bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maintaining structural and functional homeostasis of theDrosophilarespiratory epithelia requires stress-modulated JAK/STAT activity
Authors: Niu Xiao , Fink Christine , Kallsen Kimberley , Shi Leizhi , Mincheva Viktoria , Franzenburg Sören , Prange Ruben , Bruchhaus Iris , Bossen Judith , Heine Holger , Roeder Thomas 
Published: June 2020

SummarySignaling mediated by the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is critical for maintaining cellular and functional homeostasis in the lung. Thus, chronically activated JAK/STAT signaling is causally associated with lung diseases such as lung cancer, asthma, and chronic obstructive pulmonary disease. To elucidate the molecular processes that transform increased JAK/STAT signaling in airway epithelial cells into the known pathological states, we used a highly simplified model system, the fruit flyDrosophila melanogaster. Here, the JAK/STAT pathway is permanently active in almost all airway cells and responds to airborne stressors with increased activity. Silencing of this signaling pathway in epithelial cells resulted in apoptosis. Since the above-mentioned lung diseases are commonly associated with increased JAK/STAT signaling, we assessed this by its ectopic activation in the respiratory epithelium ofDrosophila. This intervention triggered cell-autonomous structural changes in epithelial cells. These structural changes included phenotypes associated with asthma, namely, thickening of the epithelium, substantial narrowing of the air-conducting space, and impairment of the secretory epicuticular structure of the tracheae. Pharmacological manipulation of JAK/STAT signaling reversed this pathological phenotype. Transcriptomic analyses revealed that several biological processes were affected, which is consistent with the impairment of junction protein trafficking also observed in this study. These results indicate that balanced JAK/STAT signaling is essential for the functionality of the respiratory epithelium and, by extension, the entire organ. In contrast, chronic overactivation of this signaling leads to massive structural changes that are closely associated with pathologies typical of chronic inflammatory lung diseases.HighlightsJAK/STAT signaling is active in the entireDrosophilarespiratory system in all developmental stages.The signaling pathway is indispensable for the survival of the tracheal cell.Overactivation of the signaling has significant effects on tracheal development and also displays a human disease-associated phenotype inDrosophilatrachea.Abstract Figure
Convergence of modality invariance and attention selectivity in the cortical semantic circuit
Authors: Nakai Tomoya , Yamaguchi Hiroto Q. , Nishimoto Shinji 
Published: June 2020

AbstractThe human linguistic system is characterized by modality invariance and attention selectivity. Previous studies have examined these properties independently and reported perisylvian region involvement for both; however, their relationship and the linguistic information they harbor remain unknown. Participants were assessed by functional MRI, while spoken narratives (auditory) and written texts (visual) were presented, either separately or simultaneously. Participants were asked to attend to one stimulus when both were presented. We extracted phonemic and semantic features from these auditory and visual modalities, to train multiple, voxel-wise encoding models. Cross-modal examinations of the trained models revealed that perisylvian regions were associated with modality-invariant semantic representations. Attentional modulation was quantified by examining the modeling performance for attended and unattended conditions. We have determined that perisylvian regions exhibited attention selectivity. Both modality invariance and attention selectivity are both prominent in models that use semantic but not phonemic features. Modality invariance was significantly correlated with attention selectivity in some brain regions; however, we also identified cortical regions associated with only modality invariance or only attention selectivity. Thus, paying selective attention to a specific sensory input modality may regulate the semantic information that is partly processed in brain networks that are shared across modalities.
Unravelling the genetic basis for the rapid diversification of male genitalia betweenDrosophilaspecies
Authors: Hagen Joanna F. D. , Mendes Cláudia C. , Booth Shamma R. , Jimenez Javier Figueras , Tanaka Kentaro M. , Franke Franziska A. , Baudouin-Gonzalez Luis. , Ridgway Amber M. , Arif Saad , Nunes Maria D. S. , McGregor Alistair P. 
Published: June 2020

AbstractIn the last 240,000 years, males of theDrosophila simulansspecies clade have evolved striking differences in the morphology of their epandrial posterior lobes and claspers (surstyli). These changes have most likely been driven by sexual selection and mapping studies indicate a highly polygenic and generally additive genetic basis. However, we have limited understanding of the gene regulatory networks that control the development of genital structures and how they evolved to result in this rapid phenotypic diversification. Here, we used newD. simulans / D. mauritianaintrogression lines on chromosome 3L to generate higher resolution maps of posterior lobe and clasper differences between these species. We then carried out RNA-seq on the developing genitalia of both species to identify the genes expressed during this process and those that are differentially expressed between the two species. This allowed us to test the function of expressed positional candidates during genital development inD. melanogaster. We identified several new genes involved in the development and possibly the evolution of these genital structures, including the transcription factors Hairy and Grunge. Furthermore, we discovered that during clasper development Hairy negatively regulatestartan, a gene known to contribute to divergence in clasper morphology. Taken together our results provide new insights into the regulation of genital development and how this evolves between species.
Transgene codon usage drives viral fitness and therapeutic efficacy in oncolytic adenoviruses
Authors: Núñez-Manchón Estela , Farrera-Sal Martí , Castellano Giancarlo , Medel David , Alemany Ramon , Villanueva Eneko , Fillat Cristina 
Published: June 2020

AbstractArming oncolytic adenoviruses with therapeutic transgenes is a well-established strategy for multimodal tumour attack. However, this strategy sometimes leads to unexpected attenuated viral replication and a loss of oncolytic effects, preventing these viruses from reaching the clinic. Previous work has shown that altering codon usage in viral genes can hamper viral fitness. Here, we have analysed how transgene codon usage impacts viral replication and oncolytic activity. We observe that, although transgenes with optimised codons show high expression levels at a first round of infection, they impair viral fitness and are therefore not expressed in a sustained manner. Conversely, transgenes encoded by suboptimal codons do not compromise viral replication and are thus stably expressed over time allowing a greater oncolytic activity bothin vitroandin vivo. Altogether, our work shows that fine-tuning codon usage leads to a concerted optimisation of transgene expression and viral replication paving the way for the rational design of more efficacious oncolytic therapies.
Experimental manipulation of body size alters senescence in hydra
Authors: Ngo Kha Sach , Almási Berta , Barta Zoltán , Tökölyi Jácint 
Published: June 2020

ABSTRACTBody size has a fundamental impact on the ecology and physiology of animals. Large size, for instance, is often associated with increased fecundity and reproductive success. A persistent correlation between body size and individual longevity is also observed across the animal world, although this relationship proved difficult to understand due to the inseparability of body size from growth rate and the widespread collinear relationship between body size with other life history traits. Here, we usedHydra oligactis, a freshwater cnidarian with high tissue plasticity and inducible ageing as an experimental system to understand the causal roles of body size on reproduction and senescence. We first show that large size predicts accelerated sexual development, increased fecundity and reduced survival in a population sample of this species kept under common garden conditions in the laboratory. Next, using phenotypic engineering, we experimentally increased or decreased body size by reciprocally grafting pieces of the body column differing in size between hydra polyps. Experimentally reduced body size was associated with delayed sexual development and reduced fecundity. In parallel, post–reproductive survival was significantly higher in polyps with reduced size. These results suggest that small hydra can physiologically detect their reduced body size and adjust reproductive decisions to achieve a higher post–reproductive survival. Our observations offer a new perspective on why smaller individuals within a species live longer by suggesting a growth–independent link between body size, reproduction and senescence.
Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2
Authors: Dittmar Mark , Lee Jae Seung , Whig Kanupriya , Segrist Elisha , Li Minghua , Jurado Kellie , Samby Kirandeep , Ramage Holly , Schultz David , Cherry Sara 
Published: June 2020

AbstractThere are an urgent need for antivirals to treat the newly emerged SARS-CoV-2. To identify new candidates we screened a repurposing library of ~3,000 drugs. Screening in Vero cells found few antivirals, while screening in human Huh7.5 cells validated 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we found that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH-independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we found 9 drugs are antiviral in lung cells, 7 of which have been tested in humans, and 3 are FDA approved including Cyclosporine which we found is targeting Cyclophilin rather than Calcineurin for its antiviral activity. These antivirals reveal essential host targets and have the potential for rapid clinical implementation.
A nanobody suite for yeast scaffold nucleoporins provides details of the Nuclear Pore Complex structure
Authors: Nordeen Sarah A , Andersen Kasper , Knockenhauer Kevin E , Ingram Jessica R , Ploegh Hidde , Schwartz Thomas U 
Published: June 2020

AbstractNuclear pore complexes (NPCs) are the main conduits for molecular exchange across the nuclear envelope. The NPC is a modular assembly of ~500 individual proteins, called nucleoporins or nups. Most scaffolding nups are organized in two multimeric subcomplexes, the Nup84 or Y complex and the Nic96 or inner ring complex. Working inS. cerevisiae, and to study the assembly of these two essential subcomplexes, we developed a set of twelve nanobodies that recognize seven constituent nucleoporins of the Y and Nic96 complexes. These nanobodies all bind specifically and with high affinity. We present structures of several nup-nanobody complexes, revealing their binding sites. Additionally, constitutive expression of the nanobody suite inS. cerevisiaerevealed accessible and obstructed surfaces of the Y complex and Nic96 within the NPC. Overall, this suite of nanobodies provides a unique and versatile toolkit for the study of the NPC.
Enhancing mitochondrial activity in neurons protects against neurodegeneration in CNS inflammation
Authors: Rosenkranz Sina C. , Shaposhnykov Artem A. , Träger Simone , Engler Jan Broder , Witte Maarten E. , Roth Vanessa , Vieira Vanessa , Paauw Nanne , Bauer Simone , Schwencke-Westphal Celina , Bal Lukas , Schattling Benjamin , Pless Ole , van Horssen Jack , Freichel Marc , Friese Manuel A. 
Published: June 2020

ABSTRACTCentral nervous system (CNS) inflammation in multiple sclerosis (MS) drives neuro-axonal loss resulting in irreversible disability. While transcripts of mitochondrial genes are strongly suppressed in neurons during CNS inflammation, it is unknown whether this results in mitochondrial dysfunction and whether interventions that increase mitochondrial function can rescue neurodegeneration. Here we show that suppression of mitochondrial gene transcripts in inflamed neurons was predominantly affecting genes of the electron transport chain resulting in impaired mitochondrial complex IV activity. This was associated with posttranslational inactivation of the transcriptional co-regulator peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α). Neuronal overexpression ofPgc-1αled to increased numbers of mitochondria, complex IV activity and elevated maximum respiratory capacity. Moreover,Pgc-1α-overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion ofPgc-1αaggravated neurodegeneration during experimental autoimmune encephalomyelitis (EAE), while neuronal overexpression ofPgc-1αameliorated EAE disease course and preserved neurons. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.
Anti-Bacterial Activity of Substances Produced from Lactic Acid Bacteria in Metata Ayib (Traditional Ethiopian Spiced Fermented Cottage)
Authors: Essayas Alazar , Pandit Sujata , Verma Deepak Kumar 
Published: June 2020

AbstractThere have been incerases in antibiotic resistant strains of human pathogens and causing treatment of microbial infections difficult. These days more attention is given to seraching new antimicrobial drugs to combat pathogenic microbes. Traditional fermented cottage of Metata Ayib which is naturally enriched with lactic acid bacteria (LAB) and used to preserve cheese for long time in Northern Ethiopia, may have antimicrobial activity against various human pathogens. However, there was no scientific report on the antimicrobial activity of lactic acid bacteria isolated from Metata Ayib. The objective of this study is to evaluate antibacterial activity of lactic acid bacteria fromMetata Ayibagainst clinical and standard human pathogens. The study was laboratory based experiment. Antibiotic production by the LAB was performed by inoculating the LAB isolates into 6.0 ml MRS medium and incubating at 30 °C. Cell free supernatants (CFS) were collected by centrifugation (10,000 rpm for 15 min at 4 °C) of the six day fermented broth cultures. The pH of the CFS was adjusted to 6.5 with 4 N NaOH to eliminate the effect of organic acids.The susceptibility of produced antibiotic against test organisms was done by growing on Muller Hinton agar in triplicate using well diffusion method and the inhibition zone was recorded. Preceddingly, MIC and MBC was determined using standard methods. The antibiotic substance exhibited antimicrobial activity towards standard and drug resistant bacteral strains with the inhibition zone ranges upto 25.33±3.21 mm. The result of MIC against tested ornaisnms showed a considerable antimicrobial activity of the antibiotic substance withn the range values 6.25% to12.5%. In addition, the result of this study showed that LAB obtained from Metata Ayib exhibits antimicrobial activity against standard and pathogenic pathogenic test bacterial species ranged from 12.5-25% of MBC value. This might be due to the production of organic acids, but also other compounds, such as ethanol, hydrogen peroxide, diacetyl, reuterin and bacteriocins. The results of this investigation can also provide baseline for information for future studies about the application of antibacterial substances produced by LAB from fermented Metata ayib.
Lymph node swelling combined with temporary effector T cell retention aids T cell response in a model of adaptive immunity
Authors: Johnson Sarah C , Frattolin Jennifer , Edgar Lowell T. , Jafarnejad Mohammad , Moore James E. 
Published: June 2020

AbstractSwelling of lymph nodes is commonly observed during the adaptive immune response, yet the impact on T cell trafficking and subsequent immune response is not well known. To better understand the effect of macro-scale alterations, we developed an agent-based model of the lymph node para-cortex, describing T cell trafficking and response to antigen-presenting dendritic cells alongside swelling-induced changes in T cell recruitment and egress, and regulation of expression of egress-modulating T cell receptor Sphingosine-1-phosphate receptor-1. Analysis of effector T cell response under varying swelling conditions showed that swelling consistently aided T cell activation. However, subsequent effector CD8+T cell production could be reduced if swelling occurred too early in the T cell proliferative phase or if T cell cognate frequency was low due to increased opportunity for T cell exit. Temporarily extending retention of newly differentiated effector T cells, mediated by Sphingosine-1-phosphate receptor-1 expression, mitigated any negative effects of swelling by allowing facilitation of activation to outweigh increased access to exit areas. These results suggest targeting temporary effector T cell retention and egress associated with swelling may offer new ways to modulate effector TC responses in, for example, immuno-suppressed patients and optimisation of vaccine design.
Structural analysis of different LINC complexes reveals distinct binding modes
Authors: Cruz Victor E. , Demircioglu F. Esra , Schwartz Thomas U. 
Published: June 2020

AbstractLinker of nucleoskeleton and cytoskeleton (LINC) complexes are molecular tethers that span the nuclear envelope (NE) and physically connect the nucleus to the cytoskeleton. They transmit mechanical force across the NE in processes such as nuclear anchorage, nuclear migration, and homologous chromosome pairing during meiosis. LINC complexes are composed of KASH proteins traversing the outer nuclear membrane, and SUN proteins crossing the inner nuclear membrane. Humans have several SUN- and KASH-containing proteins, yet what governs their proper engagement is poorly understood. To investigate this question, we solved high resolution crystal structures of human SUN2 in complex with the KASH-peptides of Nesprin3, Nesprin4, and KASH5. In comparison to the published structures of SUN2-KASH1/2 we observe alternative binding modes for these KASH peptides. While the core interactions between SUN and the C-terminal residues of the KASH peptide are similar in all five complexes, the extended KASH-peptide adopts at least two different conformations. The much-improved resolution allows for a more detailed analysis of other elements critical for KASH interaction, including the KASH-lid and the cation loop, and a possible self-locked state for unbound SUN. In summary, we observe distinct differences between the examined SUN-KASH complexes. These differences may have an important role in regulating the SUN-KASH network.
Role of livestock parameters on cattle vulnerability to drought in the coastal semi-arid areas, Kenya
Authors: Omolo Jack Owiti , Mathew Muturi , Owiny Maurice , Ngugi Jeremiah N , Ganda Joseph Ogola , Malenga Cornel K , Musimba Stephen Kioko 
Published: June 2020

AbstractLivestock keeping forms main occupation in arid and semi-arid lands. Increase in drought frequency and intensity globally negatively affect livestock production and livelihood. Cattle are the most drought sensitive livestock due to size, grazing behavior and nutritional requirements. Factors for vulnerability of cattle to droughts are individual cattle parameters, health and husbandry practices. This cross sectional study aimed to those factors in semi-arid Kaloleni sub-county. Data on household (HH) head demographics, cattle and production collected from 194 enrolled HH using structured questionnaires. Cattle ages were grouped into young (<1 year old), growers (1-2 years old) and adults (>2years old). Data was analyzed using STATA 12 software. Univariate, bivariate and multivariate logistic regression analysis conducted and reported in Crude Odds Ratio (cOR), Adjusted Odds Ratio (aOR) and Confidence Interval (CI). We used Pearson product-moment correlation to determine relationship between HH head, cattle herd, individual cattle characteristics and drought characteristics, p = <0.05 being significant. Mean age HH heads was 40.7 ± 12.6 years, 44.3% (86) had basic education, males were 65.3% (n=126). Mixed livestock production was practiced by 69.1% (134), while 86.1% (167) practiced free range communal grazing. Adult cattle were 54.1% (1295). Female cattle were 72.7% (1741). Average body condition score was 3.0 ± 0.6, and calves had 2.6 ± 1.3. About 20.6% had various forms of illness, calves mostly affected at 29.1%. Up to 63.4% HH, spray cattle at home, 93.3% HH reported no vaccination history. Home straying was protective (cOR 0.3, 95% CI 0.14 – 0.53). Herd size (aOR 2.9, 95% CI 1.5 – 5.5) and having no disease control method (aOR 2.8, 95% CI 1.85 – 9.19) were contributing to reporting disease. We report positive correlation between drought outcomes and HH head (r=0.076, p>0.01), cattle herd (r=0.216, p=0.003 and individual cattle characteristics(r=0.139, p>0.01). The findings on cattle conditions exacerbate their vulnerability in presence of stressful conditions like droughts especially in calves and cows. This study demonstrates weak disease control efforts and unorganized husbandry practices. We propose strategic and focused disease control plans to improve cattle resilience and further research on livestock based factors as drought response metrics for the livestock livelihood.
Genome-wide correlation analysis revealsRorcas potential amplitude regulator of circadian transcriptome output
Authors: Littleton Evan S. , Kojima Shihoko 
Published: June 2020

AbstractCell-autonomous circadian system, consisting of core clock genes, generates near 24-hour rhythms and regulates the downstream rhythmic gene expression. While it has become clear that the percentage of rhythmic genes varies among mouse tissues, it remains unclear how this variation can be generated, particularly when the clock machinery is nearly identical in all tissues. In this study, we sought to characterize circadian transcriptome datasets that are publicly available and identify the critical component(s) involved in creating this variation. We found that the relative amplitude of 13 genes and the average level of 197 genes correlated with the percentage of cycling genes. Of those, the correlation ofRorcin both relative amplitude and the average level was one of the strongest. In addition, the level ofPer2AS, a novel non-coding transcript that is expressed at thePeriod 2locus, was also linearly correlated, although with a much lesser degree compared toRorc. Overall, our study provides insight into how the variation in the percentage of clock-controlled genes can be generated in mouse tissues and suggests thatRorcand potentiallyPer2ASare involved in regulating the amplitude of circadian transcriptome output.