bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced progress of the relationship between renin–angiotensin–aldosterone system inhibitors and cancers
Authors: Zhang Ruixing , Yin Hongtao , Yang Mengdi , Liu Jinjin , Zhen Donghu , Zhang Zheng
Published: September 2024

Hypertension and cancers are the most common causes of death in humans, as well as common co-diseases among elderly population. Studies have shown that hypertension is associated with carcinogenesis. The renin–angiotensin–aldosterone system (RAAS) is a crucial regulatory system of blood pressure, fluid, and electrolyte homeostasis, which plays an essential role in the pathogenesis of hypertension, whose mechanism is relatively clear. Studies have indicated that RAAS also widely exists in cancer tissues of different systems, which can affect the risk of cancers by stimulating cancer angiogenesis, participating in cancer-related oxidative stress, and regulating cancer-related immunity. Therefore, inhibiting RAAS activity seems beneficial to decreasing the risk of cancers. As one of the most commonly used antihypertensive drugs, RAAS inhibitors have been widely used in clinical practice. However, the conclusions of clinical studies on the relationship between RAAS inhibitors and cancers are not entirely consistent, which has been widely concerned by clinicians. The latest findings suggest that while RAAS inhibitors may reduce the risk of digestive cancers, respiratory cancers, urological cancers, gynecological cancers, and skin cancers, ACEIs may increase the risk of lung cancer, endometrial cancer, basal cell carcinoma, and squamous cell carcinoma. This article comprehensively reviews animal experiments, clinical studies, and meta-analyses on the relationship between RAAS inhibitors and cancers, to provide references for related studies in the future.
Comparison of the Effects of Orthokeratology and Highly Aspherical Lenselets in Achieving Myopia Control and Defocus in Adolescents
Authors: Yu Jia , Guo Yujuan , Zhou Yuehua
Published: September 2024

Objectives:

To compare the control effectiveness and periretinal defocus between orthokeratology (OK) and highly aspherical lenslets (HAL) in adolescents with myopia.

Methods:

In this prospective study, 211 children (211 right eyes) were enrolled in Beijing Ming Vision and Ophthalmology between October 2022 and February 2023. Based on the myopia correction method, participants were divided into three groups: OK, HAL, and single-vision spectacles (SVS). They were further divided into two subgroups according to the spherical equivalent (SE), namely, subgroup A with −1.0≤SE≤−2.0 D and subgroup B with −2.0<SE≤−3.0 D. All children were followed up for 12 months, and the changes in axial length (AL) and periretinal defocus before and after treatment were recorded, and the factors affecting the corneal shaping force for 1-day post-OK were analyzed.

Results:

Axial length growth in those with OK lenses and HAL was lower than what was observed for those with SVS after 6, 9, and 12 months. Comparison of the difference in AL change between OK and HAL was not statistically significant with −1.0≤SE≤−2.0 D. The myopic defocus of RDV270° to 300° in group HAL was higher than that in group OK, the difference was statistically significant (P<0.05), and in other regions, the myopic defocus was higher in the group OK. Em, SRI (corneal regularity index), variation in cell area, and corneal thickness were significantly associated with shaping force.

Conclusions:

Orthokeratology is one of the most effective optical treatments for controlling myopia, and the factors that affect the corneal shaping force under different corneal parameters are different. For mild myopia, HAL can achieve the same effectiveness as OK.
Extended reality used in the treatment of phantom limb pain: a multicenter, double-blind, randomized controlled trial
Authors: Lendaro Eva , Van der Sluis Corry K. , Hermansson Liselotte , Bunketorp-Käll Lina , Burger Helena , Keesom Els , Widehammar Cathrine , Munoz-Novoa Maria , McGuire Brian E. , O’Reilly Paul , Earley Eric J. , Iqbal Sonam , Kristoffersen Morten B. , Stockselius Anita , Gudmundson Lena , Hill Wendy , Diers Martin , Turner Kristi L. , Weiss Thomas , Ortiz-Catalan Max
Published: September 2024

Phantom limb pain (PLP) represents a significant challenge after amputation. This study investigated the use of phantom motor execution (PME) and phantom motor imagery (PMI) facilitated by extended reality (XR) for the treatment of PLP. Both treatments used XR, but PME involved overt execution of phantom movements, relying on the decoding of motor intent using machine learning to enable real-time control in XR. In contrast, PMI involved mental rehearsal of phantom movements guided by XR. The study hypothesized that PME would be superior to PMI. A multicenter, double-blind, randomized controlled trial was conducted in 9 outpatient clinics across 7 countries. Eighty-one participants with PLP were randomly assigned to PME or PMI training. The primary outcome was the change in PLP, measured by the Pain Rating Index, from baseline to treatment cessation. Secondary outcomes included various aspects related to PLP, such as the rate of clinically meaningful reduction in pain (CMRP; >50% pain decrease). No evidence was found for superiority of overt execution (PME) over imagery (PMI) using XR. PLP decreased by 64.5% and 68.2% in PME and PMI groups, respectively. Thirty-seven PME participants (71%) and 19 PMI participants (68%) experienced CMRP. Positive changes were recorded in all other outcomes, without group differences. Pain reduction for PME was larger than previously reported. Despite our initial hypothesis not being confirmed, PME and PMI, aided by XR, are likely to offer meaningful PLP relief to most patients. These findings merit consideration of these therapies as viable treatment options and alternatives to pharmacological treatments.
Fluid management in the septic peri-operative patient
Authors: Nasa Prashant , Wise Robert , Malbrain Manu L.N.G.
Published: September 2024

Purpose of review

This review provides insight into recent clinical studies involving septic peri-operative patients and highlights gaps in understanding fluid management. The aim is to enhance the understanding of safe fluid resuscitation to optimize peri-operative outcomes and reduce complications.

Recent findings

Recent research shows adverse surgical and clinical outcomes with both under- and over-hydration of peri-operative patients. The kinetic of intravenous fluids varies significantly during surgery, general anaesthesia, and sepsis with damage to endothelial glycocalyx (EG), which increases vascular permeability and interstitial oedema. Among clinical anaesthesia, neuraxial anaesthesia and sevoflurane have less effect on EG. Hypervolemia and the speed and volume of fluid infusion are also linked to EG shedding. Despite improvement in the antisepsis strategies, peri-operative sepsis is not uncommon. Fluid resuscitation is the cornerstone of sepsis management. However, overzealous fluid resuscitation is associated with increased mortality in patients with sepsis and septic shock. Personalized fluid resuscitation based on a careful assessment of intravascular volume status, dynamic haemodynamic variables and fluid tolerance appears to be a safe approach. Balanced solutions (BS) are preferred over 0.9% saline in patients with sepsis and septic shock due to a potential reduction in mortality, when exclusive BS are used and/or large volume of fluids are required for fluid resuscitation. Peri-operative goal-directed fluid therapy (GDFT) using dynamic haemodynamic variables remains an area of interest in reducing postoperative complications and can be considered for sepsis management (Supplementary Digital Content).

Optimization of peri-operative fluid management is crucial for improving surgical outcomes and reducing postoperative complications in patients with sepsis. Individualized and GDFT using BS is the preferred approach for fluid resuscitation in septic peri-operative patients. Future research should evaluate the interaction between clinical anaesthesia and EG, its implications on fluid resuscitation, and the impact of GDFT in septic peri-operative patients.
Renal dysfunction in surgical patients
Authors: Booke Hendrik , Zarbock Alexander , Meersch Melanie
Published: September 2024

Purpose of review

To provide an overview of the current diagnostic criteria for acute kidney injury (AKI) including their limitations and to discuss prevention and treatment approaches in the perioperative setting.

Recent findings

AKI is common in the perioperative period and is associated with worse short- and long-term outcomes. Current definitions of AKI have several limitations and lead to delayed recognition of kidney dysfunction which is why novel diagnostic approaches by using renal biomarkers may be helpful. In general, prevention of the development and progression of AKI is vital as a causal treatment for AKI is currently not available. Optimization of kidney perfusion and avoidance of nephrotoxic drugs reduce the occurrence of AKI in surgical patients. Angiotensin II as a new vasopressor, the use of remote ischemic preconditioning, and amino acids may be approaches with a positive effect on the kidneys.

Evidence suggests that the implementation of supportive measures in patients at high risk for AKI might reduce the occurrence of AKI. Novel biomarkers can help allocating resources by detecting patients at high risk for AKI.
Development of an Evidence-Based List of Non-Antineoplastic Vesicants
Authors: Gorski Lisa A. , Ong Jennie , Van Gerpen Ruth , Nickel Barb , Kokotis Kathy , Hadaway Lynn
Published: September 2024

Infiltration of a vesicant, calledextravasation, can result in severe patient injuries. Recognition of vesicants and their relative risk of injury is essential to extravasation prevention, early recognition, and appropriate treatment. In this article, the Vesicant Task Force (VTF) updates the previously published Infusion Nurses Society (INS) vesicant list from 2017. The 2024 INS list diverges from earlier vesicant lists, such as the 2017 VTF list, by adopting a risk stratification approach based upon documented patient outcomes, in contrast to the reliance on expert consensus or only surrogate risk indicators, such as pH and osmolarity. The methodology used to create the updated list is explained, and the criteria for high- and moderate-risk vesicants and cautionary vesicants are defined.
Using Existing Resources to Create a Successful End-of-Life Doula Program
Authors: de Campos Amisha Parekh , Santostefano Diane , Daniels Susan
Published: September 2024

The end-of-life doula role has emerged as an integral part of the interdisciplinary team caring for patients. The doulas provide an extra layer of support from a non-clinical lens to prevent crises, follow-up with families, and guide them through their journey. This manuscript describes how a hospice agency developed a performance improvement project to train volunteers to become end-of-life doulas through a rigorous training program, based on the Doula Model of Care. The implementation of the program was evaluated based on caregiver and staff satisfaction, and volunteer knowledge competency. The results from the pilot program showed mixed outcomes for patient and staff satisfaction, but created a rigorous training program for hospice volunteers. The COVID-19 pandemic disrupted data gathering and implementation of the program, so outcomes were varied. However, the program remains successful with ongoing training of the end-of-life doulas and an increase in new volunteers to support the program.
Linking Interprofessional Community Health Experiences With Nursing Education
Authors: Hadinger Margaret A. , Miller Mary Ellen , Letcher Abby
Published: September 2024

Background:

Ensuring that nurses and other health care professionals are trained to work together in teams is critical.

Problem:

Recent literature describes interprofessional education (IPE) programs that meet community health needs. However, there is a need for descriptions of IPE programs embedded in the communities they serve.

Approach:

Bridging the Gaps (BTG) is a collaboration between academic health institutions/universities and community organizations in the northeastern United States. BTG links IPE with the provision of health-related services for under resourced communities. This article describes the development of one BTG Community Health Internship Program (BTG CHIP) affiliate site (BTG, Lehigh Valley).

Outcomes:

Since inception, 114 interns completed the program as part of BTG CHIP, Lehigh Valley, for a total of 3192 days of service provided to the community. BTG CHIP, Lehigh Valley, serves as a case study for establishing similar community-based IPE programs. This article describes challenges, opportunities, and replication strategies.
Sham feeding as a nursing technology: Recent progress and future perspective
Authors: Li Ka , Han Yanting , Ullah Hanif , Chang Chenting , Cao Liujiao
Published: September 2024

Sham feeding is a conventional technique employed in enhanced recovery after surgery (ERAS) protocols to facilitate the restoration of gastrointestinal motility. Currently, the effectiveness of sham feeding extends beyond the postoperative phase after abdominal surgery, demonstrating potential applicability in nonabdominal postoperative rehabilitation. Studies have shown that sham feeding triggers the head-vagal reflex, thereby promoting gastrointestinal motility through a combination of humoral and neural stimulation. Recognized as a highly promising ERAS technology, sham feeding needs to be further investigated regarding the form, mechanism, and application of sham feeding. This paper summarized the research progress and limitations of sham feeding. Considering contemporary research focus on the gut-brain axis, we proposed a new concept of sham feeding that integrates visual, auditory, and olfactory stimuli. In addition, we provide suggestions and perspectives to guide future exploration of sham feeding for its potential impact on the development of non-drug nursing intervention technology based on the concept of ERAS.
Rural-Urban Differences in Self-Reported Participation in Diabetes Self-Management Education
Authors: Boswell Emma , Probst Jan , Hung Peiyin , Herbert Laura , Crouch Elizabeth
Published: September 2024

Context:

Rural America faces a dual challenge with a higher prevalence of diabetes mellitus (hereafter, diabetes) and diabetes-related mortality. Diabetes self-management education (DSME) can improve glucose control and reduce adverse effects of diabetes, but certified DSME programs remain disproportionately limited in rural counties than in urban counties.

Objective:

The goal of this study is to examine the proportion of urban and rural adults who report having received DSME using a nationwide, 29-state survey while considering the potential consequences of lower service availability.

Design:

This cross-sectional study used data from the 2019 Behavioral Risk Factor Surveillance System (BRFSS). Residence was defined as urban (metropolitan county) vs rural (non-metropolitan county). Logistic regression, incorporated survey weights, was used to determine the odds of having received DSME by residence.

Setting:

BRFSS is a nationally representative survey, and this study included participants from 29 states that were distributed throughout all regions of the United States.

Participants:

The study sample consisted of 28,179 adults who reported having diabetes, lived in one of the states that administered the diabetes module in 2019, and answered all relevant questions.

Main Outcome Measure(s):

The main outcome measure was whether a participant had ever received DSME. Participants were considered to have received DSME if they self-reported having ever taken a class on how to manage diabetes themselves.

Results:

Overall, 54.5% of participants reported having received DSME; proportionately fewer rural residents (50.4%, ±1.1%) than urban residents (55.5%, ±1.0%) reported DSME. Rural disparities persisted after adjusting for demographic, enabling, and need factors (Adjusted Odds Ratio  = 0.79; CI, 0.71-0.89). By sociodemographic factors, Hispanic persons vs non-Hispanic White persons and single vs married/coupled individuals were less likely to report DSME receipt (both 0.76 [0.62-0.94]).

Conclusions:

Ongoing national efforts addressing rural disparities in diabetes-related complications should target individuals most at risk for missing current diabetes educational programming and design appropriate interventions.
A myriad of methods to determine temporal summation of pain in people with musculoskeletal pain and healthy participants: a scoping review
Authors: Kielstra Sjoerd C. , Reezigt Roland R. , Coppieters Michel W. , de Vries Ralph , Arendt-Nielsen Lars , Petersen Kristian K. , Yarnitsky David , Scholten-Peeters Gwendolyne G.M.
Published: September 2024

Temporal summation of pain (TSP) is a human proxy for wind-up of dorsal horn neurons as assessed in animals. The common paradigm for eliciting TSP is evoked by repetitive nociceptive stimuli of equal intensity. Various stimulation and assessment protocols have been used. This scoping review aims to provide insight into key elements of TSP stimulation and assessment: modality, instruments, test location, familiarization, train characteristics, and calculations. PubMed, Embase, and Ebsco/CINAHL were searched for studies that measured TSP in adults with musculoskeletal conditions and healthy people. Four hundred six studies were included. Mechanical stimuli were the most commonly used modality (250 studies), followed by thermal stimuli (125 studies). Forty-six different instruments were used. Disregarding studies on widespread musculoskeletal pain and healthy participants, 40 studies evaluated TSP at painful sites, 77 in remote areas, and 66 in both locations. Of the 13 tested locations in patients, the hand (74 studies), lower leg (64 studies), and forearm (59 studies) were most commonly tested. A single practice round was the most common familiarization method (46 studies). Repeated stimuli were applied using 31 different frequencies (0.03-200 Hz) and sustained stimulations ranging from 5 to 1080 seconds were used. Twenty-two different train lengths, 63 different calculations (37 absolute, 19 relative, and 7 alternatives using data directly), and 14 different outcome measures (eg, self-reported pain rating scales and reflex thresholds) were used. Temporal summation of pain protocols vary excessively, hindering the comparison and pooling of results. None of the studies provided substantiation for their protocol choice.
Interfacility Competition and its Impact on Cost of Carpal Tunnel Release
Authors: Rivedal David D. , Cichocki Meghan N. , Tong Yanlin , Wang Lu , Chung Kevin C.
Published: September 2024

Background:

Carpal tunnel release (CTR) is the most common hand surgery procedure, but little is known about how healthcare market characteristics influence cost. The objective of this study was to understand the association of healthcare market competition and facility availability on out-of-pocket and total insurer payments for patients undergoing CTR.

Methods:

This retrospective cross-sectional study used a national sample of private insurance claims from 2015-2020. Adults who had CTR were included, while acute or inpatient CTRs, or lacking geographical information were excluded. Linear regression was applied to investigate the impact of the healthcare market competition and facility availability (ambulatory surgery center (ASC), hospital outpatient departments (HOPD), outpatient clinics) on the out-of-pocket expenses and total insurer payment. Market competition was measured using the Herfindahl-Hirschman Index.

Results:

Of 119,828 patients, 76% underwent open CTR. The most competitive hospital markets were HOPDs and ASCs, respectively. As HOPD competition decreased, out-of-pocket expenses and total insurer payment decreased significantly. As ASC competition decreased, only total insurer payments decreased significantly. CTRs performed in outpatient clinics increased slightly over time. However, HOPDs remained the most common location until 2020 when their popularity was similar to ASCs. Finally, out-of-pocket expenses increased significantly whereas total insurer payments did not change significantly throughout the study period.

Conclusions:

This study found decreased healthcare market competition was not associated with increased CTR costs, suggesting that costs are complex and multifactorial. To reduce healthcare costs, this study supports the movement of CTRs to clinic and ASCs.
How to evaluate exertional breathlessness using normative reference equations in research
Authors: Ekström Magnus , Lewthwaite Hayley , Jensen Dennis
Published: September 2024

Purpose of review

Breathlessness is a common, distressing and limiting symptom in people with advanced disease, but is challenging to assess as the symptom intensity depends on the level of exertion (symptom stimulus) during the assessment. This review outlines how to use recently developed normative reference equations to evaluate breathlessness responses, accounting for level of exertion, for valid assessment in symptom research.

Recent findings

Published normative reference equations are freely available to predict the breathlessness intensity response (on a 0–10 Borg scale) among healthy people after a 6-minute walking test (6MWT) or an incremental cycle cardiopulmonary exercise test (iCPET). The predicted normal values account for individual characteristics (including age, sex, height, and body mass) and level of exertion (walk distance for 6MWT; power output, oxygen uptake, or minute ventilation at any point during the iCPET). The equations can be used to (1) construct a matched healthy control dataset for a study; (2) determine how abnormal an individual’s exertional breathlessness is compared with healthy controls; (3) identify abnormal exertional breathlessness (rating > upper limit of normal); and (4) validly compare exertional breathlessness levels across individuals and groups.

Methods for standardized and valid assessment of exertional breathlessness have emerged for improved symptoms research.
Targeted Broader Sharing for Liver Continuous Distribution
Authors: Mankowski Michal A. , Wood Nicholas L. , Massie Allan B. , Segev Dorry L. , Trichakis Nikolaos , Gentry Sommer E.
Published: September 2024

Background.

In recent years, changes to US organ allocation have aimed to improve equity and accessibility across regions. The Organ Procurement and Transplantation Network plans to adopt continuous liver distribution, prioritizing candidates based on a weighted composite allocation score (CAS) incorporating proximity, ABO types, medical urgency, and pediatric priority. The Liver Committee has requested research on CAS variations that account for geographical heterogenicity.

Methods.

We describe a method for designing a geographically heterogeneous CAS with targeted broader sharing (CAS-TBS) to balance the highly variable geographic distributions of liver transplant listings and liver donations. CAS-TBS assigns each donor hospital to either broader sharing or nearby sharing, adjusting donor-candidate distance allocation points accordingly.

Results.

We found that to reduce geographic disparity in the median Model for End-stage Liver Disease at transplant (MMaT), >75% of livers recovered in regions 2 and 10 should be distributed with broader sharing, whereas 95% of livers recovered in regions 5 and 1 should be distributed with nearby sharing. In a 3-y simulation of liver allocation, CAS-TBS decreased MMaT by 2.1 points in high-MMaT areas such as region 5 while increasing MMaT only by 0.65 points in low-MMaT areas such as region 3. CAS-TBS significantly decreased median transport distance from 202 to 167 nautical miles under acuity circles and decreased waitlist deaths.

Conclusions.

Our CAS-TBS design methodology could be applied to design geographically heterogeneous allocation scores that reflect transplant community values and priorities within the continuous distribution project of the Organ Procurement and Transplantation Network. In our simulations, the incremental benefit of CAS-TBS over CAS was modest.
REACTIVE ARTHRITIS: A CASE REPORT AT THE MOHAMMED V MILITARY TRAINING HOSPITAL IN RABAT
Authors: laatiris hamid , Zniber Nabil , el mostafa benaissa , benlahlou yassine , chadli mariama
Published: September 2024

Reactive arthritis (RA) is a type of joint inflammation that usually occurs after a genitourinary or digestive infection, without the presence of germs in the joint itself. It often presents as asymmetric arthritis, joint pain, swelling, deformities in fingers or toes, and various skin or mucosal symptoms. The diagnosis is mainly based on clinical signs and is frequently associated with spondyloarthropathies, with severe cases often linked to the presence of the HLA-B27 gene.We present the case of a 23-year-old patient admitted to the Mohammed V Military Training Hospital in Rabat for bilateral knee pain, lumbosciatica, dactylitis, urethral discharge, and bloody mucus diarrhea. Radiographic and MRI examinations were atypical for RA, showing neither focal bone lesions nor intra-articular effusion. Biological tests revealed leukocytosis, an elevated sedimentation rate, and high CRP levels, while the joint fluid remained sterile. Tests detected an infection with Ureaplasma urealyticum and Chlamydia trachomatis through PCR, along with a co-infection with hepatitis C. HLA-B27 genotyping and the presence of antinuclear antibodies were also noted.
Cell identity revealed by precise cell cycle state mapping links data modalities
Authors: Alahmari Saeed , Schultz Andrew , Albrecht Jordan , Tagal Vural , Siddiqui Zaid , Prabhakaran Sandhya , El Naqa Issam , Anderson Alexander , Heiser Laura , Andor Noemi
Published: September 2024

Several methods for cell cycle inference from sequencing data exist and are widely adopted. In contrast, methods for classification of cell cycle state from imaging data are scarce. We have for the first time integrated sequencing and imaging derived cell cycle pseudo-times for assigning 449 imaged cells to 693 sequenced cells at an average resolution of 3.4 and 2.4 cells for sequencing and imaging data respectively. Data integration revealed thousands of pathways and organelle features that are correlated with each other, including several previously known interactions and novel associations. The ability to assign the transcriptome state of a profiled cell to its closest living relative, which is still actively growing and expanding opens the door for genotype-phenotype mapping at single cell resolution forward in time.
AI-enabled Alkaline-resistant Evolution of Protein to Apply in Mass Production
Authors: Kang Liqi , Wu Banghao , Zhou Bingxin , Tan Pan , Kang Yun (Kenneth) , Yan Yongzhen , Zong Yi , Li Shuang , Liu Zhuo , Hong Liang
Published: September 2024

Artificial intelligence (AI) models have been used to study the compositional regularities of proteins in nature, enabling it to assist in protein design to improve the efficiency of protein engineering and reduce manufacturing cost. However, in industrial settings, proteins are often required to work in extreme environments where they are relatively scarce or even non-existent in nature. Since such proteins are almost absent in the training datasets, it is uncertain whether AI model possesses the capability of evolving the protein to adapt extreme conditions. Antibodies are crucial components of affinity chromatography, and they are hoped to remain active at the extreme environments where most proteins cannot tolerate. In this study, we applied an advanced large language model (LLM), the Pro-PRIME model, to improve the alkali resistance of a representative antibody, a VHH antibody capable of binding to growth hormone. Through two rounds of design, we ensured that the selected mutant has enhanced functionality, including higher thermal stability, extreme pH resistance and stronger affinity, thereby validating the generalized capability of the LLM in meeting specific demands. To the best of our knowledge, this is the first LLM-designed protein product, which is successfully applied in mass production.
MIP3α-RelMtbintranasal DNA vaccination induces reactive T-cell infiltration into the lungs in mice and macaques
Authors: Gordy James T. , Zheng Jean J. , Maxwell Amanda R. , Taylor Alannah D. , Karanika Styliani , Bates Rowan E. , Ton Heemee , Meza Jacob , Li Yangchen , Zhang Jiaqi , Karakousis Petros C. , Markham Richard B.
Published: September 2024

Mycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB), is the leading cause of mortality due to a single infectious organism. While generally curable, TB requires a lengthy and complex antibiotic regimen, due in large part to bacteria that can shift to a persistent state in the presence of antibiotic pressure. RelMtbis the primary enzyme regulating the stringent response, which contributes to the metabolic shift of Mtb to a persistent state. Targeting RelMtbwith a vaccine to eliminate persistent bacteria through the induction of RelMtb-specific T-cell immunity in combination with antibiotics to kill dividing bacteria has shown promise in model systems. In a mouse model of Mtb infection, a vaccine created by genetically fusingrelMtbto the chemokine macrophage inflammatory protein 3α (MIP3α), a ligand for the CC chemokine receptor type 6 (CCR6) present on immature dendritic cells, has been shown to enhance T-cell responses and accelerate eradication of infection in mouse models compared to a vaccine lacking the chemokine component. In this study, immunogenicity studies in the mouse and rhesus macaque models provide evidence that intranasal administrations of the DNA form of the MipRel vaccine led to enhanced lung infiltration of T cells after a series of immunizations. Furthermore, despite similar T-cell immunity seen in PBMCs between MipRel and Rel vaccinations, lung and bronchoalveolar lavage cell samples are more enriched for cytokine-secreting T cells in MipRel groups compared to Rel groups. We conclude that intranasal immunization with a MIP-3α fusion vaccine represents a novel strategy for use of a simple DNA vaccine formulation to elicit T-cell immune responses within the respiratory tract. That this formulation is immunogenic in a non-human primate model historically viewed as poorly responsive to DNA vaccines indicates the potential for clinical application in the treatment of Mtb infection, with possible application to other respiratory pathogens. Future studies will further characterize the protective effect of this vaccination platform.
Proximity labeling defines the phagosome lumen proteome of murine and primary human macrophages
Authors: Allsup Benjamin L. , Gharpure Supriya , Bryson Bryan D.
Published: September 2024

Proteomic analyses of the phagosome has significantly improved our understanding of the proteins which contribute to critical phagosome functions such as apoptotic cell clearance and microbial killing. However, previous methods of isolating phagosomes for proteomic analysis have relied on cell fractionation with some intrinsic limitations. Here, we present an alternative and modular proximity-labeling based strategy for mass spectrometry proteomic analysis of the phagosome lumen, termed PhagoID. We optimize proximity labeling in the phagosome and apply PhagoID to immortalized murine macrophages as well as primary human macrophages. Analysis of proteins detected by PhagoID in murine macrophages demonstrate that PhagoID corroborates previous proteomic studies, but also nominates novel proteins with unexpected residence at the phagosome for further study. A direct comparison between the proteins detected by PhagoID between mouse and human macrophages further reveals that human macrophage phagosomes have an increased abundance of proteins involved in the oxidative burst and antigen presentation. Our study develops and benchmarks a new approach to measure the protein composition of the phagosome and validates a subset of these findings, ultimately using PhagoID to grant further insight into the core constituent proteins and species differences at the phagosome lumen.
A systematic evaluation of the language-of-viral-escape model using multiple machine learning frameworks
Authors: Allman Brent , Vieira Luiz , Diaz Daniel J. , Wilke Claus O.
Published: September 2024

Predicting the evolutionary patterns of emerging and endemic viruses is key for mitigating their spread in host populations. In particular, it is critical to rapidly identify mutations with the potential for immune escape or increased disease burden (variants of concern). Knowing which circulating mutations are such variants of concern can inform treatment or mitigation strategies such as alternative vaccines or targeted social distancing. A recent study proposed that variants of concern can be identified using two quantities extracted from protein language models, grammaticality and semantic change. These quantities are defined in analogy to concepts from natural language processing. Grammaticality is intended to be a measure of whether a variant viral protein is viable, and semantic change is intended to be a measure of potential for immune escape. Here, we systematically test this hypothesis, taking advantage of several high-throughput datasets that have become available, and also testing additional machine learning models for calculating the grammaticality metric. We find that grammaticality can be a measure of protein viability, though the more traditional metric ΔΔGappears to be more effective. By contrast, we do not find compelling evidence that semantic change is a useful tool for identifying immune escape mutations.
Advancing Variant Phenotyping in Myelodysplastic Syndromes via Computational Genomics of Mitochondrial Enzyme Complexes
Authors: Dong Jing , Zimmermann Michael T. , Haque Neshatul , Arsang-Jang Shahram , Saber Wael , Urrutia Raul
Published: September 2024

Mitochondria are essential cellular organelles that play critical roles in hematological disorders. Recurrent mutations in mitochondrial DNA (mtDNA) have been identified in patients with myelodysplastic syndromes (MDS) and serve as significant prognostic indicators for their outcomes following allogeneic hematopoietic stem-cell transplantation (allo-HCT). However, the biological mechanisms of mtDNA mutations remain unclear. The current study utilizes computational structural genomics to improve our understanding of pathogenic variants in mitochondria-encoded genes. This emerging genomics discipline employs structural models, molecular mechanic calculations, and accelerated molecular dynamic simulations to analyze gene products, focusing on their structures and motions that determine their function. We applied this methodology to perform deep variant phenotyping of entire mitochondria-encoded protein complexes associated with the pathobiology of MDS and their prognosis after HCT. Our results demonstrate that this approach significantly outperforms conventional analytical methods, providing enhanced and more accurate information to support the potential pathogenicity of these variants and better infer their dysfunctional mechanisms. We conclude that the adoption and further expansion of computational structural genomics approaches, as applied to the mitochondrial genome, have the potential to significantly increase our understanding of molecular mechanisms underlying the disease. Our study lays a foundation for translating mitochondrial biology into clinical applications, which is of significant mechanistic and biomedical relevance and should be considered in modern biomedical research.
Aberrant prefrontal activity and arousal level correlate with action initiation and response vigor
Authors: Klein Frederike J. , Vasilev Dmitrii , Iwai Ryo , Watanabe Masataka , Totah Nelson K.
Published: September 2024

Orchestrating learned Stimulus-Response (S-R) mappings has been suggested as one of the central functions of the prefrontal cortex (PFC). While S-R selective activity has been demonstrated, it remains unclear whether the strength of such activity is related to the vigor of the subsequent response. Here, we trained male rats to perform a Go/NoGo response task while head-fixed on a treadmill. This allowed us to record PFC (cingulate, area 24) single unit spiking, as well as running speed as a proxy for response vigor. We show that aberrant activation of the “wrong” S-R mapping is correlated with initiation of the incorrect response. The vigor of the incorrect response was directly related to the strength of the aberrant stimulus-evoked activity. A similar relationship was observed for pre-trial arousal state and response vigor. Our findings confirm the long-standing concept, established in psychology and cognitive neuroscience, that S-R mappings are directly related to response vigor. Moreover, we provide evidence for the often suggested but rarely tested relationship between arousal and response vigor and a potential underlying neuronal mechanism involving neuromodulation of S-R mapping activity.

Significance statement

The concept of stimulus-response (S-R) mappings is fundamental in psychology and has been widely documented as a key function of the prefrontal cortex. Here, the authors directly link prefrontal single neuron mapping-selective activity to the vigor of responses. Moreover, they link a physiological measure of arousal to response vigor and suggest that neuromodulatory systems invigorate responses by potentially modulating PFC S-R mapping-selective activity.
A Graph Curvature-Based Pipeline for Discovering Immune Checkpoint Response Biomarkers
Authors: Bannon James , Cantor Charles R. , Mishra Bud
Published: September 2024

Immune checkpoint inhibitors (ICIs), also called immune checkpoint blockers, are a promising category of targeted therapy for solid tumors. Predicting which patients will respond to ICI therapy remains an open problem under active investigation. This paper adds to this effort by developing a modular pipeline for the discovery of biomarkers from tumor RNA-sequencing data. We contextualize gene expression measurements using a protein-protein interaction (PPI) network and use a notion of graph curvature to find (pairs of) genes in the PPI that could serve as potential biomarkers. Our candidate biomarkers are evaluated using an extensive literature search and transfer learning experiments. We also provide a harmonized collection of drug-specific candidate markers found through rank aggregation that we believe merit further study.
Combination of cycling hyperthermia and Echinacoside creates synergistic curing effect on pancreatic cancer PANC-1 cells
Authors: Chen Wei-Ting , Chen You-Ming , Lin Guan-Bo , Kuo Yu-Yi , Liu Hsu-Hsiang , Chao Chih-Yu
Published: September 2024

Therapy targeting the suppression of human MutT homolog 1 (MTH1) has been gaining ground in recent years, thanks to its resulting significant increase of 8-hydroxy-2’-deoxyguanosine triphosphate (8-oxo-dGTP) accumulation in genomic DNA, causing DNA damage and apoptotic cell death. Echinacoside (Ech), a natural phenylethanoid glycoside first extracted from Echinacea angustifolia or desert plant Cistanches is one of a few natural products which are capable of inhibiting the MTH1 function. It, however, is difficult to apply it in clinical trials, due to high cost for effective dosage in need. In the study, we show that combination with thermal-cycling hyperthermia (TC-HT), a novel physical treatment, can amplify the curative effect of Ech, reducing its dosage in need significantly. The combination resulted in a multipronged mechanism targeting multiple key apoptotic regulating proteins such as Bcl-2 and MAPK family proteins. Its effect is expected to be comparable to the treatment strategy containing MTH1, Bcl-2, and ERK inhibitors, posing as new promising approach in cancer treatment.
Reclaiming Hand Functions after Complete Spinal Cord Injury with Epidural Brain-Computer Interface
Authors: Liu Dingkun , Shan Yongzhi , Wei Penghu , Li Wenzheng , Xu Honglai , Liang Fangshuo , Liu Tao , Zhao Guoguang , Hong Bo
Published: September 2024

Background

Spinal cord injuries significantly impair patients’ ability to perform daily activities independently. While cortically implanted brain-computer interfaces (BCIs) offer high communication bandwidth to assist and rehabilitate these patients, their invasiveness and long-term stability limits broader adoption.

Methods

We developed a minimally invasive BCI with 8 chronic epidural electrodes above primary sensorimotor cortex to restore hand functions of tetraplegia patients. With wireless powering and neural data transmission, this system enables real-time BCI control of hand movements and hand function rehabilitation in home use. A complete spinal cord injury (SCI) patient with paralyzed hand functions was recruited in this study.

Results

Over a 9-month period of home use, the patient achieved an average grasping detection F1-score of 0.91, and a 100% success rate in object transfer tests, with this minimally invasive BCI and a wearable exoskeleton hand. This system allowed the patient to perform eating, drinking and other daily tasks involving hand functions. Additionally, the patient showed substantial neurological recovery through consecutive BCI training, regaining the ability to hold objects without BCI. The patient exhibited a 5-point improvement in upper limb motor scores and a 27-point increase in the action research arm test (ARAT). A maximal increase of 12.2 μV was observed in the peak of somatosensory evoked potential, which points to a considerable recovery in impaired spinal cord connections.

Conclusions

In a tetraplegia patient with complete spinal cord injury, an epidural minimally invasive BCI assisted the patient’s hand grasping to perform daily tasks, and 9-month consecutive BCI use significantly improved the hand functions.
A robust unsupervised clustering approach for high-dimensional biological imaging data reveals shared drug-induced morphological signatures
Authors: Bao Shaine Chenxin , Mizikovsky Dalia , Pishas Kathleen , Cowley Karla J , Zhao Qiongyi , Marinovic Evanny , Carey Mark , Campbell Ian , Simpson Kaylene J , Cheasley Dane , Palpant Nathan J.
Published: September 2024

High-throughput analysis methods have emerged as central technologies to accelerate discovery by accelerating generation of large-scale data. Analysis and interpretation of these datasets remains challenging due to limitations in computational approaches for dimensionality reduction. Here, we present UnTANGLeD, a versatile computational pipeline that prioritises biologically robust and meaningful information to guide actionable strategies from input screening data which we demonstrate using results from image-based drug screening. By providing a robust framework for analysing high dimensional biological data, UnTANGLeD offers a powerful tool for analysis of theoretically any data type from any screening platform.
HHIP’s Dynamic Role in Epithelial Wound Healing Reveals a Potential Mechanism of COPD Susceptibility
Authors: Deritei Dávid , Anamika Wardatul Jannat , Zhou Xiaobo , Silverman Edwin K. , Regan Erzsébet Ravasz , Glass Kimberly
Published: September 2024

A genetic variant nearHHIPhas been consistently identified as associated with increased risk for Chronic Obstructive Pulmonary Disease (COPD), the third leading cause of death worldwide. However HHIP’s role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the hedgehog pathway and downstream GLI1 and GLI2 activation. The hedgehog pathway plays an important role in wound healing, specifically in activating transcription factors that drive the epithelial mesenchymal transition (EMT), which in its intermediate state (partial EMT) is necessary for the collective movement of cells closing the wound. Herein, we propose a mechanism to explain HHIP’s role in faulty epithelial wound healing, which could contribute to the development of emphysema, a key feature of COPD. Using two different Boolean models compiled from the literature, we show dysfunctional HHIP results in a lack of negative feedback on GLI, triggering a full EMT, where cells become mesenchymal and do not properly close the wound. We validate these Boolean models with experimental evidence gathered from published scientific literature. We also experimentally test if low HHIP expression is associated with EMT at the edge of wounds by using a scratch assay in a human lung epithelial cell line. Finally, we show evidence supporting our hypothesis in bulk and single cell RNA-Seq data from different COPD cohorts. Overall, our analyses suggest that aberrant wound healing due to dysfunctional HHIP, combined with chronic epithelial damage through cigarette smoke exposure, may be a primary cause of COPD-associated emphysema.

Graphical abstract
Dynamic epigenomic landscape of carbon-concentrating mechanisms in the model industrial oleaginous microalgaNannochloropsis oceanica
Authors: Gong Yanhai , Wang Qintao , Wei Li , Wang Lianhong , Lv Nana , Du Xuefeng , Shen Chen , Xin Yi , Sun Luyang , Xu Jian
Published: September 2024

Despite their ecological and physiological significance, how carbon-concentrating mechanisms (CCM) are regulated in microalgae remains elusive. Here in the model industrial microalgaNannochloropsis oceanica, we uncovered an epigenetic regulatory mechanism for CCM via comprehensive, multi-dimensional epigenomic analyses. Our integrated study reveals the complex interplay among histone modifications, dynamic nucleosome positioning, and 3D chromatin structure in regulating gene expression during low CO2adaptation, despite minimal DNA methylation. Histone modifications, including lysine acetylation (H3K9ac and H3K27ac), crotonylation (Kcr), and methylation (H3K4me2), were associated with active chromatin states. Significantly altered ChIP-Seq peaks were linked to 43.1% of the differentially expressed genes (DEGs). Notably, H3K4me2 exhibited a distinct dual-peak profile around the transcription start site (TSS), which is unique among microalgae and plants. Chromatin compartment dynamics were correlated with gene expression and histone modifications, particularly H3K4me2, while differentially positioned nucleosomes were associated with key CCM-related genes and transcription factors. To further elucidate the role of H3K4me2, we knocked out its methyltransferase, resulting in genome-wide H3K4me2 peak shifts, slower growth, and reduced photosynthesis. These changes were accompanied by differential expression of key genes of NoHINT and NoPMA2, whose subsequent deletion and overexpression revealed their subtle yet significant impacts on growth and photosynthetic efficiency under low CO2conditions, with NoHINT regulating growth and NoPMA2 influencing photosynthesis. Finally, we proposed a comprehensive model for epigenetic regulation of CCM inN. oceanica, which established a foundation for enhancing microalgal productivity through targeted epigenetic modifications.

Highlights

Multi-layered epigenetic modifications contribute to the regulation of CCM and its adaptation to low CO2inN. oceanica.

The histone modification H3K4me2 regulates the growth and photosynthesis ofN. oceanicaunder low CO2conditions.

H3K4me2 targets NoHINT and NoPMA2 inN. oceanica, with NoHINT influencing growth dynamics and NoPMA2 modulating photosynthetic efficiency under low CO2conditions.