tbuckley/cabot-search huggingface dataset:
Protein modification in neurodegenerative diseases
Authors: Shahin Ramazi, Maedeh Dadzadi, Mona Darvazi, Nasrin Seddigh, Abdollah Allahverdi
Journal: MedComm (2024)

Abstract Posttranslational modifications play a crucial role in governing cellular functions and protein behavior. Researchers have implicated dysregulated posttranslational modifications in protein misfolding, which results in cytotoxicity, particularly in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease. These aberrant posttranslational modifications cause proteins to gather in certain parts of the brain that are linked to the development of the diseases. This leads to neuronal dysfunction and the start of neurodegenerative disease symptoms. Cognitive decline and neurological impairments commonly manifest in neurodegenerative disease patients, underscoring the urgency of comprehending the posttranslational modifications’ impact on protein function for targeted therapeutic interventions. This review elucidates the critical link between neurodegenerative diseases and specific posttranslational modifications, focusing on Tau, APP, α‐synuclein, Huntingtin protein, Parkin, DJ‐1, and Drp1. By delineating the prominent aberrant posttranslational modifications within Alzheimer disease, Parkinson disease, and Huntington disease, the review underscores the significance of understanding the interplay among these modifications. Emphasizing 10 key abnormal posttranslational modifications, this study aims to provide a comprehensive framework for investigating neurodegenerative diseases holistically. The insights presented herein shed light on potential therapeutic avenues aimed at modulating posttranslational modifications to mitigate protein aggregation and retard neurodegenerative disease progression.
A clinically used anti‐human papilloma virus agent (3‐hydroxyphthalic anhydride‐modified bovine β‐lactoglobulin) has a potential for topical application to prevent sexual transmission of monkeypox virus
Authors: Yi'ou Sha, Baoying Huang, Chen Hua, Yun Zhu, Wanbo Tai, Jiewei Sun, Yixin Li, Anqi Xia, Qiao Wang, Lu Lu, Wenjie Tan, Shibo Jiang
Journal: MedComm (2024)

Abstract A global outbreak of monkeypox (mpox) caused by the mpox virus (MPXV) has posed a serious threat to public health worldwide, thus calling for the urgent development of antivirals and vaccines to curb its further spread. In this study, we screened 41 anhydride‐modified proteins and found that 3‐hydroxyphthalic anhydride‐modified β‐lactoglobulin (3HP‐β‐LG), a clinically used anti‐HPV agent, was highly effective in inhibiting infection of vaccinia virus Tiantan strain (VACV‐VTT) and MPXV. Mechanistic studies demonstrated that 3HP‐β‐LG bound to the virus, not the host cell, by targeting the early stage of virus entry, possibly through the interaction between the amino acids with negatively charges in 3HP‐β‐LG and the key amino acids with positive charges in the target region of A29L, a key surface protein of MPXV. A synergistic effect was observed when 3HP‐β‐LG was combined with tecovirimat, a small‐molecule antiviral drug approved by the United States Food and Drug Administration and the European Medicine Agency for the treatment of smallpox and mpox. Because of its clinically proven safety and stability, 3HP‐β‐LG shows promise for further development as a prophylactic agent to prevent the sexual transmission of MPXV.
Poor sleep and decreased cortical thickness in veterans with mild traumatic brain injury and post-traumatic stress disorder
Authors: Murray J. Andrews, David H. Salat, William P. Milberg, Regina E. McGlinchey, Catherine B. Fortier
Journal: Military Medical Research (2024)

Abstract Background Poor sleep quality has been associated with changes in brain volume among veterans, particularly those who have experienced mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). This study sought to investigate (1) whether poor sleep quality is associated with decreased cortical thickness in Iraq and Afghanistan war veterans, and (2) whether these associations differ topographically depending on the presence or absence of mTBI and PTSD. Methods A sample of 440 post-9/11 era U.S. veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders study at VA Boston, MA from 2010 to 2022 was included in the study. We examined the relationship between sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), and cortical thickness in veterans with mTBI ( n = 57), PTSD ( n = 110), comorbid mTBI and PTSD ( n = 129), and neither PTSD nor mTBI ( n = 144). To determine the topographical relationship between subjective sleep quality and cortical thickness in each diagnostic group, we employed a General Linear Model (GLM) at each vertex on the cortical mantle. The extent of topographical overlap between the resulting statistical maps was assessed using Dice coefficients. Results There were no significant associations between PSQI and cortical thickness in the group without PTSD or mTBI ( n = 144) or in the PTSD-only group ( n = 110). In the mTBI-only group ( n = 57), lower sleep quality was significantly associated with reduced thickness bilaterally in frontal, cingulate, and precuneus regions, as well as in the right parietal and temporal regions (β = −0.0137, P &lt; 0.0005). In the comorbid mTBI and PTSD group ( n = 129), significant associations were observed bilaterally in frontal, precentral, and precuneus regions, in the left cingulate and the right parietal regions (β = −0.0094, P &lt; 0.0005). Interaction analysis revealed that there was a stronger relationship between poor sleep quality and decreased cortical thickness in individuals with mTBI ( n = 186) compared to those without mTBI ( n = 254) specifically in the frontal and cingulate regions (β = −0.0077, P &lt; 0.0005). Conclusions This study demonstrates a significant relationship between poor sleep quality and lower cortical thickness primarily within frontal regions among individuals with both isolated mTBI or comorbid diagnoses of mTBI and PTSD. Thus, if directionality is established in longitudinal and interventional studies, it may be crucial to consider addressing sleep in the treatment of veterans who have sustained mTBI.
Dissolvable microneedle patch enables local delivery of immunomodulatory microparticles containing bifunctional molecules for periodontal tissue regeneration
Authors: Xuexiang Zhang, Mohammad Mahdi Hasani-Sadrabadi, Erfan Dashtimighadam, Farahnaz Fahimipour, Bhumika Shokeen, Olga Bezouglaia, Ruxing Fu, Isabelle Hong, Yang Yang, Tara Aghaloo, Benjamin M. Wu, Zhen Gu, Renate Lux, Song Li
Journal: Med-X (2024)

Abstract Periodontitis is initiated by dysbiosis of the oral microbiome. Pathogenic bacteria elicit ineffective immune responses, which damage surrounding tissues and lead to chronic inflammation. Although current treatments typically aim for microbial eradication, they fail to address the significance of immune cell reactions in disease progression. Here, we searched for small molecules as drug candidates and identified a bifunctional antibiotic, azithromycin (AZM), that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation. We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues. Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro. In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration. In addition, microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles, had similar or slightly enhanced therapeutic outcomes respectively. The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents, providing a practical and streamlined approach for clinical treatment. Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation. Graphical Abstract
KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression
Authors: Young Hoon Jung, Yun Ji Lee, Tam Dao, Kyung Hee Jung, Junjie Yu, Ah-Reum Oh, Yelin Jeong, HyunJoon Gi, Young Un Kim, Dongryeol Ryu, Michele Carrer, Utpal B. Pajvani, Sang Bae Lee, Soon-Sun Hong, KyeongJin Kim
Journal: Clinical and Molecular Hepatology (2024)

Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression.
Lifetime incidence and healthcare disparities in alopecia areata: A UK population-based cohort study
Authors: Andrew R Thompson, Christos Tziotzios, John Nesnas, Rowena Randall, Maciej Czachorowski, Andrew G Messenger
Journal: British Journal of Dermatology (2024)

Abstract Background Alopecia areata (AA) is an immune-mediated form of hair loss that can occur at any age, often with a significant mental health burden. Objectives We aimed to provide estimates of the lifetime incidence of AA, and the impacts on mental health, healthcare utilization and work-related outcomes, assessing variation across major sociodemographic subgroups. Methods AA cases were identified in primary care from the UK population-based Oxford-Royal College of General Practitioners Research and Surveillance Centre database (2009–2018). Lifetime incidence of AA was estimated at age 80 years using modified time-to-event models with age as the timescale, overall and stratified by sex, ethnicity, deprivation and geography. Mental health, healthcare utilization and work-related outcomes were assessed in the 2 years after AA diagnosis compared with matched unaffected controls, and stratified by the same sociodemographic subgroups. Results During the study period, 6961 people developed AA. Overall lifetime incidence of AA was 2.11% [95% confidence interval (CI) 2.06–2.16]. Females had a higher lifetime incidence (2.35%, 95% CI 2.28–2.43) than males (1.88%, 95% CI 1.81–1.94). Lifetime incidence was higher in those of Asian ethnicity (5.87%, 95% CI 5.51–6.24), Other (4.5%, 95% CI 3.63–5.31), Mixed (4.4%, 95% CI 3.50–5.37) and Black (3.0%, 95% CI 2.63–3.42) ethnicity, compared with White ethnicity (1.7%, 95% CI 1.68–1.80). Lifetime incidence was highest in those with the greatest deprivation: most-deprived quintile (2.92%, 95% CI 2.77–3.07) compared with least-deprived (1.68%, 95% CI 1.59–1.78). Across sociodemographic subgroups, people with AA of Black ethnicity were most likely to have anxiety (adjusted odds ratio vs. matched controls 2.92, 95% CI 1.71–4.91), and had the greatest risk of time off work (adjusted hazard ratio vs. matched controls 2.54, 95% CI 1.80–3.56). Conclusions AA affects around 1 in 50 people over their lifetime. The incidence and impact of AA on mental health and work outcomes is highest in ethnic groups other than White. Clinicians should be aware of the marked heterogeneity in the incidence and impact of AA, and support targeted healthcare to groups at the highest risk of alopecia and its consequences.
Paternal Exposure: Two patients’ perspectives in an evolving landscape of therapeutics. Can we now provide reassurance?
Authors: Bhaskar Narayan, Leila Asfour
Journal: British Journal of Dermatology (2024)

There is now substantial evidence of safety in pregnancy for several newer medications, particularly biologic disease-modifying antirheumatic drugs, although clinician confidence varies. There is much less information available regarding paternal exposure. This article provides insight from two patients who describe the impact of family planning on their therapeutic decision making.
Evolution of Virus-like Features and Intrinsically Disordered Regions in Retrotransposon-derived Mammalian Genes
Authors: Rachele Cagliani, Diego Forni, Alessandra Mozzi, Rotem Fuchs, Dafna Tussia-Cohen, Federica Arrigoni, Uberto Pozzoli, Luca De Gioia, Tzachi Hagai, Manuela Sironi
Journal: Molecular Biology and Evolution (2024)

Abstract Several mammalian genes have originated from the domestication of retrotransposons, selfish mobile elements related to retroviruses. Some of the proteins encoded by these genes have maintained virus-like features; including self-processing, capsid structure formation, and the generation of different isoforms through −1 programmed ribosomal frameshifting. Using quantitative approaches in molecular evolution and biophysical analyses, we studied 28 retrotransposon-derived genes, with a focus on the evolution of virus-like features. By analyzing the rate of synonymous substitutions, we show that the −1 programmed ribosomal frameshifting mechanism in three of these genes (PEG10, PNMA3, and PNMA5) is conserved across mammals and originates alternative proteins. These genes were targets of positive selection in primates, and one of the positively selected sites affects a B-cell epitope on the spike domain of the PNMA5 capsid, a finding reminiscent of observations in infectious viruses. More generally, we found that retrotransposon-derived proteins vary in their intrinsically disordered region content and this is directly associated with their evolutionary rates. Most positively selected sites in these proteins are located in intrinsically disordered regions and some of them impact protein posttranslational modifications, such as autocleavage and phosphorylation. Detailed analyses of the biophysical properties of intrinsically disordered regions showed that positive selection preferentially targeted regions with lower conformational entropy. Furthermore, positive selection introduces variation in binary sequence patterns across orthologues, as well as in chain compaction. Our results shed light on the evolutionary trajectories of a unique class of mammalian genes and suggest a novel approach to study how intrinsically disordered region biophysical characteristics are affected by evolution.
Definition and management of right ventricular injury in adult patients receiving extracorporeal membrane oxygenation for respiratory support using the Delphi method: a PRORVnet study. Expert position statements
Authors: Vasileios Zochios, Prashant Nasa, Hakeem Yusuff, Marcus J Schultz, Marta Velia Antonini, Abhijit Duggal, Siddharth Dugar, Kollengode Ramanathan, Kiran Shekar, Matthieu Schmidt
Journal: Intensive Care Medicine (2024)
Augmenting osteoporotic bone regeneration through a hydrogel-based rejuvenating microenvironment
Authors: Xiaoting Zhang, Boguang Yang, Lu Feng, Xiayi Xu, Chenmin Wang, Yuk-Wai Lee, Ming Wang, Xuan Lu, Ling Qin, Sien Lin, Liming Bian, Gang Li
Journal: Bioactive Materials (2024)

Osteoporotic bone defects pose a significant challenge for bone regeneration as they exhibit impaired healing capacity and delayed healing period. To address this issue, this study introduces a hydrogel that creates a rejuvenating microenvironment, thereby facilitating efficient bone repair during the initial two weeks following bone defect surgery. The hydrogel, named GelHFS, was created through host-guest polymerization of gelatin and acrylated β-cyclodextrin. Incorporation of the human fetal mesenchymal stem cell secretome (HFS) formed GelHFS hydrogel aimed at mimicking a rejuvenated stem cell niche. Our results demonstrated that GelHFS hydrogel promotes cell stellate spreading and osteogenic differentiation via integrin β1-induced focal adhesion pathway. Implantation of GelHFS hydrogel in an osteoporotic bone defect rat model recruited endogenous integrin β1-expressing cells and enhanced new bone formation and bone strength. Our findings reveal that GelHFS hydrogel provides a rejuvenating niche for endogenous MSCs and enhances bone regeneration in osteoporotic bone defect. These findings highlight the potential of GelHFS hydrogel as an effective therapeutic strategy for addressing challenging bone healing such as osteoporotic bone regeneration.
Effect of wearable activity trackers on physical activity in children and adolescents: a systematic review and meta-analysis
Authors: Whitney W Au, Francesco Recchia, Daniel Y Fong, Stephen H S Wong, Derwin K C Chan, Catherine M Capio, Clare C W Yu, Sam W S Wong, Cindy H P Sit, Patrick Ip, Ya-Jun Chen, Walter R Thompson, Parco M Siu
Journal: The Lancet Digital Health (2024)
Completion axillary lymph node dissection for the identification of pN2–3 status as an indication for adjuvant CDK4/6 inhibitor treatment: a post-hoc analysis of the randomised, phase 3 SENOMAC trial
Authors: Jana de Boniface, Matilda Appelgren, Robert Szulkin, Sara Alkner, Yvette Andersson, Leif Bergkvist, Jan Frisell, Oreste Davide Gentilini, Michalis Kontos, Thorsten Kühn, Dan Lundstedt, Birgitte Vrou Offersen, Roger Olofsson Bagge, Toralf Reimer, Malin Sund, Peer Christiansen, Lisa Rydén, Tove Filtenborg Tvedskov
Journal: The Lancet Oncology (2024)
Recommendations for the implementation of a national lung cancer screening program in Portugal—A consensus statement
Authors: M.G.O. Fernandes, M. Dias, R. Santos, S. Ravara, P. Fernandes, J. Firmino-Machado, J.P. Antunes, O. Fernandes, A. Madureira, V. Hespanhol, C. Rodrigues, C.A. Vicente, S. Alves, G. Mendes, R. Ilgenfritz, B.S. Pinto, J. Alves, I. Saraiva, C. Bárbara, M.A. Cipriano, A. Figueiredo, M.S. Uva, N. Jacinto, L. Curvo-Semedo, A. Morais
Journal: Pulmonology (2024)

Lung cancer (LC) is a leading cause of cancer-related mortality worldwide. Lung Cancer Screening (LCS) programs that use low-dose computed tomography (LDCT) have been shown to reduce LC mortality by up to 25 % and are considered cost-effective. The European Health Union has encouraged its Member States to explore the feasibility of LCS implementation in their respective countries. The task force conducted a comprehensive literature review and engaged in extensive discussions to provide recommendations. These recommendations encompass the essential components required to initiate pilot LCS programs following the guidelines established by the World Health Organization. They were tailored to align with the specific context of the Portuguese healthcare system. The document addresses critical aspects, including the eligible population, methods for issuing invitations, radiological prerequisites, procedures for reporting results, referral processes, diagnostic strategies, program implementation, and ongoing monitoring. Furthermore, the task force emphasized that pairing LCS with evidence-based smoking cessation should be the standard of care for a high-quality screening program. This document also identifies areas for further research. These recommendations aim to guarantee that the implementation of a Portuguese LCS program ensures high-quality standards, consistency, and uniformity across centres.
Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy
Authors: Grace G. Bushnell, Deeksha Sharma, Henry C. Wilmot, Michelle Zheng, Toluwaleke D. Fashina, Chloe M. Hutchens, Samuel Osipov, Monika Burness, Max S. Wicha
Journal: Cancer Research (2024)

Patients with breast cancer with estrogen receptor-positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display "stem-like" properties (cancer stem cell, CSC), which may be regulated by the immune system. To elucidate the role of the immune system in controlling dormancy and its escape, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. Three mouse breast cancer cell lines, PyMT, Met1, and D2.0R, contained CSCs that displayed short- and long-term metastatic dormancy in vivo, which was dependent on the host immune system. Each model was regulated by different components of the immune system. Natural killer (NK) cells were key for the metastatic dormancy phenotype in D2.0R cells. Quiescent D2.0R CSCs were resistant to NK cell cytotoxicity, whereas proliferative CSCs were sensitive. Resistance to NK cell cytotoxicity was mediated, in part, by the expression of BACH1 and SOX2 transcription factors. Expression of STING and STING targets was decreased in quiescent CSCs, and the STING agonist MSA-2 enhanced NK cell killing. Collectively, these findings demonstrate the role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon. Significance: The immune system controls disseminated breast cancer cells during disease latency, highlighting the need to utilize immunocompetent models to identify strategies for targeting dormant cancer cells and reducing metastatic recurrence. See related commentary by Cackowski and Korkaya, p. 3319.
Induced Pluripotent Stem Cells Facilitate the Development and Evaluation of Cancer Vaccines
Authors: Yuewen Zhai, Xinyu Xu, Ji Fang, Fang He, Siwen Li
Journal: Cancer Research (2024)

Cancer vaccines are an approach to elicit amplified antigen-specific immune responses. Induced pluripotent stem cells (iPSC) have potential utility for the development of universal vaccines because of their intrinsic antigenic epitopes. Concurrently, iPSCs can undergo pluripotent differentiation and are thus a stable source of both antigen-presenting cells for producing immune cell-based vaccines and tumor organoids for facilitating the exploration and adaptive assessment of tumor vaccines. This review describes the specific contributions of iPSCs to vaccine development, summarizes their diverse developmental trajectories, and discusses the obstacles to their application along with potential solutions.