bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Personalized Treatment of Metastatic Porocarcinoma
Authors: Chan Sharon Pei Yi , Low Chen Ee , Yau Chun En , Lin Tzu Ping , Wang Weining , Xiu Sam Xin , Tang Po Yin , Luo Baiwen , Noor Nur Fazlin Bte Mohamed , Lee Kristen Alexa , Chiang Jianbang , Toh Tan Boon , Chow Edward Kai-Hua , Yang Valerie Shiwen 
Published: May 2023

SummaryMetastatic porocarcinomas (PC) have high mortality rates of 70%. PC is extremely rare, accounting for 0.01% of malignant cutaneous neoplasms, precluding the possibility of conducting clinical trials to evaluate treatment. Pathogenesis and clinical management of PC remain largely unknown Surgical resection of localized PC remains the mainstay of treatment. There are no effective agents for unresectable PC. Comprehensive genomic profiling did not yield any actionable genomic aberrations in our patient with metastatic PC.Ex vivodrug testing predicted pazopanib efficacy and treatment elicited remarkable clinicoradiological response. A functional precision medicine approach may be effective for the treatment of rare cancers.
Functional filter for whole genome sequence data identifies stress impact, non-coding alternate polyadenylation site variants >5kb from coding DNA
Authors: Xiao Sihao , Kai Zhentian , Murphy Daniel , Li Dongyang , Patel Dilip , Bielowka Adrianna , Bernabeu-Herrero Maria E. , Abdulmogith Awatif , Mumford Andrew D , Westbury Sarah , Aldred Micheala A , Vargesson Neil , Caulfield Mark J ,   Genomics England Research Consortium, Shovlin Claire L 
Published: May 2023

AbstractDespite whole genome sequencing (WGS), why do many single gene disorder cases remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection? Early WGS data analytic steps prioritize protein-coding sequences. To simultaneously prioritise variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool which integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants per DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3’ untranslated region (UTR) of the proto-oncogeneSMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis. Sited >5.4kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16 nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. MonocyteSMAD4RNA expression differed between patients and controls in resting and cycloheximide-stressed states. Patterns predicted the mutational site for an unrelated case, where a complex insertion was subsequently identified. In conclusion, a new type of functional rare variant is described, exposing novel regulatory systems based on polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.
Closing the Pneumococcal Conjugate Vaccine (PCV) Introduction Gap: An Archetype Analysis of ‘last-mile’ countries
Authors: Banerjee Preetika , Huber Jasmine , Denti Veronica , Sauer Molly , Weeks Rose , Dhaliwal Baldeep K. , Shet Anita 
Published: May 2023

AbstractPneumonia remains the leading infectious cause of global childhood deaths, despite the availability of World Health Organization (WHO)-prequalified pneumococcal conjugate vaccine (PCV) products and the evidence of their safety and efficacy for over two decades, along with financial and technical support from Gavi The Vaccine Alliance (Gavi). There are 39 remaining “last-mile” countries (33 low- and middle-income countries [LMICs] and six high-income countries) that haven’t fully included PCV in their National Immunization Programs. To address this inequitable distribution of PCV, we conducted a rapid assessment and landscaping exercise of country indicators related to barriers and facilitators for PCV decision-making, aiming to categorize countries into archetypes that could benefit from shared advocacy approaches. The archetype analysis first created a country matrix focused on three domains - health characteristics, immunization factors, and policy framework - and identified ten related indicators. Countries were scored based on indicator performance and subsequently ranked and grouped into three overarching archetypes of low-, moderate-, and high-barrier to PCV introduction.15 countries were classified as “low-barrier,” indicating that they have more factors favorable for PCV introduction, such as high immunization coverage of common childhood vaccines, recent “new” vaccine introductions, and supportive governments, as well as substantial disease burden and eligibility for Gavi support. Most of the countries classified in the “moderate-barrier” (12 countries) and “high-barrier” (6 countries) archetypes have strong immunization systems, but competing country priorities and cost barriers impede policy decision-making on PCV introduction. Other countries require strengthening of their health systems despite political will.The barrier-based categorization can provide an actionable framework to design tailored PCV advocacy that addresses obstacles to new vaccine introductions within these “last-mile” countries. Implementation approaches that emerge from this framework can lead to strengthened decision-making on vaccine introduction and mobilization of investments in vaccine access that can enhance child survival worldwide.
Valve Sparing Aortic Root Replacement: long term predictors of outcomes and mortality
Authors: Sharma Varun J. , Kangarajah Abbie , Yang Amy , Kim Michelle , Seevayanagam Siven , Matalanis George 
Published: May 2023

AbstractIntroductionIn aortic root surgery, Valve Sparing Aortic Root Replacement (VSARR) is an attractive alternative by mitigating the risks inherent to prosthetic valves, however little is known about the variables that impact its performance and durability. We have reviewed our mid to long-term outcomes following VSARR and describe factors that impact patient survival and aortic valve reintervention and insufficiency.MethodsA retrospective review of 284 consecutive patients undergoing VSARR between November 1999 and January 2022 at Austin Health, Melbourne, Australia, was undertaken, with median follow up of 6.43 ± 4.83 years, but up to 22.0 years.ResultsThe median age at intervention was 60.0 years (IQR 48.0-67.0), of which 68 (23.9%) had bicuspid aortic valve (BAV) disease, 27 (9.5%) Marfan’s disease, 119 (41.9%) severe aortic root dilation (>50mm), and 155 (54.6%) severe aortic insufficiency at the time of intervention. The 30-day mortality was 1.8%, with freedom from mortality of 96.0% (95% CI 92.6-97.8%) at 5 years, 88.2% (95% CI 81.4-92.6%) at 10 years and 78.6% (66.2-86.9%) at 15 years. Freedom from aortic re-intervention was 92.2% (95% CI 87.7-95.2%) at 5 years, 79.8% (95% CI 71.8-85.8%) at 10 years, and 74.1% (63.5-82.0%) at 15 years. Predictors of re-intervention were concomitant leaflet repair (HR 8.13, 95%CI 1.07-61.7) and bicuspid valvulopathy (HR 2.23, 95% CI 1.07-4.68). The freedom from aortic insufficiency was 89.1% (95% CI 83.5-92.9%), 84.9% (95% CI 77.8-89.9%) and 80.7% (71.0-87.4%) at 5-, 10- and 15-years respectively.ConclusionVSARR has excellent long-term outcomes, with low mortality and re-intervention rates. Concomitant Leaflet repair and Bicuspid Aortopathy are the only long-term predictors of re-intervention.
Application of AMR in evaluating microvascular dysfunction after ST-segment elevation myocardial infarction
Authors: Wang Hao , Wu Qi , Yang Lang , Chen Long , Liu Wen-Zhong , Xu Jing-Song 
Published: May 2023

AbstractBACKGROUNDQuantitative flow ratio (QFR) is a new method to estimate fractional flow reserve based on three-dimensional quantitative coronary angiography, from which angiography-derived microcirculatory resistance (AMR) without guidewires and adenosine is derived as an indicator of microvascular dysfunction. This study aimed to assess coronary microvascular dysfunction (CMD) in patients with ST-segment elevation myocardial infarction (STEMI) by AMR.METHODSA retrospective collection of 506 STEMI patients who successfully underwent percutaneous coronary intervention (PCI) from June 1, 2020, to September 28, 2021, was divided into the CMD group and the non-CMD group based on the value of AMR, while we used propensity score matching (PSM) to adjust for baseline characteristics. The primary endpoint was the 1-year rate of major adverse cardiac events (MACE), a composite of death from any cause, myocardial infarction, readmission for heart failure, or ischemia-driven revascularization.RESULTSThe 1-year rate of MACE in CMD group was higher than that in the non-CMD group (post-match HR 1.954, 95% CI:1.025 to 3.726; 14.1% vs. 7.3%, P=0.042); Subgroup analysis showed that the readmission rate of heart failure (HF) was higher in the CMD group than in the non-CMD group (post-match HR 5.082, 95% CI:1.471 to 17.554; 7.9% vs. 1.6%. P=0.010). The results of survival analysis suggested that AMR ≥250mmHg*s/m was an independent predictor of the primary endpoint in STEMI patients (post-match adjusted HR 2.265, 95% CI: 1.136 to 4.515, P = 0.020). CONCLUSION: As an indicator of microvascular dysfunction, AMR can be a viable alternative to invasive wire-based IMR in STEMI patients.
Serialized On-grid Lift-In Sectioning for Tomography (SOLIST)
Authors: Dung Nguyen Ho Thuy , Perone Gaia , Vazzana Roberta , Don Flaminia Kaluthantrige , Silva Malan , Sorrentino Simona , Swuec Paolo , Leroux Frederic , Kalebic Nereo , Coscia Francesca , Erdmann Philipp S. 
Published: May 2023

AbstractCryo-focused ion beam milling has enabled groundbreaking structural discoveries in native cells. Progress toward medically relevant applications, however, has been slow. We here present an adaptation of the cryo-lift out procedure for Serialized On-grid Lift-In Sectioning for Tomography (SOLIST), which increases throughput, reduces ice contamination, and enhances sample stability. With these improvements, new specimens, ranging from high-pressure frozen reconstituted LLPS droplets to human forebrain organoids, are accessible to cryo-electron tomography.
Forest characteristics predict tri-colored bat activity within novel Colorado habitats
Authors: Bevan Zientek Amanda J. , Colpitts Alexandria B. , Adams Rick. A. 
Published: May 2023

ABSTRACTClimate change and other anthropogenic pressures are altering species distributions. Several studies have indicated that tri-colored bats (Perimyotis subflavus) are extending their distributional range westward in the United States. Montane and subalpine habitats consist of a mosaic of forest types including lodgepole pine woodlands and montane meadows, which provide an opportunity to study how a newly arriving species, typically associated with lowland riparian systems, is adapting to novel environmental conditions. The objective of this study is to document tri-colored bat activity in these novel habitats using acoustic surveys and to quantify what factors are influencing activity patterns in habitats and at elevations not previously documented. We selected sites at 2700m elevation that differed in stand structure, driven primarily by beetle kill outbreaks, and were in various stages of secondary succession. We used acoustic monitoring to model habitat activity patterns using nonparametric multiplicative regression. Results showed that tri-colored bats used meadows and lodgepole pine stands undergoing secondary succession following bark beetle outbreaks. Activity was highest in meadows and early time-since-kill (TSK) forests in the beginning of the survey period, and tri-colored bats had increased activity in late TSK forest habitats at the end of the survey period in early August. Temporally, activity was lowest during the middle of the survey period (mid-July) indicating that tri-colored bats moved away from our study area. However, activity significantly returned by the end of the survey. Our study demonstrates that tri-colored bats are not restricting their activity to lower elevation riparian areas in the Colorado foothills, but instead appear to be using high elevation habitat types in areas dominated by lodgepole pine and subalpine meadows. We hope this study will support conservation efforts for this species following the proposed U.S. Fish and Wildlife Service listing.
Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5Lhihepatic macrophages
Authors: Sato Ryota , Liu Kaiwen , Shibata Takuma , Hoshino Katsuaki , Yamaguchi Kiyoshi , Miyazaki Toru , Hiranuma Ryosuke , Fukui Ryutaro , Motoi Yuji , Fukuda-Ohta Yuri , Zhang Yun , Reuter Tatjana , Ishida Yuko , Kondo Toshikazu , Chiba Tomoki , Asahara Hiroshi , Taoka Masato , Yamauchi Yoshio , Isobe Toshiaki , Kaisho Tsuneyasu , Furukawa Yoichi , Latz Eicke , Miyake Kensuke 
Published: May 2023

AbstractHepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5Lhihepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6Clomacrophages activated the transcription factors LXRα and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently,Rnaset2−/−mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses inRnaset2−/−mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages inRnaset2−/−mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages.Graphical AbstractIn the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine.
Foldy: a web application for interactive protein structure analysis
Authors: Roberts Jacob B. , Nava Alberto A. , Pearson Allison N. , Incha Matthew R. , Valencia Luis E. , Ma Melody , Rao Abhay , Keasling Jay D. 
Published: May 2023

AbstractFoldy is a cloud-based application that allows non-expert scientists to easily access and utilize advanced AI-based structural biology tools, including AlphaFold and DiffDock. Built on Kubernetes, it can be deployed by universities, departments, and labs without requiring hardware resources, but can also be configured to utilize available computers. Foldy enables scientists to predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock.Our manuscript describes the user interface and deployment considerations of Foldy, as well as some of our applications. By democratizing access to sophisticated AI-based tools, Foldy can facilitate life science research and promote the wider adoption of structural bioinformatics tools. Our work demonstrates that even the most advanced tools can be made accessible to a broad audience through user-friendly platforms like Foldy, and we believe it will be a valuable resource for researchers across scientific disciplines. The public structures available on the Lawrence Berkeley Labs Foldy deployment can be viewed athttps://foldy.lbl.gov.Author SummaryFoldy is a cloud-based application that enables scientists to use AI-based structural biology tools such as AlphaFold and DiffDock without software expertise. Built on Kubernetes, it can be set up by universities, departments, and labs with no need for hardware resources. Foldy can predict the structure of proteins and complexes up to 3000 amino acids, visualize Pfam annotations, and dock ligands with AutoDock Vina and DiffDock. Our public structures can be viewed athttps://foldy.lbl.gov.Our manuscript highlights the user interface, deployment considerations, and product applications of Foldy. It’s an accessible solution for researchers who are not software experts and can handle the traffic of thousands of users and hundreds of thousands of protein structures and docked ligands. This makes advanced AI-based tools more widely available, paving the way for accelerating life science research.By developing an easy-to-use platform, our work demonstrates that even the most sophisticated AI-based tools can be made accessible to a wide audience. Foldy enables more scientists to draw from the rapidly growing field of structural biology, making it a valuable tool for researchers across scientific disciplines. We look forward to its adoption by the scientific community.
Hybrid computational modeling highlights reverse Warburg effect in breast cancer-associated fibroblasts
Authors: Aghakhani Sahar , Silva-Saffar Sacha E , Soliman Sylvain , Niarakis Anna 
Published: May 2023

AbstractCancer-associated fibroblasts (CAFs) are key players of the tumor microenvironment (TME) involved in cancer initiation, progression, and resistance to therapy. These cells exhibit aggressive phenotypes affecting, among others, extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining an asynchronous cell- and disease-specific regulatory Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, considering our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis.All analyses are compiled and thoroughly annotated in Jupyter notebooks and R scripts available on a GitLab repository (https://gitlab.com/genhotel/breast-cafs-reverse-warburg-effect) and a Zenodo permanent archive [1].
The early macrophage response to pathogens requires dynamic regulation of the nuclear paraspeckle
Authors: Azam Sikandar , Armijo Kaitlyn S. , Weindel Chi G. , Devigne Alice , Nakagawa Shinichi , Hirose Tetsuro , Carpenter Susan , Watson Robert O. , Patrick Kristin L. 
Published: May 2023

ABSTRACTTo ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages needs to be exquisitely well-controlled. There is a growing appreciation for stress-responsive membraneless organelles (MLOs) regulating various steps of eukaryotic gene expression in response to extrinsic cues. Here, we implicate the nuclear paraspeckle, a highly ordered biomolecular condensate that nucleates on theNeat1lncRNA, in tuning innate immune gene expression in murine macrophages. In response to a variety of innate agonists, macrophage paraspeckles rapidly aggregate (0.5 h post-stimulation) and disaggregate (2h post-stimulation). Paraspeckle maintenance and aggregation require active transcription and MAPK signaling whereas paraspeckle disaggregation requires degradation ofNeat1via the nuclear RNA exosome. Expression of a large cohort of cytokines, chemokines, and antimicrobial mediators is compromised in lipopolysaccharide-treated macrophages lackingNeat1, resulting in a failure to express a cohort of pro-inflammatory cytokines, chemokines, and antimicrobial mediators. Consequently,Neat1KO macrophages cannot control replication ofSalmonella entericaserovar Typhimurium or vesicular stomatitis virus. These findings highlight a prominent role for MLOs in orchestrating the macrophage response to pathogens and support a model whereby dynamic assembly and disassembly of paraspeckles reprograms the nuclear RNA binding protein landscape to enable inflammatory gene expression following innate stimuli.SIGNIFICANCE STATEMENTTo mount appropriate immune responses and fight infection, macrophages need to sense and respond to pathogen-associated signals with incredible precision. Membraneless organelles (MLOs) are complexes of RNAs and proteins that change in size, shape, and abundance in response to extracellular signals. We hypothesized that an MLO called the nuclear paraspeckle helps macrophages initiate and calibrate innate immune gene expression during infection. We found that paraspeckles rapidly aggregate and then dissolve in macrophages following pathogen sensing. Macrophages lacking paraspeckles cannot properly induce inflammatory genes, resulting in a failure to control replication of intracellular bacterial and viral pathogens. These data suggest that altered paraspeckle dynamics may dysregulate inflammatory gene expression in a variety of human diseases.