkers in identifying chemoresistant patients before chemotherapy using bulk transcriptome data. Additionally, chemotherapy-induced fibroblasts (Fibroblasts_01_after) emerged as key stromal cells for chemoresistance. One network module containing one subnetwork formed by cholesterol biosynthesis-related genes and one subnetwork formed by cancer-related genes such as STAT3 and MYC, was significantly overexpressed in these cells in the chemoresistant patient. Notably, the NAMPT-INSR was the most prioritized ligand-receptor pair for cells interacting with Fibroblasts_01_after cells and Epithelial cells_0 cells to drive the up-regulation of their core genes, including IL1R1, MYC and INSR itself. Our findings deepen the understandings about mechanisms of early chemoresistance in HGSOC patients.
PRESCOTT: a population aware, epistatic and structural model accurately predicts missense effect
Authors: Tekpinar Mustafa , David Laurent , Henry Thomas , Carbone Alessandra
Published: February 2024

Predicting the functional impact of point mutations is a complex yet vital task in genomics. PRESCOTT stands at the forefront of this challenge and reconstructs complete mutational landscapes of proteins, enables the identification of protein regions most vulnerable to mutations and assigns scores to individual mutations, assisting pathologists in evaluating the pathogenic potential of missense variants. PRESCOTT categorizes these variants into three distinct classes: Benign, Pathogenic, or Variants of Uncertain Significance (VUS). The model leverages protein sequences across millions of species, advanced protein structural models, and extensive genomic and exomic data from diverse human populations. By using only sequence and structural information, it significantly improves on current standards for predicting mutations in human proteins and matches AlphaMissense performance, which incorporates allele frequency data in its analysis. By including population-specific allele frequencies, PRESCOTT excels in genome-scale score separation of ClinVar benign and pathogenic variants and surpasses AlphaMissense in analyzing the ACMG reference human dataset and the over 1800 proteins from the Human Protein Dataset. Its efficacy is particularly notable in autoinflammatory diseases, accurately predicting pathogenic gain-of-function missense mutations, a task known for its difficulty. Efficiency and accessibility are key aspects of PRESCOTT. The user-friendly PRESCOTT webserver facilitates mutation effect calculations on any protein and protein variants. The server hosts a Comprehensive Human Protein Database for over 19,000 human proteins, based on sequences and structures, ready for a customized allele population analysis. Additionally, the tool provides open access to all intermediate scores, ensuring interpretability and transparency in variant analysis. PRESCOTT is a significant stride forward in the field of genomic medicine, offering unparalleled insights into protein mutational impacts.
In vivoaffinity maturation of the HIV-1 Env-binding domain of CD4
Authors: Pan Andi , Bailey Charles C. , Ou Tianling , Xu Jinge , Liu Xin , Hu Baodan , Crynen Gogce , Skamangas Nickolas , Bronkema Naomi , Tran Mai , Mu Huihui , Zhang Xia , Yin Yiming , Alpert Michael D. , He Wenhui , Farzan Michael
Published: February 2024

Many human proteins have been repurposed as biologics for clinical use. These proteins have been engineered within vitrotechniques that improve affinity for their ligands. However, these approaches do not select against properties that impair efficacy such as protease sensitivity or self-reactivity. Here we engineer the B-cell receptor of primary murine B cells to express a human protein biologic without disrupting their ability to affinity mature. Specifically, CD4 domains 1 and 2 (D1D2) of a half-life enhanced-HIV-1 entry inhibitor CD4-Ig (CD4-Ig-v0) were introduced into the heavy-chain loci of murine B cells, which were then adoptively transferred to wild-type mice. After immunization, transferred B cells proliferated, class switched, affinity matured, and efficiently produced D1D2-presenting antibodies. Somatic hypermutations found in the D1D2-encoding region of engrafted B cells improved binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein (Env) and the neutralization potency of CD4-Ig-v0 by more than ten-fold across a global panel of HIV-1 isolates, without impairing its pharmacokinetic properties. Thus, affinity maturation of non-antibody protein biologicsin vivocan guide development of more effective therapeutics.
Genomic insights into photosymbiotic evolution inTridacna squamosa
Authors: Zhang Yang , Mao Fan , Li Yuanning , Wong Nai-Kei , Bao Yongbo , Dai He , Sun Jin , Yi Wenjie , Xiao Shu , Xiang Zhiming , Li Jun , Zhang Yuehuan , Xia Xiaomin , Zhang Lvping , Zhou Huawei , Yu Ziniu
Published: February 2024

Photosymbiosis is fundamental driving force for ecological success of benthic coral reef ecosystems, and contributing to their biodiversity and resilience. As a benchmark organism indicative of reef health, the fluted giant clam (Tridacna squamosa) forms an exemplary photosymbiotic relationship with the symbiont Symbiodiniaceae dinoflagellates, whose initiation and maturation require finely coordinated interactions. However, much of the origin and dynamics of this reciprocal interplay remains unclarified. Here, we report the first complete whole genome ofT. squamosa, in conjunction with integrated multi-omics data, to illuminate the key evolutionary innovations and molecular events supporting the establishment and maintenance of photosymbiotic lifestyle in the giant clam. Programmed regulation of symbiont recognition, host immune system and GPCRs signaling activation co-contributed to dinoflagellates acquisition inT. squamosalarvae. Adaptive metabolic remodeling in the host siphonal mantle, a photosymbiotic niche, is critical to maintain the robustness of phtosymbiosis.T. squamosahas expanded light sensing gene family and evolved sophisticated signaling pathways to protect against UV photo-damage. Evidence also supports significant contribution of positive selection to host DNA-repair. Overall, our study here offers fresh mechanistic insights into the parallel evolution and molecular machinery of photosymbiosis in the giant clam-dinoflagellates duet, with implications for devising solutions to sustainable conservation.