bluuebunny/crossref_metadata_2025 huggingface dataset:
Supporting the Primary Care Workforce Through Training in Advanced Generalist Practice: An Evaluation of the Catalyst Program
Authors: Dell’Olio Myriam , Reeve Joanne
Published: August 2024

Introduction:

As a workforce crisis is causing recruitment and retention issues for new to practice GPs, we designed Catalyst, a one-year pilot career development program aiming to help new to practice GPs develop the skills of advanced generalist practice and build capacity for the complex work of primary care. In this paper, we report the findings of our evaluation of Catalyst.

Methods:

We used normalization process theory to investigate how Catalyst was contributing to the participants' understanding and implementation of generalist practice. We conducted 36 interviews and six focus groups investigating the participants' clinical practice and experience with the program and analyzed data using framework analysis.

Results:

Establishing a shared language and reframing professional identity helped GPs develop an understanding of their role through generalist lenses. Generalist practice was legitimized by access to scientific evidence and facilitated interactive learning. Integration of scientific, applied knowledge and quality improvement work fostered the enactment of such practice. Structured reflection and research-informed quality improvement projects contributed to the participants' awareness of the primary care context.

Discussion:

Knowledge creation activities observed through interactive learning and the integration of different types of knowledge facilitated the implementation of advanced generalist practice. The participants valued the community of practice gained through the program and would come to rely on programs designed to encourage networking and enable peer support. Finally, research-informed quality improvement projects built to analyze problems and monitor solutions are crucial for an early career physician to develop a sense of agency that shapes their primary care practice.
Single-cell RNA sequencing in tuberculosis: Application and future perspectives
Authors: Zhan Yuejuan , Zhang Qiran , Wang Wenyang , Liang Wenyi , Wang Chengdi
Published: August 2024

Tuberculosis (TB) has one of the highest mortality rates among infectious diseases worldwide. The immune response in the host after infection is proposed to contribute significantly to the progression of TB, but the specific mechanisms involved remain to be elucidated. Single-cell RNA sequencing (scRNA-seq) provides unbiased transcriptome sequencing of large quantities of individual cells, thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research. Here, we first briefly introduce the concept of scRNA-seq, followed by a summarization on the application of scRNA-seq to TB. Furthermore, we underscore the potential of scRNA-seq for clinical biomarker exploration, host-directed therapy, and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.
A New Start with HAART: Evaluating Breast Reconstruction in the Era of Highly Active Antiretroviral Therapy
Authors: Amakiri Uchechukwu O. , Shah Jennifer K. , Akhter Maheen F. , Fung Ethan , Sheckter Clifford C. , Nazerali Rahim S.
Published: August 2024

Background:

As HIV-positive individuals utilizing highly active antiretroviral therapy live longer, the burden of breast cancer increases in the population. Breast reconstruction is an integral aspect of surgical treatment for many patients after a breast cancer diagnosis, prompting this examination of the characteristics and outcomes of breast reconstruction in this growing patient population.

Methods:

Using Merative MarketScan Research Databases, a large multipayer database, HIV-positive adult patients who underwent autologous or implant-based breast reconstruction between 2007 and 2021 were identified using International Classification of Disease codes and Common Procedural Terminology codes. In both HIV-positive and -negative cohorts, patient demographics, procedure-related complications, and postoperative revisions were recorded. Shapiro-Wilk, chi-square, Wilcoxon-Mann-Whitney, and multivariable logistic regression tests were used for statistical analysis.

Results:

Of 173,421 patients who underwent breast reconstruction, 1816 had an HIV diagnosis. HIV-positive patients were younger (P < 0.001), underwent surgery more recently (P < 0.001), more often underwent immediate breast reconstruction (P < 0.001), and had higher comorbidity levels (P < 0.001). There was a regional variation in which the patient cohorts underwent breast reconstruction. There was no significant difference in overall complication rates between patient groups, but HIV-negative patients more often underwent revision procedures (P = 0.009).

Conclusions:

When compared to their HIV-negative counterparts, breast reconstruction can be considered safe and efficacious in patients living with HIV. HIV-positive patients are a growing demographic who seek breast reconstruction, and surgeons must continue to further understand the unique implications of breast reconstruction in this population.
Managing Soft Tissue Defects in Parry-Romberg Syndrome: An Individualized Approach
Authors: Salita Alona D. , Shaheen Matthew K. , Gowda Arvind U. , Kouzounis Konstantinos , Lohasammakul Suphalerk , Chaiyasate Kongkrit
Published: August 2024

Background:

Parry-Romberg syndrome (PRS) is a rare condition characterized by a progressive shrinkage and degeneration of the tissues beneath the skin, usually on one side of the face. Managing this disease presents numerous challenges due to its heterogeneity and unpredictable outcomes. The existing literature is primarily composed of case reports and series, leading to a lack of comprehensive guidelines on surgical intervention for the various manifestations of PRS. We propose an approach to address these challenges and optimize surgical outcomes.

Methods:

We conducted a retrospective review of all patients who underwent surgical correction for PRS between 2012 and 2022. Surgical interventions were determined based on the location and severity of the facial defect. The revision procedures were tailored to each patient until they were satisfied with the results.

Results:

Eleven patients underwent surgical correction, with an average of 3.2 procedures per patient. Fat grafting or dermal fat grafting was sufficiently effective for mild deficits in all areas and for upper-third deficits regardless of severity. For moderate to severe defects in the mid and lower face, a combination of buried free flaps and fat grafting yielded satisfactory results. Upon final revision, all patients rated their results as satisfactory or excellent.

Conclusions:

We propose an approach to surgical management that takes into account the specific deficits of each patient. Our approach has proven to yield aesthetically pleasing and reliable results, aligning with findings in the existing literature. This method could provide a foundation for standardized guidelines and improve the prognosis for individuals with PRS.
Foot and Ankle Curricular Guidelines in Entry-Level Physical Therapist Education: How Are We Doing?
Authors: Stevens Karen , Winiger Kyle , DiLiberto Frank
Published: August 2024

Introduction.

The Foot and Ankle Curricular Guidelines for Physical Therapist Professional Degree Programs (FACG) provided recommendations regarding essential entry-level content and skills. Eight years later, the extent of its implementation is unknown. This study characterizes entry-level Doctor of Physical Therapy (DPT) programs' foot and ankle curriculum with reference to the FACG.

Review of Literature.

Curricular guidelines offer recommendations to professional degree programs striving for excellence. Review and revisions of guidelines are important to keep pace with and reflect evolving evidence and practice.

Subjects.

One faculty member from 116 of 250 DPT programs participated (46.6% response rate). Participants were an average of 50.8 years old and taught a mean of 14.5 years.

Methods.

A cross-sectional 25-item online survey assessed foot and ankle contact hours, coverage of FACG recommended content, coverage of surgical procedures, and the use of FACG for curricular assessment, modification, and development.

Results.

Foot and ankle content was covered in physical therapy curriculum for a mean of 48.2 hours (range 12–120 hours). Eleven of the 25 recommended diagnoses, 29 of the 49 examination skills, 6 of the 7 intervention skills, and 3 of the 14 surgical procedures were covered by most (≥90%) of the programs. Reported use of FACG for curricular processes averaged 50.1–51.5 (0–100 numerical scale).

Discussion and Conclusions.

Across a wide range of contact hours, coverage of FACG recommended content was approximately 57% (46/81 recommended elements in ≥90% of programs). Although not specifically recommended by FACG, surgical procedures were less commonly covered by programs. Study findings question FACG implementation and may reflect differences across programs in depth and breadth of content. Identified curricular gaps may warrant addressing in future guidelines.
Predictors of Success in a Graduate, Entry-Level Professional Program: From Admissions to Graduation
Authors: Spadoni Gregory F. , Wojkowski Sarah , Smith-Turchyn Jenna , Stratford Paul W. , Grierson Lawrence
Published: August 2024

Introduction.

Admission to health professional programs (HPPs) in Canada is competitive. The purpose of this study is to evaluate how factors identifiable by the admissions package may predict incidences of academic concerns in one physiotherapy program in Canada.

Review of Literature.

Previous literature has identified many concepts that contribute to “academic success.” Some HPPs have investigated if admissions criteria can predict students' academic performance. However, this has not been reported in physiotherapy programs in Canada.

Subjects.

Study data included candidates' admissions' metrics and physiotherapy students' program data for 4 graduating cohorts, who were admitted from 2016 to 2019 inclusive (N= 256).

Methods.

A retrospective, nonconcurrent cohort study was used to estimate the relationship between applicant's admissions data and students' program data pertaining to academic success. Data were summarized as frequencies for categorical variables and means for continuous variables. We calculated odds ratios (ORs) and probabilities of an academic or professional concern for standard scores. Significance was set atP< .05.

Results.

Cohorts participating in the multiple mini-interview (MMI) had an academic concern incidence of 14/131. The virtual MMI (VMMI) cohort had an incidence of 7/125. Students with higher MMI scores were less likely to have an academic concern (OR = 0.52 [95% CI: 0.30–0.89,P= .017]). Grade point average was not significantly associated with an academic concern when combined with either MMI or VMMI (Ps > 0.05). Admissions round offer was also significantly associated with an academic concern (OR = 2.48 [95% CI: 1.00–6.12,P= .049]), with those beyond the initial round of offers having increased risk of concerns.

Discussion and Conclusion.

Results of the study reflect the generally low event rates for incidences of academic concerns and the relative homogeneity and range restriction of independent variables across the 4 cohorts of students. HPP's reflection on current admissions processes and ability to identify opportunities for change in admission processes helps ensure that programs are selecting candidates who are likely to succeed.
Evidence from recent clinical trials in fibrotic interstitial lung diseases
Authors: Cottin Vincent , Valenzuela Claudia
Published: August 2024

Purpose of review

Idiopathic pulmonary fibrosis (IPF) is the prototype of fibrosing interstitial lung diseases. It is mirrored by progressive pulmonary fibrosis (PPF), an umbrella term which characterizes disease behavior of various fibrotic interstitial lung diseases with irreversible progression, accounting for loss of lung function, exercise intolerance and respiratory failure leading to early mortality. Pirfenidone and nintedanib halve the decline in lung function but do not halt disease progression.

Recent findings

Since the publication in 2014 of pivotal pirfenidone and nintedanib studies, a number of clinical trials were conducted, many of them did not reach their primary endpoints. In IPF, promising phase 2 trials were followed by large phase 3 trials that did not confirm a favorable efficacy to tolerability favorable profile, including those with ziritaxestat, an autotaxin-1 inhibitor, zinpentraxin-alpha (human recombinant pentraxin-2), and the monoclonal antibody pamrevlumab targeting connective tissue growth factor. Nevertheless, newer compounds that hold promise are currently being evaluated in phase 3 or phase 2b randomized controlled trials, including: nerandomilast, a preferential phosphodiesterase 4B inhibitor; admilparant, a lysophosphatidic acid receptor antagonist; inhaled treprostinil, a prostacyclin agonist; and bexotegrast, a dual-selective inhibitor of αvβ6 and αvβ1 integrins. Nerandomilast, admilparant, inhaled treprostinil, and inhaled AP01 (pirfenidone), are currently studied in patients with PPF.

Despite recent frustrating negative results, there is a growing portfolio of candidate drugs developed in both IPF and PPF.
Impact of COVID-19 and Mpox on Sexual Practices and Disease Mitigation Strategies Over Time Among Men Who Have Sex With Men Affiliated With Collective Sex Venues
Authors: Hazra Aniruddha , Rusie Laura K. , Wasanwala Tasneem , Sachdev Nirmalpal , Guidry Taylor , Tabidze Irina , Mehta Supriya D.
Published: August 2024

Background

The COVID-19 pandemic and subsequent multinational mpox outbreak significantly disrupted sexual health care delivery, particularly impacting men who have sex with men (MSM). This study investigated these public health emergencies in relation to perceptions, attitudes, and sexual practices among MSM affiliated with a collective sex venue (CSV).

Methods

Electronic surveys were sent to clientele of a high-volume CSV between June 2021 and November 2022 across 3 time periods defined as pre-Omicron, post-Omicron, and mpox. Data collection encompassed sociodemographics, health care access, sexually transmitted infection/HIV status, COVID-19 testing, and sexual behaviors. Multivariable regression analyses identified factors associated with self-reported COVID-19 testing and positivity, and mpox exposure.

Results

Among 1135 responses, demographics were largely cisgender MSM and predominantly White. Increased self-reported COVID-19 positivity was associated with having more sex partners and frequenting bathhouses for meeting sex partners. Confidence in COVID-19 mitigation strategies decreased post-Omicron. Factors linked to mpox exposure included younger age, increased sex partners, sexually transmitted infection positivity, and lower confidence in mitigation strategies.

Discussion

These findings underscore the intersectionality between sexual behaviors and public health responses to COVID-19 and mpox among MSM communities affiliated with a CSV. Decreased confidence in mitigation strategies and changes in sexual behaviors during public health emergencies underscore the need for targeted interventions and messaging. Collaboration between health departments and CSVs can facilitate responses to current and future public health threats and interventions.
Gonorrhea and Chlamydia Opt-Out Screening of Justice-Involved Women During Intake at the Los Angeles County Jail: The Pivotal Role of Correctional Health Systems
Authors: Qureshi Nazia S. , Herrera Sulma J. , Miller Loren G. , Judge Stephen P. , Cardenas Charles M. , Henderson Sean O.
Published: August 2024

Background

Chlamydia and gonorrhea are 2 of the most common sexually transmitted infections (STIs) worldwide, presenting major public health challenges and resulting in billions of dollars in direct medical costs in the United States. Incarcerated women have a particularly elevated risk of these infections, which can result in serious sequelae if left untreated. On December 13, 2021, the Los Angeles County Jail system began offering opt-out urogenital chlamydia and gonorrhea screening to all newly incarcerated women.

Methods

We retrospectively analyzed electronic health record data for completed urogenital chlamydia/gonorrhea screening among newly incarcerated women between December 13, 2021, and May 31, 2023. We used multivariable logistic regression to examine the association of STIs and treatment non-initiation outcomes with various demographic and self-reported variables.

Results

Of the 13,739 female entrants offered STI testing, 10,717 (78%) completed screening, with 1151 (11%) having a chlamydial infection, 788 (7%) having a gonococcal infection, and 1626 (15%) having ≥1 infection. Sexually transmitted infection positivity was associated with age 18 to 34 years, reported houselessness, amphetamine use, and history of a positive prior treponemal antibody test result. Sexually transmitted infection treatment non-initiation was associated with shorter jail stay for both chlamydial (adjusted odds ratio, 87.4; 95% confidence interval, 34.2–223.2) and gonococcal (adjusted odds ratio, 9.0; 95% confidence interval, 5.2–15.7) infections.

Conclusion

The STI prevalence among female detainees tested was many-fold higher than that of the general population. The implementation of routine opt-out STI screening in carceral settings provides a unique opportunity to benefit the health of both the correctional population and potentially that of the surrounding community.
Prospective Validation of the Pancreatic Fistula Risk Classification by the International Study Group for Pancreatic Surgery (PARIS trial)
Authors: Schuh Fabian , Yildirim Berk , Klotz Rosa , Pianka Frank , Boskovic Andrea , Werba Alexander , Fink Matthias A. , Wild Caroline , Schwab Constantin , Eckert Christoph , Feisst Manuel , Mihaljevic André L. , Loos Martin , Büchler Markus , Probst Pascal
Published: August 2024

Objective:

The aim of this study was a prospective validation of the recently established ISGPS pancreas classification as a parenchymal risk classification system for pancreatic fistula after pancreatoduodenectomy.

Summary Background Data:

Postoperative pancreatic fistula (POPF) is the major driver for complications after partial pancreatoduodenectomy (PD). Recently, the International Study Group for Pancreatic Surgery (ISGPS) published a pancreas classification containing the parameters main pancreatic duct diameter (MPD) and pancreatic texture to help assess the risk of POPF development following pancreatoduodenectomy.

Methods:

From January 2020 to July 2021, 271 patients receiving elective PD were included after informed consent. The postoperative course was documented prospectively up to postoperative day 30. Among the pancreas characteristics, MPD and pancreatic texture were assessed intraoperatively at the pancreatic resection margin and the pancreatic glands were assigned to one of the four pancreas classes according to the ISGPS (A to D). The primary endpoint was POPF according to the updated ISGPS definition. Secondary endpoints comprised other post-PD morbidity and mortality.

Results:

Of 271 patients, 264 had available data according to the ISGPS pancreas classification. Of those, 78 were assigned to class A (30%), 53 to class B (20%), 50 to class C (19%) and 83 to class D (31%). POPF occurred in 54 of 271 patients (19.9%). The 30-day mortality was 7/271 (2.6%), with 6/7 having developed POPF (86%). POPF rates within the classes A, B, C and D were 9.0%, 11.3%, 20.0% and 37.4%, respectively (P<0.001). In the univariable regression analysis, only patients in pancreas class D demonstrated a significantly higher risk for POPF when compared to class A (OR 6.05, 95%-CI: 2.6-15.9, P<0.001). In the multivariable regression model, patients in class D had a significantly higher risk for POPF compared to class A (OR 3.45, 95%-CI: 1.15-11.3, P=0.032). The model comprised Body Mass Index, surgery duration, microscopic fibrosis and the ISGPS pancreas classification, demonstrating an AUC-value of approximately 0.82 when tested on the PARIS dataset.

Conclusion:

This prospective trial shows that the ISGPS pancreas classification is valid. Patients in risk class D are prone to POPF independently of other factors. Therefore, all future publications on pancreatic surgery should report the risk class according to the ISGPS pancreas classification to allow for a better comparison of reported cohorts.
The Association of Adverse Pregnancy Outcomes With Overactive Bladder Anticholinergics
Authors: Welk Blayne , McClure J. Andrew , McArthur Eric , Leong Yvonne
Published: August 2024

Importance

The pregnancy safety and teratogenicity of overactive bladder (OAB) anticholinergic medications in humans are unknown.

Objective

The aim of this study was to determine if the use of OAB anticholinergics during pregnancy was associated with adverse pregnancy outcomes or congenital malformation.

Study Design

Using routinely collected health care data from Ontario, Canada, we conducted a retrospective cohort study and identified women aged 18–45 years who gave birth between 2004 and 2022 and were eligible for provincial drug benefits. We used gestational age and birth dates to approximate conception dates. The primary exposure was filling a prescription for an OAB anticholinergic during pregnancy (compared with nonusers). The coprimary outcomes were pregnancy complication (which included preterm birth or low birth weight) and congenital malformation. Poisson regression models with generalized estimating equations and inverse probability of treatment weighting were used to estimate risk ratios (RRs).

Results

We identified 138,271 births, of which 479 (0.3%) had exposure to an OAB anticholinergic, for a median of 60 (interquartile range, 30–120) days. The most common OAB anticholinergic was oxybutynin (84%). In the weighted cohort, the risk of a pregnancy complication was significantly elevated (RR, 1.65; 95% confidence interval [CI], 1.40–1.95; P < 0.01; absolute risk difference + 9.9% [95% CI, +5.9, +13.9]), with a dose-response relationship close to statistical significance (P = 0.07). The risk of congenital malformations with OAB anticholinergic use was not significant (RR, 1.24; 95% CI, 0.85–1.80; P = 0.26).

Conclusions

Pregnant women who take OAB anticholinergic medications have a higher risk of pregnancy complications, but not congenital malformations, compared with non-OAB anticholinergic users. This information can be used when counseling women of child-bearing age about these medications.
Intrinsic dynamic shapes responses to external stimulation in the human brain
Authors: Nentwich Maximilian , Leszczynski Marcin , Schroeder Charles E. , Bickel Stephan , Parra Lucas C.
Published: August 2024

Sensory stimulation of the brain reverberates in its recurrent neuronal networks. However, current computational models of brain activity do not separate immediate sensory responses from intrinsic recurrent dynamics. We apply a vector-autoregressive model with external input (VARX), combining the concepts of “functional connectivity” and “encoding models”, to intracranial recordings in humans. We find that the recurrent connectivity during rest is largely unaltered during movie watching. The intrinsic recurrent dynamic enhances and prolongs the neural responses to scene cuts, eye movements, and sounds. Failing to account for these exogenous inputs, leads to spurious connections in the intrinsic “connectivity”. The model shows that an external stimulus can reduce intrinsic noise. It also shows that sensory areas have mostly outward, whereas higher-order brain areas mostly incoming connections. We conclude that the response to an external audiovisual stimulus can largely be attributed to the intrinsic dynamic of the brain, already observed during rest.
Desegregation of neuronal predictive processing
Authors: Wang Bin , Audette Nicholas J , Schneider David M , Aljadeff Johnatan
Published: August 2024

Neural circuits construct internal ‘world-models’ to guide behavior. The predictive processing framework posits that neural activity signaling sensory predictions and concurrently computing prediction-errors is a signature of those internal models. Here, to understand how the brain generates predictions for complex sensorimotor signals, we investigate the emergence of high-dimensional, multi-modal predictive representations in recurrent networks. We find that robust predictive processing arises in a network with loose excitatory/inhibitory balance. Contrary to previous proposals of functionally specialized cell-types, the network exhibits desegregation of stimulus and prediction-error representations. We confirmed these model predictions by experimentally probing predictive-coding circuits using a rich stimulus-set to violate learned expectations. When constrained by data, our model further reveals and makes concrete testable experimental predictions for the distinct functional roles of excitatory and inhibitory neurons, and of neurons in different layers along a laminar hierarchy, in computing multi-modal predictions. These results together imply that in natural conditions, neural representations of internal models are highly distributed, yet structured to allow flexible readout of behaviorally-relevant information. The generality of our model advances the understanding of computation of internal models across species, by incorporating different types of predictive computations into a unified framework.
MUC2 Expression Modulates Immune Infiltration in Colorectal Cancer
Authors: Raynaud Christophe M. , Jabeen Ayesha , Ahmed Eiman I. , Hubrack Satanay , Sanchez Apryl , Sherif Shimaa , Al-Shaibi Ahmad A , Roelands Jessica , Lo Bernice , Bedognetti Davide , Hendrickx Wouter
Published: August 2024

Introduction

Colorectal cancer (CRC) is a prevalent malignancy with significant morbidity and mortality worldwide. A deeper understanding of the interaction of cancer cells with other cells in the tumor microenvironment is crucial for devising effective therapeutic strategies. MUC2, a major component of the protective mucus layer in the gastrointestinal tract, has been implicated in CRC progression and immune response regulation.

Method

In this study, we sought to elucidate the relationship between MUC2 expression and immune infiltration within CRC, usingin-vitromodels involving two well-established cell lines, HT-29 and LS-174T. By employing CRISPR-mediated MUC2 knockout, we investigated the influence of MUC2 on tumor immune infiltration and its interplay with T cells and NK cells enriched peripheral blood mononuclear cells (PBMCs) in 3D spheroid cultures.

Results

While MUC2 was more abundant in LS-174T cell lines compared to HT-29, its knockout resulted in increased immune infiltration solely in the HT-29 cell line, but not in LS-174T. We revealed that the removal of MUC2 protein was compensated in LS-174T by the expression of other gel forming mucin proteins (Muc6, Muc5B) commonly expressed in gastrointestinal epithelium, while this was not observed in HT-29 cell line.

Discussion

We propose that the role of MUC2 documented in CRC progression can partially be explained by impairing immune infiltration due to physical barrier established by the gel forming proteins such as MUC2 in mucinous CRC. On the other hand, the removal of MUC2 expression can be compensated by alternative gel forming mucin proteins, thereby impeding any increase in tumor immune infiltration.
Meta-analysis of Public RNA-sequencing Data of Drought and Salt Stresses in Different Phenotypes ofOryza sativa
Authors: Shintani Mitsuo , Bono Hidemasa
Published: August 2024

Environmental stresses, such as drought and salt, adversely affect plant growth and crop productivity. While many studies have focused on established components of stress signaling pathways, research on unknown elements remains limited. In this study, we collected RNA sequencing (RNA-Seq) data fromOryza sativaregistered in public databases and conducted a meta-analysis integrating multiple studies. We analyzed 105 paired RNA-Seq datasets from resistant or susceptibleOryza sativacultivars under salt and drought conditions to identify novel stress-responsive genes with common expression changes across these datasets. A meta-analysis identified 10 genes specifically upregulated in resistant cultivars and 12 specifically upregulated in susceptible cultivars under both drought and salt conditions. Furthermore, by comparing previously identified stress-responsive genes inArabidopsis thaliana, we explored genes potentially involved in stress response mechanisms that are conserved across plant species. The genes identified in this data-driven study may serve as targets for future research and genome editing.
Touch inhibits cold: non-contact cooling reveals a novel thermotactile gating mechanism
Authors: Ezquerra-Romano Ivan , Chowdhury Maansib , Haggard Patrick
Published: August 2024

Skin stimuli reach the brain via multiple neural channels specific for different stimulus types. These channels interact in the spinal cord, typically through inhibition. Interchannel interactions can be investigated by selectively stimulating one channel and comparing the sensations that result when another sensory channel is or is not concurrently stimulated. Applying this logic to thermal-mechanical interactions proves difficult, because most existing thermal stimulators involve skin contact. We used a novel non-tactile stimulator for focal cooling (9mm2) by using thermal imaging of skin temperature as a feedback signal to regulate exposure to a dry ice source. We could then investigate how touch modulates cold sensation by delivering cooling to the human hand dorsum in either the presence or absence of light touch. Across three signal detection experiments, we found that sensitivity to cooling was significantly reduced by touch. This reduction was specific to touch, since it did not occur when presenting auditory signals instead of the tactile input, making explanations based on distraction or attention unlikely. Our findings suggest that touch inhibits cold perception, recalling interactions of touch and pain previously described by Pain Gate Theory. We show, for the first time, a thermotactile gating mechanism between mechanical and cooling signals.
Heat flows solubilize apatite to boost phosphate availability for prebiotic chemistry
Authors: Matreux Thomas , Schmid Almuth , Rappold Mechthild , Weller Daniel , Çalışkanoğlu Ayşe Zeynep , Moore Kelsey R. , Bosak Tanja , Dingwell Donald B. , Karaghiosoff Konstantin , Guyot François , Scheu Bettina , Braun Dieter , Mast Christof B.
Published: August 2024

Phosphorus is an essential building block of the most prominent biomolecules, such as polynucleic acids, and has likely played that role since the beginning of life. Despite this importance for prebiotic chemistry, phosphate could not be supplied by the atmosphere, and had to be fueled mainly by geological phosphate sources. However, phosphorus was scarce in Earth’s rock record and often bound in poorly soluble minerals, with the calcium phosphate mineral apatite as key example. While specific chemical boundary conditions that bind calcium have been used to address this so-called phosphate problem, a fundamental process that solubilizes and enriches phosphate from geological sources remains elusive. Here, we show that ubiquitous heat flows through rock cracks can liberate phosphate from apatite by the selective removal of calcium. Phosphate’s surprisingly strong thermophoresis not only achieves its 100-fold up-concentration in aqueous solution, in particular it also boosts its solubility by two orders of magnitude. We show that the heat-flow-solubilized phosphate can feed the synthesis of trimetaphosphate, increasing the conversion 260-fold compared to the thermal equilibrium case. Heat flows thus enhance solubility as a geological parameter to unlock apatites as phosphate source for prebiotic chemistry, providing a key element in solving early life’s phosphate problem.
The neurophysiology of healthy and pathological aging: A comprehensive systematic review
Authors: Fernández-Rubio Gemma , Vuust Peter , Kringelbach Morten L. , Bonetti Leonardo
Published: August 2024

As the population of older adults grows, so does the prevalence of neurocognitive disorders such as mild cognitive impairment (MCI) and dementia. While biochemical, genetic, and neuroimaging biomarkers have accelerated early detection and diagnosis, neurophysiological measures are absent from daily medical use. Electroencephalography (EEG) and magnetoencephalography (MEG) are two non-invasive techniques that measure neurophysiological signals in the brain and convey information about signal strength at different frequency bands, event-related activity, signal complexity, and temporal correlation between spatially remote brain regions. Here we conducted a pre-registered, comprehensive systematic review of 942 studies using EEG, MEG, and combined MEG and EEG to characterise the neurophysiology of healthy aging, MCI, and dementia under resting-state and task conditions. To complement our search, we also reviewed 51 past reviews in the field. Relevant features of these papers were extracted to present a detailed overview of the current state of evidence. Overall, neurophysiological measures show great promise as diagnostic tools and could prove invaluable in predicting healthy and pathological aging trajectories. However, to reach this potential in clinical practice, it is crucial to adopt longitudinal designs, standardise methodologies, and identify biomarkers at the individual rather than group level.
Hierarchical optimization of biochemical networks
Authors: Viswan Nisha Ann , Tribut Alexandre , Gasparyan Manvel , Radulescu Ovidiu , Bhalla Upinder S.
Published: August 2024

Biological signalling systems are complex, and efforts to build mechanistic models must confront a huge parameter space, indirect and incomplete data, and frequently encounter multiscale and multiphysics phenomena. We present HOSS, a framework for Hierarchical Optimization of Systems Simulations, to address such problems. HOSS operates by breaking down extensive systems models into individual pathway blocks organized in a nested hierarchy. At the first level, dependencies are solely on signalling inputs, and subsequent levels rely only on the preceding ones. We demonstrate that each independent pathway in every level can be efficiently optimized. Once optimized, its parameters are held constant while the pathway serves as input for succeeding levels. We develop an algorithmic approach to identify the necessary nested hierarchies for the application of HOSS in any given biochemical network. Furthermore, we devise two parallelizable variants that generate numerous model instances using stochastic scrambling of parameters during initial and intermediate stages of optimization. Our results indicate that these variants produce superior models and offer an estimate of solution degeneracy. Additionally, we showcase the effectiveness of the optimization methods for both abstracted, event-based simulations and ODE-based models.

Author summary

Biochemical pathway models integrate quantitative and qualitative data to understand cell functioning, disease effects, and to test treatments in silico. Constructing and optimizing these models is challenging due to the complexity and multitude of variables and parameters involved. Although hundreds of biochemical models have been developed and are available in repositories, they are rarely reused. To enhance the utilization of these models in biomedicine, we propose HOSS, an innovative hierarchical model optimization method. HOSS takes advantage of the modular structure of pathway models by breaking down large mechanistic computational models into smaller modules. These modules are then optimized progressively, starting with input modules and following causality paths. This method significantly reduces the computational burden as each step involves solving a simpler problem. By making the optimization process more manageable, HOSS accelerates the lifecycle of biochemical models and promotes their broader use in biomedical research and applications.
Deciphering tumour microenvironment and elucidating the origin of cancer cells in ovarian clear cell carcinoma
Authors: Kamaraj Uma S , Gautam Pradeep , Cheng Terence , Chin Tham Su , Tay Sun Kuie , Ho Tew Hong , Nadarajah Ravichandran , Goh Ronald Chin Hong , Wong Shing Lih , Mantoo Sangeeta , Busmanis Inny , Li Hu , Le Minh TN , Li Qi-Jing , Lim Elaine Hsuen , Loh Yuin-Han
Published: August 2024

Ovarian clear cell carcinoma (CCC) has an East Asian preponderance. It is associated with endometriosis, a benign condition where endometrial (inner lining of the uterus) tissue is found outside the uterus and on the peritoneal surface, in the abdominal or pelvic space. CCC is relatively more resistant to conventional chemotherapy compared to other ovarian cancer subtypes and is associated with a poorer prognosis. In this study, we recruited and obtained tumour tissues from seven patients across the four stages of CCC. The tumour and the tumour microenvironment (TME) from 7 CCC patients spanning clinical stages 1-4 were transcriptionally profiled using high-resolution scRNA-seq to gain insight into CCC’s biological mechanisms. Firstly, we built a scRNA-seq resource for the CCC tumour microenvironment (TME). Secondly, we identified the different cell type proportions and found high levels of immune infiltration in CCC. Thirdly, since CCC is associated with endometriosis, we compared CCC with two publicly available endometriosis scRNA-seq datasets. The CCC malignant cells showed similarities with glandular secretory and ciliated epithelial cells found in endometriosis. Finally, we determined the differences in cell-cell communication between various cell types present in CCC TME and endometriosis conditions to gain insights into the transformations in CCC.
Optics-free reconstruction of 2D images via DNA barcode proximity graphs
Authors: Liao Hanna , Kottapalli Sanjay , Huang Yuqi , Chaw Matthew , Gehring Jase , Waltner Olivia , Phung-Rojas Melissa , Daza Riza M. , Matsen Frederick A. , Trapnell Cole , Shendure Jay , Srivatsan Sanjay
Published: August 2024

Spatial genomic technologies include imaging- and sequencing-based methods (1–3). An emerging subcategory of sequencing-based methods relies on a surface coated with coordinate-associated DNA barcodes, which are leveraged to tag endogenous nucleic acids or cells in an overlaid tissue section (4–7). However, the physical registration of DNA barcodes to spatial coordinates is challenging, necessitating either high density printing of coordinate-specific oligonucleotides orin situsequencing/probing of randomly deposited, oligonucleotide-bearing beads. As a consequence, the surface areas available to sequencing-based spatial genomic methods are constrained by the time, labor, cost, and instrumentation required to either print, synthesize or decode a coordinate-tagged surface. To address this challenge, we developed SCOPE (Spatial reConstruction via Oligonucleotide Proximity Encoding), an optics-free, DNA microscopy (8) inspired method. With SCOPE, the relative positions of randomly deposited beads on a 2D surface are inferred from theex situsequencing of chimeric molecules formed from diffusing “sender” and tethered “receiver” oligonucleotides. As a first proof-of-concept, we apply SCOPE to reconstruct an asymmetric “swoosh” shape resembling the Nike logo (16.75 × 9.25 mm). Next, we use a microarray printer to encode a “color” version of the Snellen eye chart for visual acuity (17.18 × 40.97 mm), and apply SCOPE to achieve optics-free reconstruction of individual letters. Although these are early demonstrations of the concept and much work remains to be done, we envision that the optics-free, sequencing-based quantitation of the molecular proximities of DNA barcodes will enable spatial genomics in constant experimental time, across fields of view and at resolutions that are determined by sequencing depth, bead size, and diffusion kinetics, rather than the limitations of optical instruments or microarray printers.
Gut microbiome shifts in chronic systolic heart failure are associated with disease severity and clinical improvement
Authors: Mamic Petra , Shi Handuo , Zhou Wenyu , Bararpour Nasim , Contrepois Kevin , Park Heyjun , Avina Monika , Rose Sophia Miryam Schüssler-Fiorenza , Heidenreich Paul A. , Khush Kiran Kaur , Fowler Michael B. , Tang W. H. Wilson , Sallam Karim , Sonnenburg Justin , Huang Kerwyn Casey , Snyder Michael P.
Published: August 2024

Chronic systolic heart failure (HF) is a prevalent and morbid disease with marked variability in its progression and response to therapies. The gut microbiome may play a role in pathophysiology and progression of chronic HF, but clinical studies investigating relationships between the two are lacking. We analyzed the gut microbiome in a cohort of adults with chronic systolic HF caused by non-ischemic cardiomyopathy (n=59) using multi-omics profiling and, in some cases, longitudinal sampling. We identified microbiome differences compared to healthy subjects (n=50) and associated these differences with host metabolites, inflammatory markers and physiology. We found depletion of the anti-inflammatory probioticBifidobacteriumand the associated short chain fatty acid producing and formaldehyde detoxifying pathways in the chronic HF cohort. We also discovered HF-specific microbiome-host immunome interactions. In addition to identifying several taxa and microbial pathways broadly associated with HF disease severity, we found significant links betweenBifidobacteriumand clinical HF improvement over time. Gut microbiome-host multi-omic data integration revealed a close association betweenBifidobacteriumand circulating metabolites previously implicated in cardiovascular physiology (e.g., malonic acid), thus pointing to potential mechanisms through whichBifidobacteriummay affect chronic HF physiology. Our results suggest thatBifidobacteriummay serve as a biomarker for chronic HF trajectory as well as suggest potential novel therapeutic interventions strategies.
MMINT: a Metabolic Model Interactive Network Tool for the exploration and comparative visualisation of metabolic networks
Authors: Molina Ortiz Juan P. , Morgan Matthew J. , Paten Amy M. , Warden Andrew C. , Kilby Philip
Published: August 2024

Genome-scale metabolic models (GEMs) are essential tools in systems and synthetic biology, enabling the mathematical simulation of metabolic pathways encoded in genomes to predict phenotypes. The complexity of GEMs, however, can often limit the interpretation and comparison of their outputs. Here, we present MMINT (Metabolic Modelling Interactive Network Tool), designed to facilitate the exploration and comparison of metabolic networks. MMINT employs GEM networks and flux solutions derived from Constraint Based Analysis (e.g. Flux Balance Analysis) to create interactive visualizations. This tool allows for seamless toggling of source and target metabolites, network decluttering, enabling exploration and comparison of flux solutions by highlighting similarities and differences between metabolic states, which enhances the identification of mechanistic drivers of phenotypes. We demonstrate MMINT’s capabilities using thePyrococcus furiosusGEM, showcasing its application in distinguishing the metabolic drivers of acetate- and ethanol-producing phenotypes. By providing an intuitive and responsive model-exploration experience, MMINT addresses the need for a tool that simplifies the interpretation of GEM outputs and supports the discovery of novel metabolic engineering strategies. MMINT is available athttps://doi.org/10.6084/m9.figshare.26409328

Graphical abstract

MMINT functionalities provide an intuitive and responsive model-exploration experience, enabling flux solution comparison and the identification of metabolic drivers of phenotypes
Evaluation of resistant starch from teff (Eragrostis tef) grain as a film coating material for colon-targeted drug delivery
Authors: Teshome Yohannes , Belete Anteneh , Gebre-Mariam Tsige
Published: August 2024

Teff (Eragrostis tef, family Poaceae) is a native cereal crop widely grown in Ethiopia, containing approximately 73% carbohydrates, of which about 30% is resistant starch. This study evaluates resistant starch extracted from teff grain as a film coating material for colon-targeted delivery of metronidazole, used as a model drug. Starch was extracted from teff and resistant starch was isolated from the total starch. Metronidazole core tablets were prepared by wet granulation, compressed, and coated with a resistant starch-based film. The physicochemical properties of the tablets were evaluatedin vitro. To prevent premature film disruption caused by the swelling of amylose, a dominant component of resistant starch, a water-insoluble polymer, ethylcellulose, was added. Various proportions of amylose and ethylcellulose were used as film coating materials and evaluated in simulated conditions to determine the optimal combination for drug release in the colon, but not in the upper gastrointestinal tract. The results of the dissolution and fermentation studies indicated the best film coating proportions of amylose to ethylcellulose and the corresponding thicknesses in percentage of total weight gain were: 1:1 ratio at 6% thickness, 1:2 ratio at 4% and 6% thickness, and 1:3 ratio at 2% and 4% thickness. The targeted drug release of the film material is attributed to bacterial enzyme digestion of the resistant starch component in the colon. The digestion of resistant starch creates pores in the ethylcellulose film scaffold, leading to the disruption of the film and release of the drug exclusively in the colon, where the bacterial microflora reside. Based on these results, resistant starch from teff grain shows potential as a colon-targeting excipient.
Paraptosome: A Novel Pathological Feature in Paraptotic Cell Death
Authors: Cui Xiang , Zheng Hongda , Li Haoming , Zhang Fang , Yang Liao , Ni Jiayu , Wang Dengfeng , Zhang Huali , Tang Pan , Li Ru , Zhang Qi , Cui Min
Published: August 2024

Paraptosis is a novel form of programmed cell death characterized by distinct morphological features such as swelling of the endoplasmic reticulum and mitochondria, and cytoplasmic vacuolation. Unlike apoptosis, paraptosis does not involve the activation of caspases or DNA fragmentation. These unique features make paraptosis an intriguing target for cancer therapy, particularly against apoptosis-resistant cells. Here, we report a novel morphological feature of paraptosis: the formation of high-density spherical structure, which we tentatively term “paraptosome.” We found that these putative paraptosomes originate from the Golgi apparatus, appearing as high-density formations under light microscopy and colocalizing with the trans-Golgi marker β4GALT1-RFP. Time-lapse confocal microscopy and immunostaining demonstrated that putative paraptosomes form due to Golgi stress or disintegration, leading to severe disruption of Golgi function. Furthermore, we show that paraptosis inducers such as glabridin, morusin, and honokiol can cause significant alterations in the endoplasmic reticulum, mitochondria, autophagosomes, and lysosomes in U251MG glioblastoma cells; however, the formation of putative paraptosomes is not induced by isolated stress inducers. Collectively, these findings suggest that the putative paraptosome may be a novel characteristic structure of paraptosis. The discovery of paraptosomes provides a unique marker for defining paraptotic cell death and offers new insights into the characteristic pathological phenomena associated with multiple organelle dysfunction. This finding broadens the scope of cell biology research by introducing a new structural paradigm linked to paraptosis and may have implications for developing targeted therapies against apoptosis-resistant cancers.