bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visceral Fat Inflammation and Fat Embolism are associated with Lung’s Lipidic Hyaline Membranes in COVID-19 patients
Authors: Colleluori Georgia , Graciotti Laura , Pesaresi Mauro , Di Vincenzo Angelica , Perugini Jessica , Di Mercurio Eleonora , Caucci Sara , Bagnarelli Patrizia , Zingaretti Cristina M. , Nisoli Enzo , Menzo Stefano , Tagliabracci Adriano , Ladoux Annie , Dani Christian , Giordano Antonio , Cinti Saverio 
Published: November 2021

AbstractBackgroundVisceral obesity is a critical determinant of severe coronavirus disease-2019 (COVID-19). Methods: In this study, we performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissues (VAT), lungs and livers of 19 COVID-19 and 23 non-COVID-19 subjects.ResultsAlthough there were no between-groups differences in body-mass-index and adipocytes size, higher prevalence of CD68+ macrophages in COVID-19 subjects’ VAT was detected (p=0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution employing Oil-Red-O staining (ORO). Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels’ lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19 individuals (p<0.001). Notably, signs of fat embolism were more prevalent among obese (p=0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication, exacerbated by SARS-CoV2 infection. Importantly, all infected subjects’ lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control with non-COVID-19 pneumonia.ConclusionsThis study describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in obese SARS-CoV2-infected-subjects.
Manual curation and phylogenetic analysis of chitinase family genes in the Asian citrus psyllid, Diaphorina citri
Authors: Shippy Teresa D. , Miller Sherry , Tamayo Blessy , Hosmani Prashant S , Flores-Gonzalez Mirella , Mueller Lukas A , Hunter Wayne B , Brown Susan J , D’Elia Tom , Saha Surya 
Published: November 2021

AbstractChitinases are enzymes that digest the polysaccharide polymer chitin. Chitin is a major component of insect exoskeletons, which must be replaced multiple times during growth and development in a process known as molting. Insect genomes usually have multiple chitinase genes, some of which are required for molting and some whose functions are still unknown. Since knockdown of the chitinases required for molting causes high levels of lethality, chitinase genes have drawn interest as targets for RNAi-based pest control methods. The Asian citrus psyllid, Diaphorina citri, carries the bacterium that causes Huanglongbing, also known as citrus greening disease, which is devastating the citrus industry worldwide. We have identified and annotated 12 chitinase family genes from D. citri as part of a community effort to create high quality gene models to facilitate the design of interdictory molecules for pest control. Using predicted protein domain content and phylogenetic analysis, we categorized the D. citri chitinases according to a previously established classification scheme and re-evaluated the classification of chitinases in other hemipterans. In addition to chitinases belonging to known groups, we identified a novel class of chitinases present in D. citri and several related hemipterans that appears to be the result of horizontal gene transfer.
Antibiotic inhibition of the Plasmodium apicoplast decreases haemoglobin degradation and antagonises dihydroartemisinin action
Authors: Crisafulli Emily M. , De Paoli Amanda , Tutor Madel V. , Siddiqui Ghizal , Creek Darren J. , Tilley Leann , Ralph Stuart A. 
Published: November 2021

AbstractThe World Health Organisation (WHO) recommends artemisinin (ART) combinations for treatment of uncomplicated Plasmodium falciparum malaria. Understanding the interaction between co-administered drugs within combination therapies is clinically important to prevent unintended consequences. The WHO guidelines recommend second line treatments that combine artesunate with tetracycline, doxycycline, or clindamycin—antibiotics that target the Plasmodium relict plastid, the apicoplast. In addition, antibiotics can be used simultaneously against other infectious diseases, leading to their inadvertent combination with ARTs. One consequence of apicoplast inhibition is a perturbation to haemoglobin uptake and trafficking—a pathway required for activation of ART derivatives. Here, we show that apicoplast-targeting antibiotics reduce the abundance of the catalyst of ART activation (free haem) in P. falciparum, likely through diminished haemoglobin digestion. We demonstrate antagonism between ART and these antibiotics, suggesting that apicoplast inhibitors reduce ART activation. These data have potential clinical implications due to the reliance on—and widespread use of—both ARTs and these antibiotics in malaria endemic regions.
Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in PSC
Authors: Awoniyi Muyiwa , Wang Jeremy , Ngo Billy , Meadows Vik , Tam Jason , Viswanathan Amba , Lai Yunjia , Montgomery Stephanie A. , Farmer Morgan , Kummen Martin , Thingholm Louise B. , Schramm Christoph , Bang Corinna , Franke Andre , Schnabl Bernd , Lu Kun , Ting Jenny PY , Popov Yuri V. , Hov Johannes R. , Francis Heather , Sartor R. Balfour 
Published: November 2021

AbstractObjectiveConflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. Goal: Define complex interactions between resident microbes and their association in PSC patients by studying antibiotic-treated specific pathogen-free (SPF) and germ-free (GF) multi-drug-resistant 2 deficient (mdr2-/-) mice.DesignWe measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, fecal 16s rRNA gene profiling, and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients.ResultsGF mdr2-/- mice had exaggerated hepatic inflammation and fibrosis with 100% mortality by 8 weeks; early SPF autologous stool transplantation rescued liver-related mortality. Broad-spectrum antibiotics and vancomycin alone accelerated disease in weanling SPF mdr2-/- mice, indicating that vancomycin-sensitive resident microbiota protect against hepatobiliary disease. Vancomycin treatment selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased cytolysin-expressing E. faecalis and E. coli liver translocation; colonization of gnotobiotic mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated liver inflammation and mortality. Lachnospiraceae colonization of antibiotic pre-treated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, while Lachnospiraceae-produced SCFA decreased fibrosis. Fecal E. faecalis/ Enterobacteriaceae was positively and Lachnospiraceae was negatively associated with PSC patients’ clinical severity Mayo risk scores.ConclusionsWe identified specific functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical outcomes. These insights may guide personalized targeted therapeutic interventions in PSC patients.
The structure and organization of headache differential diagnoses: A Pilot Study of Subset Relationships between Differentials in ICHD3
Authors: Zhang Pengfei 
Published: November 2021

Structured AbstractObjectiveDifferential diagnosis is fundamental to medicine. Using DiffNet, a differential diagnosis generator, as a model we studied the structure and organization of how collections of diagnose (i.e. sets of diagnoses) are related in the ICHD3. Specifically, we asked: Which sets of differential diagnoses are subsets of each other? What is the minimum number of sets of differential diagnoses that encompass all ICHD3 codes? Furthermore, we explored the clinical and theoretical implication of these answers.MethodsDiffNet is a freely distributed differential diagnosis generator for headaches using graph theoretical properties of ICHD3. For each ICHD3 diagnosis, we generated a set of differential diagnoses using DiffNet. We then determined algorithmically the set/subset relationship between these sets. We also determined the smallest list of ICHD3 diagnosis whose differential diagnoses would encompass the totality of ICHD3 diagnoses.ResultsAll ICHD3 diagnoses can be represented by a minimum of 92 differential diagnosis sets. Differential diagnosis sets for 10 of the 14 first digit subcategories of ICHD3 are represented by more than one differential diagnosis sets. Fifty-one of the 93 differential diagnosis sets contain multiple subset relationships; the remaining 42 do not enter into any set/subset relationship with other differential diagnosis sets. Finally, we included a hierarchical presentation of differential diagnosis sets in ICHD3 according to DiffNet.ConclusionWe propose a way of interpreting headache differential diagnoses as partial ordered sets (i.e. poset). For clinicians, fluency with the 93 diagnoses and their differential put forth here implies a complete description of ICHD3. On a theoretical level, interpreting ICHD3 differential diagnosis as poset, allows researchers to translate differential diagnoses sets topologically, algebraically, and categorically.
Report 46: Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals
Authors: Brizzi Andrea , Whittaker Charles , Servo Luciana M. S. , Hawryluk Iwona , Prete Carlos A. , de Souza William M. , Aguiar Renato S. , Araujo Leonardo J. T. , Bastos Leonardo S. , Blenkinsop Alexandra , Buss Lewis F. , Candido Darlan , Castro Marcia C. , Costa Silvia F. , Croda Julio , de Souza Santos Andreza Aruska , Dye Christopher , Flaxman Seth , Fonseca Paula L. C. , Geddes Victor E. V. , Gutierrez Bernardo , Lemey Philippe , Levin Anna S. , Mellan Thomas , Bonfim Diego M. , Miscouridou Xenia , Mishra Swapnil , Monod Mélodie , Moreira Filipe R. R. , Nelson Bruce , Pereira Rafael H. M. , Ranzani Otavio , Schnekenberg Ricardo P. , Semenova Elizaveta , Sonnabend Raphael , Souza Renan P. , Xi Xiaoyue , Sabino Ester C. , Faria Nuno R. , Bhatt Samir , Ratmann Oliver 
Published: November 2021

AbstractThe SARS-CoV-2 Gamma variant spread rapidly across Brazil, causing substantial infection and death waves. We use individual-level patient records following hospitalisation with suspected or confirmed COVID-19 to document the extensive shocks in hospital fatality rates that followed Gamma’s spread across 14 state capitals, and in which more than half of hospitalised patients died over sustained time periods. We show that extensive fluctuations in COVID-19 in-hospital fatality rates also existed prior to Gamma’s detection, and were largely transient after Gamma’s detection, subsiding with hospital demand. Using a Bayesian fatality rate model, we find that the geographic and temporal fluctuations in Brazil’s COVID-19 in-hospital fatality rates are primarily associated with geographic inequities and shortages in healthcare capacity. We project that approximately half of Brazil’s COVID-19 deaths in hospitals could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization, and pandemic preparedness are critical to minimize population wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries.NoteThe following manuscript has appeared as ‘Report 46 - Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals’ at https://spiral.imperial.ac.uk:8443/handle/10044/1/91875.One sentence summaryCOVID-19 in-hospital fatality rates fluctuate dramatically in Brazil, and these fluctuations are primarily associated with geographic inequities and shortages in healthcare capacity.
Anti-SARS-CoV-2 vaccination does not induce the formation of autoantibodies but provides humoral immunity following heterologous and homologous vaccination regimens: Results from a clinical and prospective study within professionals of a German University Hospital
Authors: Thurm Christoph , Reinhold Annegret , Borucki Katrin , Kahlfuss Sascha , Feist Eugen , Schreiber Jens , Reinhold Dirk , Schraven Burkhart 
Published: November 2021

AbstractBy the end of 2019 a global pandemic by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) causing the coronavirus disease-19 (COVID-19) has emerged. Yet, COVID-19 represents a significant economic burden to healthcare systems, destabilizes global financial markets and has caused the death of almost 5 million people worldwide. In order to prevent severe disease courses of COVID-19 especially in elderly and to establish collective immunity on the long run, different vaccines have been developed, tested and were approved within a very short time period. In Germany, the first vaccines that have been approved by local authorities were AstraZeneca’s vector virus-based vaccine Vaxzevria and the mRNA vaccines Comirnaty and Spikevax, developed by BioNTech and Moderna, respectively. As it was reported that the novel coronavirus SARS-CoV2 can trigger autoimmunity, it is of significant interest to investigate whether anti-SARS-CoV2 vaccines evoke the formation of autoantibodies and subsequent autoimmunity. Here, we did set out to systematically analyze immune responses after homologous vaccinations with mRNA or vector virus-based vaccines or after heterologous Vector/mRNA vaccinations with respect to anti-COVID-19 immune responses and, in parallel, the development of autoantibodies. In our study, we obtained serum samples one day before and 14 as well as 28 days following booster vaccination and tested them for anti-SARS-CoV2 antibodies and for autoantibodies against Cardiolipin, Prothrombin, β2-Glycoprotein, cyclic citrullinated peptides (CCP), tissue-transglutaminase (TTG) and anti-nuclear antibodies (ANA). We find that compared to homologous mRNA and heterologous Vector/mRNA vaccination, anti-SARS-CoV2 antibody levels were 90% lower after homologous vector vaccination. Of note, heterologous Vector/mRNA vaccination was found to be more effective than homologous mRNA vaccination in terms of IgM and IgA responses against SARS-CoV2. However, in terms of autoantibody generation, we only detected increases after booster vaccination in participants with already pre-existing autoantibodies. In contrast, vaccinees showing no autoantibody formation before vaccination, did not respond with sustained autoantibody production upon vaccination. Taken together, our study suggests that all used SARS-CoV2 vaccines do not significantly foster autoantibody production over time but provide humoral immunity to SARS-CoV2.
Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer
Authors: Zhang Jiaren , Zimmermann Bob , Galletti Giuseppe , Halabi Susan , Gjyrezi Ada , Yang Qian , Gupta Santosh , Verma Akanksha , Sboner Andrea , Anand Monika , George Daniel J. , Gregory Simon G. , Hong Seunghee , Pascual Virginia , Mavragani Clio P. , Antonarakis Emmanuel S. , Nanus David M. , Tagawa Scott T. , Elemento Olivier , Armstrong Andrew J. , Giannakakou Paraskevi 
Published: November 2021

AbstractAndrogen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Here we performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of a prospective clinical trial of men with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). CTC RNA-sequencing identified that RB loss and enhanced E2F signaling along with BRCA loss transcriptional networks were associated with intrinsic ARSi resistance, while an inflammatory response signature was significantly associated with acquired resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of T and NK cells. Importantly, CTC gene signatures had a significant positive association with circulating immune macroenvironment (CIME) signatures. Taken together, these data demonstrate that liquid biopsy transcriptomics can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization in patients with mCRPC.
Heart-brain connections: phenotypic and genetic insights from 40,000 cardiac and brain magnetic resonance images
Authors: Zhao Bingxin , Li Tengfei , Fan Zirui , Yang Yue , Wang Xifeng , Luo Tianyou , Tang Jiarui , Xiong Di , Wu Zhenyi , Chen Jie , Shan Yue , Tomlinson Chalmer , Zhu Ziliang , Li Yun , Stein Jason L. , Zhu Hongtu 
Published: November 2021

AbstractCardiovascular health interacts with cognitive and psychological health in complex ways. Yet, little is known about the phenotypic and genetic links of heart-brain systems. Using cardiac and brain magnetic resonance imaging (CMR and brain MRI) data from over 40,000 UK Biobank subjects, we developed detailed analyses of the structural and functional connections between the heart and the brain. CMR measures of the cardiovascular system were strongly correlated with brain basic morphometry, structural connectivity, and functional connectivity after controlling for body size and body mass index. The effects of cardiovascular risk factors on the brain were partially mediated by cardiac structures and functions. Using 82 CMR traits, genome-wide association study identified 80 CMR-associated genomic loci (P < 6.09 × 10-10), which were colocalized with a wide spectrum of heart and brain diseases. Genetic correlations were observed between CMR traits and brain-related complex traits and disorders, including schizophrenia, bipolar disorder, anorexia nervosa, stroke, cognitive function, and neuroticism. Our results reveal a strong heart-brain connection and the shared genetic influences at play, advancing a multi-organ perspective on human health and clinical outcomes.
Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes
Authors: Tsai Harrison K. , Gibson Christopher J. , Murdock H. Moses , Davineni Phani , Harris Marian H. , Wang Eunice S. , Gondek Lukasz P. , Kim Annette S. , Nardi Valentina , Lindsley R. Coleman 
Published: November 2021

AbstractKMT2A partial tandem duplication (KMT2A-PTD) at 11q23.3 is associated with adverse risk in AML and MDS, is a potential therapeutic target, and is an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. While it has been reported that KMT2A-PTD affects only a single allele, it has been theorized but not proven that duplications or genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. Copy neutral loss of heterozygosity (CN-LOH) of 11q has also been described and is known to be associated with mutations in CBL but has not been reported to involve KMT2A-PTD. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including CN-LOH and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML versus MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele.
Distinct representation of cue-outcome association by D1 and D2 neurons in the ventral striatum’s olfactory tubercle
Authors: Martiros Nuné , Kapoor Vikrant , Kim Spencer E. , Murthy Venkatesh N. 
Published: November 2021

ABSTRACTPositive and negative associations acquired through olfactory experience are thought to be especially strong and long-lasting. The conserved direct olfactory sensory input to the ventral striatal olfactory tubercle (OT) and its convergence with dense dopaminergic input to the OT could underlie this privileged form of associative memory, but how this process occurs is not well understood. We imaged the activity of the two canonical types of striatal neurons, expressing D1 or D2 type dopamine receptors, in the OT at cellular resolution while mice learned odor-outcome associations ranging from aversive to rewarding. D1 and D2 neurons both responded to rewarding and aversive odors. D1 neurons in the OT robustly and bidirectionally represented odor valence, responding similarly to odors predicting similar outcomes regardless of odor identity. This valence representation persisted even in the absence of a licking response to the odors and in the absence of the outcomes, indicating a true transformation of odor sensory information by D1 OT neurons. In contrast, D2 neuronal representation of the odor-outcome associations was weaker, contingent on a licking response by the mouse, and D2 neurons were more selective for odor identity than valence. Stimulus valence coding in the OT was modality-sensitive, with separate sets of D1 neurons responding to odors and sounds predicting the same outcomes, suggesting that integration of multimodal valence information happens downstream of the OT. Our results point to distinct representation of identity and valence of odor stimuli by D1 and D2 neurons in the OT.