bluuebunny/crossref_metadata_2025_split huggingface dataset:
The molecular mechanism of temperature-dependent phase separation of Heat shock factor 1
Authors: Ren Qiunan , Li Linge , Li Juan , Shi Chaowei , Sun Yujie , Yao Xuebiao , Hou Zhonghuai , Xiang ShengQi 
Published: August 2024

ABSTRACTHeat shock factor 1 (HSF1) is the critical orchestrator for a cell responding to heat shock, and its dysfunction is linked to cancers and neurodegenerative diseases. HSF1 undergoes phase separation upon heat shock, and its activity is regulated by various post-translational modifications (PTMs). Despite its importance, the molecular details underlying HSF1 phase separation, temperature sensing, and post-translational modifications (PTMs) regulation remain poorly understood. Here, we discovered that HSF1 exhibits temperature-dependent phase separation with a lower critical solution temperature (LCST) behavior due to entropy contribution from solvent molecules, providing a new conceptual mechanism accounting for HSF1 activation. We employed a synergistic approach combining coarse-grain simulation and nuclear magnetic resonance spectroscopy to reveal the residue-level molecular details of the interactions driving the phase separation of wild-type HSF1 and its distinct PTM patterns at various temperatures. The identified interaction sites were further validated with biochemistry assays and mapped interface accounts for HSF1 functions reported. Importantly, the amino acid substitution experiment reveals the molecular grammar for temperature-dependent HSF1 phase separation is species-specific and physiologically relevant. These findings delineate chemical code that integrates protein PTM patterns with accurate phase separation for body physiological temperature control in animals.
Multivalent administration of dengue E dimers on liposomes elicits type-specific neutralizing responses without immune interference
Authors: Phan Thanh T. N. , Hvasta Matthew G. , Thiono Devina J. , Shah Ruby P. , Ajo Gisselle Prida , Huang Wei-chiao , Lovell Jonathan , Tian Shaomin , de Silva Aravinda M. , Kuhlman Brian 
Published: August 2024

AbstractThe four serotypes of dengue virus (DENV1-4) are a major health concern putting 50% of the global population at risk of infection. Crucially, DENV vaccines must be tetravalent to provide protection against all four serotypes because immunity to only one serotype can enhance infections caused by heterologous serotypes. Uneven replication of live-attenuated viruses in tetravalent vaccines can lead to disease enhancement instead of protection. Subunit vaccines are a promising alternative as the vaccine components are not dependent on viral replication and antigen doses can be controlled to achieve a balanced response. Here, we show that a tetravalent subunit vaccine of dengue envelope (E) proteins computationally stabilized to form native-like dimers elicits type-specific neutralizing antibodies in mice against all four serotypes. The immune response was enhanced by displaying the E dimers on liposomes embedded with adjuvant, and no interference was detected between the four components.
A framework for chronic care quality: results of a scoping review and Delphi survey
Authors: Ku Grace Marie V. , Van De Put Willem , Katsuva Deogratias , Ag Ahmed Mohamad Ali , Rosenberg Megumi , Meessen Bruno 
Published: August 2024

ABSTRACTFrameworks conceptualising quality of care abound and vary; some concentrate on specific aspects (e.g., safety, access, effectiveness), others all-encompassing. However, to our knowledge, tailoring to systematically arrive at a comprehensive care for chronic conditions quality (CCCQ) framework has never been done. We conducted scoping review and Delphi survey to produce a CCCQ framework, comprehensively delineating aims, determinants and measurable attributes.With the assumption that specific groups (people with chronic conditions, care providers, financiers, policy-makers, etc) view quality of care differently, we analysed 48 scientific and 26 grey literature deductively and inductively using the Institute of Medicine’s quality of care framework as the foundation. We produced a zero-version of the quality of chronic care framework, detailing aims, healthcare system determinants, and measurement mechanisms. This was presented in a Delphi survey to 49 experts with diverse chronic care expertise/experience around the world. Consensus was obtained after the first round, with the panel providing suggestions and justifications to expand the agreed-upon components. Through this exercise, a comprehensive CCCQ framework encompassing the journey through healthcare of people with chronic conditions was developed. The framework specifies seven CCCQ ‘aims’ and identifies health system determinants which can be acted upon with ‘organising principles’ and measured through chronic care quality ‘attributes’ related to structures, processes and outcomes. Tailoring quality of care based on the nature of the diseases/conditions and considering different views can be done to ensure a comprehensive offer of healthcare services, and towards better outcomes that are acceptable to both the health system and PwCCs.
Knowledge, attitude and perception regarding HIV/AIDS among Khartoum University medical campus students – a cross-sectional study 2018
Authors: Mohamed Elamir Ahmed Alasaad Kamel , Dafalla Rana Ibrahim Abdalla , Ali Raghda , Elhussain Mohamed O. , Abdelsalam Ahmed Abdelaziz Abugrain , Sharif Abraa Awad , Halali Sayed 
Published: August 2024

AbstractBackgroundClinical training is a part of curriculum for medical campus students, where there is a chance of exposure to HIV infection. Hence, this study was conducted to assess their knowledge, attitude and perception towards HIV/AIDS.MethodThis is a descriptive, non-interventional, cross-sectional study. Data collection took place December 2017 and January 2018. The study population included medical students at the University of Khartoum during the study period. Data were collected through a structured adapted questionnaire covering socio demographic details, General knowledge about HIV/AIDS, medical campus students perception towards the possible causes of HIV infection, medical campus students attitude towards HIV/AIDS patients used to collect data from medical students.ResultsThis study investigated the knowledge, attitude and perception regarding HIV/AIDS among 288 medical students at University of Khartoum. It was found that the means and standard deviation of the total knowledge, attitude and perception score towards HIV/AIDS in general were 15.45±2.93. which was categorized fair (reference ranging from 13 to 18). the total knowledge, attitude and perception was significantly associated with the academic year (p=0.000), but no association was found between the attitude score and the academic year (p = 0.620).ConclusionThe overall rate of knowledge and attitude about HIV/AIDS among medical campus students of Khartoum University was acceptable. However, appreciated number of the students have had a negative attitude towards HIV/AIDS patient.
Altered neurobehavioral reward response predicts psychotic-like experiences in youth exposed to cannabis prenatally
Authors: Amir Carolyn M. , Ghahremani Dara G. , Chang Sarah E. , Cooper Ziva D. , Bearden Carrie E. 
Published: August 2024

AbstractImportanceRates of prenatal cannabis exposure (PCE) are rising with increasingly permissive legislation regarding cannabis use, which may be a risk factor for psychosis. Disrupted reward-related neural circuitry may underlie this relationship.ObjectiveTo elucidate neural mechanisms involved in the association between PCE and youth-onset psychotic-like experiences by probing correlates of reward anticipation, a neurobehavioral marker of endocannabinoid-mediated dopaminergic function.Design, setting, and participantsThis longitudinal, prospective study analyzed task-related functional neuroimaging data from baseline (n=11,368), 2-year follow-up (n=7,928), and 4-year follow-up (n=2,982) of the ongoing Adolescent Brain and Cognitive Development (ABCD) Study, which recruited children aged 9 to 10 years old at baseline from 22 sites across the United States.ResultsPCE (n=652 exposed youth) is longitudinally associated with psychotic-like experiences. Blunted neural response to reward anticipation is associated with psychotic-like experiences, with stronger effects observed in PCE youth (all |β| > 0.5; false discovery rate [FDR]–correctedP< .05). This hypoactivation at baseline predicts psychosis symptomatology in middle adolescence (4-year follow-up visit; β=-.004; FDR-correctedP< .05). Dampened behavioral reward sensitivity is associated with psychotic-like experiences across baseline, 2-year follow-up visit, and 4-year follow-up visit (|β| = .21; FDR-correctedP< .001). Psychotic-like experiences are positively associated with trait-level measures of reward motivation and impulsivity, with stronger effects for PCE youth (all |β| > 0.1; all FDR-correctedP< .05).Conclusions and RelevanceBlunted activation in reward-related brain regions may serve as a biomarker for disrupted reward processing and increased psychosis risk during development. PCE may affect childhood behaviors and traits related to altered reward sensitivity.
Randomized Phase 2 Trial of Lirilumab as maintenance Treatment in Acute Myeloid Leukemia: Results of the EFFIKIR Trial
Authors: Vey N. , Chretien AS. , Dumas PY. , Recher C. , Gastaud L. , Lioure B. , Bulabois CE. , Pautas C. , Marolleau JP. , Lepretre S. , Raffoux E. , Thomas X. , Hichri Y. , Bonmati C. , Quesnel B. , Rousselot P. , Jourdan E. , Malfuson JV. , Guillerm G. , Bourhis JH. , Ojeda-Uribe M. , Hunault M. , Ben Amara A. , Rouvière MS. , Boucherit N. , André P. , Preudhomme C. , Dulphy N. , Toubert A. , Ifrah N. , Olive D. , Dombret H. 
Published: August 2024

ABSTRACTLirilumab is a fully human monoclonal antibody designed to block killer inhibitory receptors (KIR), which are major immune checkpoints involved in the regulation of NK cell-mediated killing of HLA-I-expressing tumors. EFFIKIR is a multicenter randomized double-blind 3-arm placebo-controlled phase II trial with lirilumab as single-agent as maintenance therapy of elderly patients with AML in first complete remission (NCT01687387). Two dose schedules led to either continuous or intermittent KIR occupancy. 153 patients were randomized and 152 patients were treated after 3+7 induction therapy. The median follow-up was 36.6 months. Lirilumab was well tolerated, with no significant hematological toxicity. The median LFS were 17.6, 6.7 and 13.9 months in the 0.1mg/kg arm, 1mg/kg arm and placebo arm, respectively. An excess in early relapse led to early termination of treatment in the 1mg/kg arm. Extensive analysis of immune cell fate following KIR blockade evidenced a decrease of KIR+NK cell absolute counts following KIR blockade, associated with a decrease of Bcl-2. Lirilumab also bound antigen-experienced CD8+T cells, and induced a transient decrease of CD69 expression. Besides, lirilumab bound vδ2+γδT cells with a high cytotoxic potential, and induced a decrease of DNAM-1 and Bcl-2, the latter being associated with a decrease of KIR+γδT cell, and with a drastic reduction of time to relapse. Overall, the potentially deleterious effects on immune effectors may have resulted in the impairment of immune surveillance associated with an unexpected high rate of early relapse in the group of patients exposed to prolonged full KIR blockade.KEY POINTSProlonged full KIR blockade leads to potentially deleterious effects on NK cells, CD8+T cells and vδ2+γδT cellsCombined inhibitory effects of KIR blockade may have resulted in the impairment of immunosurveillance associated with high rate of relapse
De novo designed inhibitor confers protection against lethal toxic shock
Authors: Ragotte Robert J. , Liang Huazhu , Berman Jacob M. , Glögl Matthias , Schramek Daniel , Melnyk Roman A. , Baker David 
Published: August 2024

AbstractPaeniclostridium sordelliicauses a toxic shock syndrome with a mortality rate of nearly 70%, primarily affecting postpartum and post-abortive women. This disease is driven by the production of theP. sordelliilethal toxin, TcsL, for which there are currently no effective treatments. We used a protein diffusion model, RFdiffusion, to design high affinity TcsL inhibitors. From a very small set of 48 starting designs and 48 additional sequence optimized designs, we developed a potent inhibitor with <100 pM affinity that protects mice prophylactically and therapeutically (post exposure) from lung edema and death in a stringent lethal challenge model. This inhibitor, which can be lyophilized without any loss of activity, is a promising therapeutic candidate for this rare but deadly disease, and our results highlight the ability of deep learning-based protein design to rapidly generate biologics with potential clinical utility.
Accurate antibody loop structure prediction enables zero-shot design of target-specific antibodies
Authors: Bang Yewon , Choi Yoon-Aa , Gu Jeonghyeon , Kwon Sohee , Lee Dohoon , Lee Eun Seo , Lee Myeong Sup , Lee Sangchoon , Lee Soyul , Lee Su Jung , Lim Jungsub , Maeng Jin Young , Nam Juno , Noh Jinsung , Oh Hyunjeong , Park Sun-Young , Park Taeyong , Seo Sumin , Seok Chaok , Song Moo Young , Won Jonghun , Woo Hyeonuk , Yang Jinsol , Yoon Min Ji , Bae Woong , Kim Jaehoon , Lee Dongjin , Lee Jaemyung , Lee Youhan , Yu Hasun 
Published: August 2024

AbstractProtein loops, characterized by their versatile structures with varying sizes and shapes, can recognize a wide range of targets with high specificity and affinity. The variable loops of the antibody complementarity-determining region (CDR) are particularly crucial for immune responses and therapeutic applications due to their effective target recognition capabilities. Accurate structure prediction of these antibody loops is essential for the efficientin silicodesign of target-binding antibodies for therapeutic or industrial use. However, predicting antibody loop structures is challenging due to the lack of evolutionary information from related proteins. Thus, a successfulab initiostructure prediction method, which operates without structural templates or related sequences, is crucial for the effective design of antibody loop-mediated interactions. This study demonstrates that highly accurate antibody loop structure prediction enables the effective zero-shot design of target-binding antibody loops. The performance of loop design has been shown to depend on the accuracy ofab initioloop structure prediction, as tested with two versions of our design model. The high affinity, diversity, novelty, and specificity of the antibody loops designed with these new methods were validated experimentally on four target proteins.
The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin
Authors: Grossi Elena , Nguyen Christie B. , Carcamo Saul , Moran Shannon , Callaú Valentina Kirigin , Filipescu Dan , Hasson Dan , Bernstein Emily 
Published: August 2024

SummaryMultimeric SWI/SNF chromatin remodelers assemble into discrete conformations with unique complex functionalities difficult to dissect. Distinct cancers harbor mutations in specific subunits, altering the chromatin landscape, such as the PBAF-specific component ARID2 in melanoma. Here, we performed comprehensive epigenomic profiling of SWI/SNF complexes and their associated chromatin states in melanoma and melanocytes and uncovered a subset of PBAF-exclusive regions that coexist with PRC2 and repressive chromatin. Time-resolved approaches revealed that PBAF regions are generally less sensitive to ATPase-mediated remodeling than BAF sites. Moreover, PBAF/PRC2-bound loci are enriched for REST, a transcription factor that represses neuronal genes. In turn, absence of ARID2 and consequent PBAF complex disruption hinders the ability of REST to bind and inactivate its targets, leading to upregulation of synaptic transcripts. Remarkably, this gene signature is conserved in melanoma patients with ARID2 mutations. In sum, we demonstrate a unique role for PBAF in generating accessibility for a silencing transcription factor at repressed chromatin, with important implications for disease.
A structural perspective on the temperature-dependent activity of enzymes
Authors: McLeod Matthew J. , Barwell Sarah A. E. , Holyoak Todd , Thorne Robert Edward 
Published: August 2024

ABSTRACTEnzymes are biomolecular catalysts whose activity varies with temperature. Unlike for small-molecule catalysts, the structural ensembles of enzymes can vary substantially with temperature, and it is in general unclear how this modulates the temperature dependence of activity. Here multi-temperature X-ray crystallography was used to record structural changes from −20°C to 40°C for a mesophilic enzyme in complex with inhibitors mimicking substrate-, intermediate-, and product-bound states, representative of major complexes underlying the kinetic constantkcat. Both inhibitors, substrates and catalytically relevant loop motifs increasingly populate catalytically competent conformations as temperature increases. These changes occur even in temperature ranges where kinetic measurements show roughly linear Arrhenius/Eyring behavior where parameters characterizing the system are assumed to be temperature independent. Simple analysis shows that linear Arrhenius/Eyring behavior can still be observed when the underlying activation energy / enthalpy values vary with temperature, e.g., due to structural changes, and that the underlying thermodynamic parameters can be far from values derived from Arrhenius/Eyring model fits. Our results indicate a critical role for temperature-dependent atomic-resolution structural data in interpreting temperature-dependent kinetic data from enzymatic systems.One-Sentence SummaryStructural data spanning a 60°C temperature range for enzyme complexes mimicking the substrate-, intermediate-, and product-bound states illuminate how small temperature-dependent structural changes may modulate activity and render parameters deduced from Arrhenius/Eyring plots unreliable.
HMGB1 restores a dynamic chromatin environment in the presence of linker histone by deforming nucleosomal DNA
Authors: Saunders Hayden S. , Chio Un Seng , Moore Camille M. , Ramani Vijay , Cheng Yifan , Narlikar Geeta J 
Published: August 2024

AbstractThe essential architectural protein HMGB1 increases accessibility of nucleosomal DNA and counteracts the effects of linker histone H1. However, HMGB1 is less abundant than H1 and binds nucleosomes more weakly raising the question of how HMGB1 effectively competes with H1. Here, we show that HMGB1 rescues H1’s inhibition of nucleosomal DNA accessibility without displacing H1. HMGB1 also increases the dynamics of condensed, H1-bound chromatin. Cryo-EM shows that HMGB1 binds at internal locations on a nucleosome and locally distorts the DNA. These sites, which are away from the binding site of H1, explain how HMGB1 and H1 co-occupy a nucleosome. Our findings lead to a model where HMGB1 counteracts the activity of H1 by distorting nucleosomal DNA and by contacting the H1 C-terminal tail. Compared to direct competition, nucleosome co-occupancy by HMGB1 and H1 allows a greater diversity of dynamic chromatin states and may be generalizable to other chromatin regulators.
The Transcription Factor Binding Landscape of Mouse Development
Authors: Nordin Anna , Zambanini Gianluca , Jonasson Mattias , Weiss Tamina , van de Grift Yorick , Pagella Pierfrancesco , Cantù Claudio 
Published: August 2024

AbstractGene regulators physically associate to the genome, in a combinatorial fashion, to drive tissue-specific gene expression programs. Uncovering the genome-wide activity of all gene regulators across tissues is therefore needed to understand how the genome is regulated during development. Here, we take a first step forward towards achieving this goal. Using CUT&RUN, we systematically measured the genome-wide binding profiles of key transcription factors and cofactors that mediate the activity of ontogenetically relevant signaling pathways in select mouse tissues at two developmental stages. Computation of the numerous genome-wide binding datasets unveiled a large degree of tissue and time-specific activity for each gene regulator, and several factor-specific idiosyncrasies. Moreover, we identified “popular” regulatory regions that are bound by a multitude of pathway regulators. Popular regions tend to be more evolutionarily conserved, implying their essentiality. Consistently, they lie in the proximity of genes whose dysregulation causes early embryonic lethality in the mouse. Moreover, the human homologs of these regions are also bound by many gene regulators and are highly conserved in human populations, indicating that they retain functional relevance for human development. This work constitutes a decisive step towards understanding how the genome is simultaneously read and used by gene regulators in a holistic fashion and unveils multiple genomic mechanisms that drive embryonic development.
ARTIC RSV amplicon sequencing reveals global RSV genotype dynamics
Authors: Maloney Daniel M , Fernandes Goncalo , Jasim Seema , Williams Tom , Namugenyi Sarah , Carr Michael , Meyer Jennifer R , Sharma Aryan , Marshal Louise , Nunley B Ethan , Xie Hong , Carvajal Mateo , Kunerth Henry D. , Tanmoy Arif , O’Toole Áine , Weixler Amelia , Lanter Kelsey R , Gonzalez Gabrial , Sereewit Jaydee , Guevara Rommel , Loose Matt , Fanning Padraic M. , Benítez Denisse , Fernandez Juan Carlos , Cárdenas Paúl , Hare Daniel , Greninger Alex , Williams Thomas , Nebbia Gaia , Fries Anthony C. , McClure Patrick , Roychoudhury Pavitra , Wang Xiong , Saha Senjuti , Dewar Rebecca , Templeton Kate , Rambaut Andrew 
Published: August 2024

AbstractRespiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LTRIs) in young children and adults over 65, contributing significantly to global healthcare burdens. With the recent approval of multiple pharmacological interventions for RSV, there is an increased demand for efficient, high-throughput sequencing methods to monitor RSV genetic diversity and any potential impact these interventions may have. Here we introduce two novel amplicon-based sequencing schemes designed for RSV A and B, optimised for integration with widespread existing ARTIC sequencing workflows. We demonstrate that these primer schemes can produce high quality genomes from RSV samples across the globe, with eight laboratories in five countries generating complete genomes on both Nanopore and Illumina sequencing platforms. The ability to effectively multiplex these RSV A and B primer schemes, enables streamlined, high-throughput sequencing without prior subtyping. Furthermore, these results provide a snapshot of the circulating diversity of RSV. Phylogenetic analysis of the 882 samples sequenced for this study suggests only minimal geographic clustering of RSV sequences, underscoring the global nature of RSV spread. It also highlights the distinct lineage dynamics seen between RSV A and B. This study represents an advancement in RSV genomics, providing robust tools for global sequencing efforts aimed at tracking RSV evolution and assessing the efficacy of new therapeutic interventions both rapidly and at scale.