bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovering gene regulatory networks of multiple phenotypic groups using dynamic Bayesian networks
Authors: Suter Polina , Kuipers Jack , Beerenwinkel Niko 
Published: December 2021

AbstractDynamic Bayesian networks (DBNs) can be used for the discovery of gene regulatory networks from time series gene expression data. Here, we suggest a strategy for learning DBNs from gene expression data by employing a Bayesian approach that is scalable to large networks and is targeted at learning models with high predictive accuracy. Our framework can be used to learn DBNs for multiple groups of samples and highlight differences and similarities in their gene regulatory networks. We learn these DBN models based on different structural and parametric assumptions and select the optimal model based on the cross-validated predictive accuracy. We show in simulation studies that our approach is better equipped to prevent overfitting than techniques used in previous studies. We applied the proposed DBN-based classification approach to two time series transcriptomic datasets from the Gene Expression Omnibus database, each comprising data from distinct phenotypic groups of the same tissue type. In the first case, we used DBNs to characterize responders and non-responders to anti-cancer therapy. In the second case, we compared normal to tumor cells of colorectal tissue. The classification accuracy reached by the DBN-based classifier for both datasets was higher than reported previously. For the colorectal cancer dataset, our analysis suggested that GRNs for cancer and normal tissues have a lot of differences, which are most pronounced in the neighborhoods of oncogenes and known cancer tissue markers. The identified differences in gene networks of cancer and normal cells may be used for the discovery of targeted therapies.
Diminished GAD67 Terminals and Ambient GABA Inhibition Associated with Reduced Motor Neuron Recruitment Threshold in the SOD1G93A ALS mouse
Authors: Venugopal Sharmila , Ghulam-Jhelani Zohal , Simmons Dwayne , Chandler Scott H 
Published: December 2021

AbstractPre-symptomatic studies in mouse models of the neurodegenerative motor neuron (MN) disease, Amyotrophic Lateral Sclerosis (ALS) highlight early alterations in intrinsic and synaptic excitability and have supported an excitotoxic theory of MN death. However, a role for synaptic inhibition in disease development is not sufficiently explored among other mechanisms. Since inhibition plays a role in both regulating motor output and in neuroprotection, we examined the age-dependent anatomical changes in inhibitory presynaptic terminals on MN cell bodies using fluorescent immunohistochemistry for GAD67 (GABA) and GlyT2 (glycine) presynaptic proteins comparing ALS-vulnerable trigeminal jaw closer (JC) motor pools with the ALS-resistant extraocular (EO) MNs in the SOD1G93A mouse model for ALS. Our results indicate differential patterns of temporal changes of these terminals in vulnerable versus resilient MNs and relative differences between SOD1G93A and wild-type (WT) MNs. Notably, we found pre-symptomatic up-regulation in inhibitory terminals in the EO MNs while the vulnerable JC MNs mostly showed a decrease in inhibitory terminals. Specifically, there was a statistically significant decrease in the GAD67 somatic abuttal in the SOD1G93A JC MNs compared to WT around P12. Using in vitro patch-clamp electrophysiology, we found a parallel decrease in the ambient GABA-dependent tonic inhibition in the SOD1G93A JC MNs. While it is unclear if the two mechanisms are directly related, pharmacological blockade of specific subtype of GABAA-α5 receptors suggests that tonic inhibition can control MN recruitment threshold. Furthermore, reduction in tonic GABA current as observed here in the mutant, identifies a putative molecular mechanism explaining our observations of hyperexcitable shifts in JC MN recruitment threshold in the SOD1G93A mouse. Lastly, we showcase non-parametric resampling-based bootstrap statistics for data analyses, and provide the Python code on GitHub for wider reuse.
Prediction of prophages and their host ranges in pathogenic and commensal Neisseria species
Authors: Orazi Giulia , Collins Alan J. , Whitaker Rachel J. 
Published: December 2021

ABSTRACTThe genus Neisseria includes two pathogenic species, N. gonorrhoeae and N. meningitidis, and numerous commensal species. Neisseria species frequently exchange DNA with one other, primarily via transformation and homologous recombination, and via multiple types of mobile genetic elements (MGEs). Few Neisseria bacteriophages (phages) have been identified and their impact on bacterial physiology is poorly understood. Furthermore, little is known about the range of species that Neisseria phages can infect. In this study, we used three virus prediction tools to scan 248 genomes of 21 different Neisseria species and identified 1302 unique predicted prophages. Using comparative genomics, we found that many predictions are dissimilar from other prophages and MGEs previously described to infect Neisseria species. We also identified similar predicted prophages in genomes of different Neisseria species. Additionally, we examined CRISPR-Cas targeting of each Neisseria genome and predicted prophage. While CRISPR targeting of chromosomal DNA appears to be common among several Neisseria species, we found that 20% of the prophages we predicted are targeted significantly more than the rest of the bacterial genome in which they were identified (i.e., backbone). Furthermore, many predicted prophages are targeted by CRISPR spacers encoded by other species. We then used these results to infer additional host species of known Neisseria prophages and predictions that are highly targeted relative to the backbone. Together, our results suggest that we have identified novel Neisseria prophages, several of which may infect multiple Neisseria species. These findings have important implications for understanding horizontal gene transfer between members of this genus.IMPORTANCEDrug-resistant Neisseria gonorrhoeae is a major threat to human health. Commensal Neisseria species are thought to serve as reservoirs of antibiotic resistance and virulence genes for the pathogenic species N. gonorrhoeae and N. meningitidis. Therefore, it is important to understand both the diversity of mobile genetic elements (MGEs) that can mediate horizontal gene transfer within this genus, and the breadth of species these MGEs can infect. In particular, few bacteriophages (phages) have been identified and characterized in Neisseria species. In this study, we identified a large number of candidate phages integrated within the genomes of commensal and pathogenic Neisseria species, many of which appear to be novel phages. Importantly, we discovered extensive interspecies targeting of predicted phages by Neisseria CRISPR-Cas systems, which may reflect their movement between different species. Uncovering the diversity and host range of phages is essential for understanding how they influence the evolution of their microbial hosts.
Enhancer RNA-based modeling of adverse events and objective responses of immunotherapy
Authors: Guo Mengbiao , Lu Zhiya , Xiong Yuanyan 
Published: December 2021

AbstractImmune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 or CTLA-4 are emerging and effective immunotherapy strategies. However, ICI treated patients present heterogeneous responses and adverse events, thus demanding effective ways to assess benefit over risk before treatment. Here, by integrating pan-cancer clinical and molecular data, we tried to predict immune-related adverse events (irAEs, risk) and objective response rates (ORRs, benefit) based on enhancer RNAs (eRNAs) expression among patients receiving anti-PD-1/PD-L1 therapy. We built two effective regression models, explaining 71% variance (R=0.84) of irAEs with three eRNAs and 79% (R=0.89) of ORRs with five eRNAs. Interestingly, target genes of irAE-related enhancers, including upstream regulators of MYC, were involved in metabolism, inflammation, and immune activation, while ORR-related enhancers target PAK2 and DLG1 which directly participate in T cell activation. Our study provides references for the identification of immunotherapy-related biomarkers and potential therapeutic targets during immunotherapy.
Optimal spatial allocation of enzymes as an investment problem
Authors: Giunta Giovanni , Tostevin Filipe , Tănase-Nicola Sorin , Gerland Ulrich 
Published: December 2021

AbstractGiven a limited number of molecular components, cells face various allocation problems demanding decisions on how to distribute their resources. For instance, cells decide which enzymes to produce at what quantity, but also where to position them. Here we focus on the spatial allocation problem of how to distribute enzymes such as to maximize the total reaction flux produced by them in a system with given geometry and boundary conditions. So far, such distributions have been studied by computational optimization, but a deeper theoretical understanding was lacking. We derive an optimal allocation principle, which demands that the available enzymes are distributed such that the marginal flux returns at each occupied position are equal. This ‘homogeneous marginal returns criterion’ (HMR criterion) corresponds to a portfolio optimization criterion in a scenario where each investment globally feeds back onto all payoffs. The HMR criterion allows us to analytically understand and characterize a localization-delocalization transition in the optimal enzyme distribution that was previously observed numerically. In particular, our analysis reveals the generality of the transition, and produces a practical test for the optimality of enzyme localization by comparing the reaction flux to the influx of substrate. Based on these results, we devise an additive construction algorithm, which builds up optimal enzyme arrangements systematically rather than by trial and error. Taken together, our results reveal a common principle in allocation problems from biology and economics, which can also serve as a design principle for synthetic biomolecular systems.
Assessment and Comparative Study of Biofilm Formation with frequency of Multi Drug Resistance in strains of Staphylococcus aureus
Authors: Fatima Kiran , Ali Kashif 
Published: December 2021

AbstractBackgroundThe study was conducted to identify the role of biofilms in the antibiotic susceptibility in the strains of Staphylococcus aureus. A total of 19 non repeated pus/wound swab samples from different anatomic locations and 17 samples that were previously identified as S. aureus and preserved in the labs were included in the study. The Staphylococcus aureus was identified on the basis of colony morphology, Gram’s stain, biochemical tests (catalase and coagulase tests) and molecular identification through PCR amplification.MethodologyA total of 26 samples were recovered out of the 31 samples. Kirby-Bauer disk diffusion susceptibility test was used to determine the sensitivity or resistance of S. aureus to methicillin. Out of the 26 strains, 4 were highly resistant, 10 were moderately resistant and 12 strains were sensitive. Three different protocols (Tube Method, Congo Red Agar Method and Tissue Culture plate method) were used for the detection of biofilm formation for both resistant and sensitive strains.ResultComparative analysis of the antibiotic susceptibility and biofilm formation by different protocols showed that 70% strains that are resistant to antibiotic methicillin produced moderate-strong biofilms. 50% have produced the moderate-strong biofilms in all 3 protocols. In case of sensitive, 50% strains had produced none-weak biofilms in all 3 protocols.DecisionsThe strains that had zone of inhibition of close to resistance produced weak-strong biofilms but they all produced weak biofilms in CRA method. It can be concluded that the strains of S. aureus that have the ability to produce biofilms become methicillin resistant.
Reconstitution of T cell immunity against EBV in the immunocompromised host by adoptive transfer of peptide-stimulated T cells after allogeneic stem cell transplantation
Authors: Lammoglia Cobo María Fernanda , Ritter Julia , Gary Regina , Seitz Volkhard , Mautner Josef , Aigner Michael , Völkl Simon , Schaffer Stefanie , Moi Stephanie , Seegebarth Anke , Bruns Heiko , Rösler Wolf , Amann Kerstin , Büttner-Herold Maike , Hennig Steffen , Mackensen Andreas , Hummel Michael , Moosmann Andreas , Gerbitz Armin 
Published: December 2021

AbstractReconstitution of T cell repertoire after allogeneic stem cell transplantation is a long and often incomplete process. As a result, reactivation of Epstein-Barr virus (EBV) is a frequent complication that may be treated by adoptive transfer of donor-derived EBV-specific T cells. We generated donor-derived EBV-specific T cells by peptide stimulation and adoptively transferred them to a patient with angioimmunoblastic T-cell lymphoma (AITL), who had developed persisting high titers of EBV concomitant to relapse after transplantation. T cell receptor beta (TCRβ) deep sequencing showed that the T cell repertoire of the patient early after transplantation (day 60) was strongly reduced and only very low numbers of EBV-specific T cells were detectable. Manufacturing andin vitroexpansion of donor-derived EBV-specific T cells resulted in enrichment of EBV epitope-specific, HLA-restricted T cells. Monitoring after adoptive transfer revealed that the dominant TCR sequences from peptide-stimulated T cells persisted long-term and established an EBV-specific TCR clonotype repertoire in the host, with many of the EBV-specific TCRs present in the donor. This reconstituted repertoire was associated with immunological control of EBV and with lack of further AITL relapse.Author summaryA characteristic feature of all herpesviruses is their persistence in the host’s body after primary infection. Hence, the host’s immune system is confronted with the problem to control these viruses life-long. Well-known representative of the herpesvirus group are the classic Herpes-Simplex Virus (HSV-1) and Varicella Zoster Virus (VZV, causing chicken pox); a less known representative is Epstein Barr Virus (EBV, causing mononucleosis). When the immune system is severely compromised, for example after stem cell transplantation from a foreign (allogeneic) donor, these viruses can reappear, as they are already in the host’s body. Especially EBV cause life-threatening complications after stem cell transplantation and only reinforcement of the host’s immune system can reestablish viral control. Here we show thatex vivomanufactured EBV-specific T cells can reestablish long-term control of EBV and that these cells persist in the host’s body over months. These results give us a better understanding of viral immune reconstitution post-transplant and of clinically-relevant T cell populations against EBV.
p166 links membrane and intramitochondrial modules of the trypanosomal tripartite attachment complex
Authors: Schimanski Bernd , Aeschlimann Salome , Käser Sandro , Gala Maria Gomez-Fabra , Vögtle Nora , Schneider André 
Published: December 2021

ABSTRACTThe protist parasiteTrypanosomabrucei has a single mitochondrion with a single unit genome termed kinetoplast DNA (kDNA). Faithfull segregation of replicated kDNA is ensured by a complicated structure termed tripartite attachment complex (TAC). The TAC physically links the basal body of the flagellum with the kDNA spanning the two mitochondrial membranes. Here, we characterized p166 as the only TAC subunit that is anchored in the inner membrane. Its C-terminal transmembrane domain separates the protein into a large N-terminal region that interacts with the kDNA-localized TAC102 and a 34 aa C-tail that binds to the intermembrane space-exposed loop of the integral outer membrane protein TAC60. Thus, in contrast to the outer membrane TAC region which requires four essential subunits for proper function a single inner membrane TAC subunit is sufficient to bridge the distance from the OM to the kDNA. Surprisingly, non-functional p166 lacking the C-terminal 34 aa still localizes to the TAC region. This suggests the existence of non-essential TAC-associated proteins in the OM. These proteins can loosely bind to non-functional p166 lacking the C-terminal 34 aa and keep it at the TAC but their binding would not be strong enough to withstand the mechanical force upon kDNA segregation.AUTHOR SUMMARYMitochondria evolved from a single endosymbiotic event and are a hallmark of eukaryotes. The large majority of genes for mitochondrial proteins are nuclear encoded now and only a small number are found in the mitochondrial genome. The protistTrypanosoma bruceiis an extreme eukaryote in many aspects. For instance, trypanosomes have a single mitochondrion and its genome – called kinetoplast DNA (kDNA) – locates as a single unit inside the mitochondrion close to the basal body of the flagellum. The tripartite attachment complex (TAC) forms a connection between the basal body and the kDNA ensuring faithful segregation of kDNA among the daughter cells upon cytokinesis. Recently, several TAC subunits of the cytoplasm, the outer mitochondrial membrane (OM) and the mitochondrial matrix have been characterized. Here, we identify p166 as the first TAC subunit of the inner mitochondrial membrane. It is anchored with a single transmembrane domain separating the protein into a N-terminal moiety located in the matrix and a short C-tail. The latter reaches into the intermembrane space and binds the OM subunit TAC60 whereas the N-terminus interacts with the matrix subunit TAC102. Thus, with p166 we identified the missing link required to connect different modules of the TAC.
Presentation, characteristics, treatments and outcomes of mechanically ventilated patients with COVID-19 in Bulgaria
Authors: Bakalova Neda , Natsev Ivats , Damov Hristo , Yatsenko Irina , Jovinska Stefanija , Enev Rostislav , Cholakov Mihail , Abedinov Filip , Kalendjieva Denitza 
Published: December 2021

AbstractBackgroundThe first surge of coronavirus disease 2019 (COVID-19) cases in Bulgaria occurred in the fall of 2020. Here we describe the clinical presentation, patient characteristics, treatments and outcomes of mechanically ventilated COVID-19 patients in a newly formed COVID-19 ICU at a tertiary cardiac center in Sofia, Bulgaria.MethodsThis is a retrospective observational study of mechanically ventilated COVID-19 patients admitted to Sveta Ekaterina University Hospital in Sofia, Bulgaria, between November 4th, 2020 and January 6th, 2021. Data were collected from electronic and written patient records and charts.ResultsWe identified 38 critical care patients admitted with respiratory failure and treated with mechanical ventilation at our COVID-19 ICU during this period. The median age was 66 (IQR 57-76, range 27-89) and 74% were male. Most patients, 36 (95%), had at least one comorbidity. The most common comorbidities were hypertension, valvular heart disease, ischemic heart disease and diabetes mellitus. Overall, 27 (71%) patients had a concomitant cardiac disease other than hypertension and 24% were recent cardiac surgical patients. Inotropic support was required in 29 (76%) patients, renal replacement therapy in 12 (32%) patients and prone positioning and ECMO were used in 5 (13%) and 2 (5%) patients respectively. The median duration of mechanical ventilation was 7.5 (IQR 5-14) days overall and 9 (IQR 6-13) days for survivors. At 30-days 28 (74%) of patients had died. Overall, 32 (84%) patients died in hospital and only 6 (16%) patients were discharged home.ConclusionsDuring the first major surge of COVID-19 cases in Bulgaria, despite the wave arriving later than in other countries, the healthcare system was largely unprepared. In our setting, mortality in mechanically ventilated patients was very high at 84%. Several factors might have contributed to these results, namely the predominance of cardiovascular comorbidities in our patient population, the strained ICU capacity and the lack of medical personnel.
Dopaminergic modulation of local non-oscillatory activity and global-network properties in Parkinson’s disease: an EEG study
Authors: Zhang Juanli , Villringer Arno , Nikulin Vadim V. 
Published: December 2021

AbstractDopaminergic medication for Parkinson’s disease (PD) modulates neuronal oscillations and functional connectivity across the basal ganglia-thalamic-cortical circuit. However, the non-oscillatory component of the neuronal activity, potentially indicating a state of excitation/inhibition balance, has not yet been investigated and previous studies have shown inconsistent changes of cortico-cortical connectivity as a response to dopaminergic medication. To further elucidate changes of regional non-oscillatory component of the neuronal power spectra, functional connectivity, and to determine which aspects of network organization obtained with graph theory respond to dopaminergic medication, we analyzed a resting-state EEG (Electroencephalogram) dataset including 15 PD patients during OFF and ON medication conditions. We found that the spectral slope, typically used to quantify the broadband non-oscillatory component of power spectra, steepened particularly in the left central region in the ON compared to OFF condition. In addition, using lagged coherence as a functional connectivity measure, we found that the functional connectivity in the beta frequency range between centro-parietal and frontal regions was enhanced in the ON compared to the OFF condition. After applying graph theory analysis, we observed that at the lower level of topology the node degree was increased, particularly in the centro-parietal area. Yet, results showed no significant difference in global topological organization between the two conditions: either in global efficiency or clustering coefficient for measuring global and local integration, respectively. Interestingly, we found a close association between local/global spectral slope and functional network global efficiency in the OFF condition, suggesting a crucial role of local non-oscillatory dynamics in forming the functional global integration which characterizes PD. These results provide further evidence and a more complete picture for the engagement of multiple cortical regions at various levels in response to dopaminergic medication in PD.