bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flavin Mononucleotide as a Biomarker of Organ Quality—A Pilot Study
Authors: Wang Lu , Thompson Emily , Bates Lucy , Pither Thomas L. , Hosgood Sarah A. , Nicholson Michael L. , Watson Christopher J.E. , Wilson Colin , Fisher Andrew J. , Ali Simi , Dark John H. 
Published: March 2021

Background.
Flavin mononucleotide (FMN), released from damaged mitochondrial complex I during hypothermic liver perfusion, has been shown to be predictive of 90-day graft loss. Normothermic machine perfusion (NMP) and normothermic regional perfusion (NRP) are used for organ reconditioning and quality assessment before transplantation. This pilot study aimed to investigate the changes of FMN levels during normothermic reperfusion of kidneys, livers, and lungs and examine whether FMN could serve as a biomarker to predict posttransplant allograft quality.

Methods.
FMN concentrations, in perfusates collected during NMP of kidneys, abdominal NRP, and ex vivo lung perfusion, were measured using fluorescence spectrometry and correlated to the available perfusion parameters and clinical outcomes.

Results.
Among 7 transplanted kidneys out of the 11 kidneys that underwent NMP, FMN levels at 60 minutes of NMP were significantly higher in the allografts that developed delayed graft function and primary nonfunction (P = 0.02). Fifteen livers from 23 circulatory death donors that underwent NRP were deemed suitable for transplantation. Their FMN levels at 30 minutes of NRP were significantly lower than those not procured for transplantation (P = 0.004). In contrast, little FMN was released during the 8 lung perfusions.

Conclusions.
This proof of concept study suggested that FMN in the perfusates of kidney NMP has the potential to predict posttransplant renal function, whereas FMN at 30 minutes of NRP predicts whether a liver would be accepted for transplantation. More work is required to validate the role of FMN as a putative biomarker to facilitate safe and reliable decision-making before embarking on transplantation.
Apolipoprotein E4 Moderates the Association Between Vascular Risk Factors and Brain Pathology
Authors: Kaufman Carolyn S. , Morris Jill K. , Vidoni Eric D. , Burns Jeffrey M. , Billinger Sandra A. 
Published: March 2021

Background:
The strongest genetic risk factor for late-onset Alzheimer disease (AD), Apolipoprotein E4 (APOE4), increases cardiovascular disease risk and may also act synergistically with vascular risk factors to contribute to AD pathogenesis. Here, we assess the interaction between APOE4 and vascular risk on cerebrovascular dysfunction and brain pathology.

Methods:
This is an observational study of cognitively normal older adults, which included positron emission tomography imaging and vascular risk factors. We measured beat-to-beat blood pressure and middle cerebral artery velocity at rest and during moderate-intensity exercise. Cerebrovascular measures included cerebrovascular conductance index and the cerebrovascular response to exercise.

Results:
There was a significant interaction between resting cerebrovascular conductance index and APOE4 carrier status on β-amyloid deposition (P=0.026), with poor conductance in the cerebrovasculature associated with elevated β-amyloid for the APOE4 carriers only. There was a significant interaction between non–high-density lipoprotein cholesterol and APOE4 carrier status (P=0.014), with elevated non–high-density lipoprotein cholesterol predicting a blunted cerebrovascular response to exercise in APOE4 carriers and the opposite relationship in noncarriers.

Conclusions:
Both cerebral and peripheral vascular risk factors are preferentially associated with brain pathology in APOE4 carriers. These findings provide insight into pathogenic vascular risk mechanisms and target strategies to potentially delay AD onset.
Cooling Intervention (MUSTCOOL) for Prevention of Lower Extremity Ulcer Recurrence
Authors: Kelechi Teresa J. , Madisetti Mohan , Prentice Margaret , Mueller Martina 
Published: March 2021

PURPOSE:
The purpose of this study was to test our MUSTCOOL cooling patch intervention on the incidence of venous leg (VLU) and diabetic foot ulcer (DFU) recurrence over a previously healed wound.

DESIGN:
A 6-month randomized controlled trial.

SUBJECTS AND SETTING:
The target population was individuals with previously healed ulcers receiving care in outpatient wound centers in the Southeastern region of the United States. The sample comprised 140 individuals with recently healed ulcers; their average age was 62.4 years (SD = 12 years); 86 (61.4%) were male; and 47 (33.6%) were Black or African American.

METHODS:
Participants were randomized to the MUSTCOOL or placebo patch. Both groups received instructions to apply the patch 3 times per week, and engage in standard of care including compression and leg elevation (VLU) or therapeutic footwear and hygiene (DFU). Demographic data were collected at baseline, and incidence measures taken at 1, 3, and 6 months. We also studied whether new ulcers developed on the adjacent leg or foot. Data were reported in frequencies/percentages.

RESULTS:
One hundred seventeen participants (84%) were analyzed who completed 6 months of study participation. Thirteen percent (9/69) and 17% (12/69) developed a recurrent or new VLU, respectively; 29% (14/48) and 13% (6/48) developed a recurrent or new DFU, respectively. One person in the DFU group developed both a recurrent and new ulcer. For 9 recurrent VLUs, 6 (66.7%) recurred in the MUSTCOOL group and 3 (33.3%) receiving the placebo. Of the 15 recurrent DFUs (includes individual who developed both a recurrent and new ulcer), 10 (66.7%) recurred in the MUSTCOOL group and 5 (33.3%) receiving the placebo.

CONCLUSIONS:
While the incidence of ulcer recurrent was slightly higher in the MUSTCOOL group, this finding was not considered clinically relevant. Overall ulcer recurrence during the 6-month study period was lower than reports in the literature, the time frame in which recurrence rates are highest.

TRIAL REGISTRATION:
The study was prospectively registered with ClinicalTrials.gov on December 10, 2015 (Identifier: NCT02626156)—https://clinicaltrials.gov/ct2/show/NCT02626156.
Deep learning-based pan-cancer classification model reveals cancer-specific gene expression signatures
Authors: Divate Mayur , Tyagi Aayush , Richard Derek J , Prasad Prathosh A , Gowda Harsha , Nagaraj Shivashankar H 
Published: March 2021

AbstractThe identification of cancer-specific biomarkers and therapeutic targets is one of the primary goals of cancer genomics. Thousands of cancer genomes, exomes, and transcriptomes have been sequenced to date. In this study, we conducted a pan-cancer analysis of transcriptome datasets from 37 cancer types provided by The Cancer Genome Atlas (TCGA) in an effort to identify cancer-specific gene expression signatures. We employed deep neural networks to train a model on the transcriptome profile datasets for all cancer types. The model was validated, and its predictive accuracy was determined using an independent dataset, achieving > 97% prediction accuracy across cancer types. This strongly suggests that there are distinct gene expression signatures associated with various cancer types. We interpreted the model using SHapley Additive exPlanations (SHAP) to identify specific gene signatures that significantly contributed to the classification of cancer types. In addition to known biomarkers, we identified several novel biomarkers in different cancer types. These cancer-specific gene signatures are valuable candidates for future studies of their potential utility as cancer biomarkers and putative therapeutic targets.
SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway
Authors: Khan Shahanshah , Shafiei Mahnoush S. , Longoria Christopher , Schoggins John , Savani Rashmin C. , Zaki Hasan 
Published: March 2021

ABSTRACTPathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1ß, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1 ß in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.
Epigallocatechin Gallate from Green Tea Effectively Blocks Infection of SARS-CoV-2 and New Variants by Inhibiting Spike Binding to ACE2 Receptor
Authors: Liu Jinbiao , Bodnar Brittany H , Meng Fengzhen , Khan Adil , Wang Xu , Luo Guangxiang , Saribas Sami , Wang Tao , Lohani Saroj Chandra , Wang Peng , Wei Zhengyu , Luo Jinjun , Zhou Lina , Wu Jianguo , Li Qingsheng , Hu Wenhui , Ho Wenzhe 
Published: March 2021

AbstractAs the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Here, we demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.
Molecular characterization reveals genomic and transcriptomic subtypes of metastatic urothelial carcinoma
Authors: Alberto Nakauma-González J. , Rijnders Maud , van Riet Job , van der Heijden Michiel S. , Voortman Jens , Cuppen Edwin , Mehra Niven , van Wilpe Sandra , Oosting Sjoukje F. , Lucia Rijstenberg L. , Westgeest Hans M. , Zwarthoff Ellen C. , de Wit Ronald , van der Veldt Astrid A.M. , van de Werken Harmen J. G. , Lolkema Martijn P. J. , Boormans Joost L. 
Published: March 2021

AbstractBackgroundMolecular characterization of primary urothelial carcinoma (UC) revealed molecular subtypes with different genomic, transcriptomic, and clinicopathological characteristics, which might guide therapeutic decision making. A comprehensive molecular characterization of metastatic UC (mUC), however, is currently lacking in the literature. Because of the lethality of mUC, with few therapeutic options available for patients, a multi-omics characterization of mUC could aid to improve patient selection for new and existing therapies.MethodsTo define the molecular landscape of mUC and to identify potential targets for therapy, we performed whole genome DNA sequencing on fresh-frozen metastatic tumor biopsies of 116 mUC patients, and mRNA sequencing on 90 matched biopsies.ResultsHierarchical clustering based on mutational signatures revealed two major genomic subtypes. The most prevalent subtype (67%) consisted almost exclusively of tumors with high APOBEC mutagenesis. APOBEC mutagenesis was detected in 91% of the samples, and appeared to be an ongoing process in mUC based on analysis of eight patients from whom serial biopsies were obtained during treatment. Contrary to the overall distribution of mutations, APOBEC associated mutations occurred throughout the genome, and independently of predicted accessible or transcribed genomic regions, suggesting that these mutations were generated during replication. Transcriptomic analysis revealed five mRNA-based subtypes: two luminal subtypes (40%), a stroma-rich (24%), basal/squamous (23%), and non-specified subtype (12%). The transcriptomic subtypes were different regarding driver gene alterations (e.g. ELF3 and TSC1), gene amplifications (NECTIN4 and PPARG), pathway activity, and immune cell infiltration. By integrating the genomic and transcriptomic data, potential therapeutic options per transcriptomic subtype and individual patient were proposed.ConclusionsThis study expands our knowledge on the molecular landscape of mUC, and serves as a reference for subtype-oriented and patient-specific research on the etiology of mUC, and for novel drug development.Trial registrationThe mUC cohort studied here is part of the Netherlands nationwide study of the center for personalized cancer treatment consortium (CPCT-02 Biopsy Protocol, NCT01855477), and the Drug Rediscovery Protocol (DRUP Trial, NCT02925234).
Programmable pattern formation in cellular systems with local signaling
Authors: Ramalho Tiago , Kremser Stephan , Wu Hao , Gerland Ulrich 
Published: March 2021

ABSTRACTDiverse complex systems, ranging from developing embryos to systems of locally communicating agents, display an apparent capability of “programmable” pattern formation: They reproducibly form a target pattern, but this target can be readily changed. A distinguishing feature of such systems, as compared to simpler physical pattern forming systems, is that their subunits are capable of information processing. Here, we explore schemes for programmable pattern formation within a theoretical framework, in which subunits process discrete local signals to update their internal state according to logical rules. We study systems with different update rules, different topologies, and different control schemes, to assess their ability to perform programmable pattern formation and their susceptibility to errors. Only a small subset of systems permits local organizer cells to dictate any target pattern. These systems follow a common principle, whereby a temporal pattern is transcribed into a spatial pattern, reminiscent of the clock-and-wavefront mechanism underlying vertebrate somitogenesis. An alternative scheme employing several different rules can only form a fraction of patterns but is robust with respect to the timing of organizer cell inputs. Our results establish a basis for the design of synthetic systems, and for more detailed models of programmable pattern formation closer to real systems.
Antibody repertoire analysis of tumor-infiltrating B cells reveals distinct signatures and distributions across tissues
Authors: Aizik Ligal , Dror Yael , Taussig David , Barzel Adi , Carmi Yaron , Wine Yariv 
Published: March 2021

AbstractThe role of B cells in the tumor microenvironment (TME) has largely been under investigated, and data regarding the antibody repertoire encoded by B cells in the TME and the adjacent lymphoid organs are scarce. Here, we utilized B cell receptor high-throughput sequencing (BCR-Seq) to profile the antibody repertoire signature of tumor-infiltrating lymphocyte B cells (TIL-Bs) in comparison to B cells from three anatomic compartments in a mouse model of triple-negative breast cancer. We found that TIL-Bs exhibit distinct antibody repertoire measures, including high clonal polarization and elevated somatic hypermutation rates, suggesting a local antigen-driven B-cell response. Importantly, TIL-Bs were highly mutated but non-class switched, suggesting that class-switch recombination may be inhibited in the TME. Tracing the distribution of TIL-B clones across various compartments indicated that they migrate to and from the TME. The data thus suggests that antibody repertoire signatures can serve as indicators for identifying tumor-reactive B cells.
Mitochondrial fission is required for proper nucleoid distribution within mitochondrial networks
Authors: Ilamathi Hema Saranya , Ouellet Mathieu , Sabouny Rasha , Desrochers-Goyette Justine , Lines Matthew A. , Pfeffer Gerald , Shutt Timothy E. , Germain Marc 
Published: March 2021

AbstractMitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.Significance statementMutation or deletion of mitochondrial DNA (mtDNA) is associated with a large number of human diseases. However, the mechanisms controlling mtDNA replication and segregation are still poorly understood. Here, we have developed a new computational method to quantify the distribution of nucleoids (mtDNA with associated proteins) and define how nucleoid distribution is affected by changes in mitochondrial network structure. We demonstrate that mitochondrial fission is required for the proper distribution of nucleoids across mitochondrial networks, cells from patients with fission defects showing irregular nucleoid distribution and perinuclear accumulation. Nonetheless, each fission mutant behaved in a distinct manner, indicating a complex relationship between mitochondrial dynamics and nucleoid distribution.
A Cdc42-Borg4-Septin 7 axis regulates HSCs polarity and function
Authors: Kandi Ravinder , Senger Katharina , Grigoryan Ani , Soller Karin , Sakk Vadim , Schuster Tanja , Eiwen Karina , Menon Manoj B. , Gaestel Matthias , Zheng Yi , Florian Maria Carolina , Geiger Hartmut 
Published: March 2021

AbstractAging of hematopoietic stem cells (HSCs) is caused by an elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal septin network. Here we show that Cdc42 interacts with borg4, which in turn interacts with septin 7 to regulate the polar distribution of Cdc42, borg4 and septin 7 within HSCs. Genetic deletion of either borg4 or septin 7 in HSCs resulted in a reduced frequency of HSCs polar for Cdc42 or borg4 or septin 7 and a reduced engraftment potential and decreased lymphoid-primed multipotent progenitors (LMPPs) frequency in the bone marrow. In aggregation our data identify a Cdc42-borg4-septin 7 axis to be essential for maintenance of polarity within HSCs and for HSC function and provide rationale for further investigating the role of borgs and septins for the regulation of compartmentalization within stem cells.Graphical Abstract
Clathrin adaptors mediate two sequential pathways of intra-Golgi recycling
Authors: Casler Jason C. , Krahn Adam H. , Pantazopoulou Areti , Johnson Natalie , Day Kasey J. , Glick Benjamin S. 
Published: March 2021

AbstractThe pathways of membrane traffic within the Golgi apparatus are not fully known. This question was addressed using the yeastSaccharomyces cerevisiae, in which the maturation of individual Golgi cisternae can be visualized. We recently proposed that the AP-1 clathrin adaptor mediates intra-Golgi recycling late in the process of cisternal maturation. Here, we demonstrate that AP-1 cooperates with the Ent5 clathrin adaptor to recycle a set of Golgi transmembrane proteins. This recycling can be detected by removing AP-1 and Ent5, thereby diverting the AP-1/Ent5-dependent Golgi proteins into an alternative recycling loop that involves traffic to the plasma membrane followed by endocytosis. Unexpectedly, various AP-1/Ent5-dependent Golgi proteins show either intermediate or late kinetics of residence in maturing cisternae. We infer that the AP-1/Ent5 pair mediates two sequential intra-Golgi recycling pathways that define two classes of Golgi proteins. This insight can explain the polarized distribution of transmembrane proteins in the Golgi.
Burrowing crabs and physical factors hasten marsh recovery at panne edges
Authors: Beheshti Kathryn M. , Endris Charlie , Goodwin Peter , Pavlak Annabelle , Wasson Kerstin 
Published: March 2021

ABSTRACTSalt marsh loss is projected to increase as sea-level rise accelerates with global climate change. Salt marsh loss occurs along both lateral creek and channel edges and in the marsh interior, when pannes expand and coalesce. Often, edge loss is attributed to erosive processes whereas dieback in the marsh interior is linked to excessive inundation or deposition of wrack. We conducted a two-year field experiment (2016-2018) in a central California estuary, where, immediately preceding our study, marsh dieback at creek edges and panne expansion occurred during a period of severe drought and an overlapping warm water event. Our study explored how an abundant burrowing crab, shown to have strong negative effects on marsh biomass near creek edges, affects panne dynamics. We also explored which panne attributes best predicted their dynamics. Overall, we found that pannes contracted during the study period, but with variable rates of marsh recovery across pannes. Our model incorporating both physical and biological factors explained 86% of the variation in panne contraction. The model revealed a positive effect of crab activity, sediment accretion, and a composite of depth and elevation on panne contraction, and a negative effect of panne size and distance to nearest panne. The positive crab effects detected in pannes contrast with negative effects we had earlier detected near creek edges, highlighting the context-dependence of top-down and bioturbation effects in marshes. As global change continues and the magnitude and frequency of disturbances increases, understanding the dynamics of marsh loss in the marsh interior as well as creek banks will be critical for the management of these coastal habitats.