bluuebunny/crossref_metadata_2025 huggingface dataset:
Wind conditions influence breeding season movements in a nomadic polygynous shorebird
Authors: Krietsch Johannes , Valcu Mihai , Kempenaers Bart
Published: February 2020

Nomadism is a behaviour where individuals respond to environmental variability with movements that seem unpredictable in timing and direction. In contrast to migration, the mechanisms underlying nomadic movements remain largely unknown. Here, we focus on a form of apparent nomadism in a polygynous shorebird, the pectoral sandpiper (
Calidris melanotos
). Local mating opportunities are unpredictable and most males sampled multiple sites across a considerable part of their breeding range. We test the hypothesis that individuals decided which part of the breeding range to sample in a given season based on the prevailing wind conditions. Using movement data from 80 males in combination with wind data from a global reanalysis model, we show that male pectoral sandpipers flew with wind support more often than expected by chance. Stronger wind support led to increased ground speed and was associated with a longer flight range. Long detours (loop-like flights) can be explained by individuals flying initially with the wind. Individuals did not fly westwards into the Russian Arctic without wind support, but occasionally flew eastwards into the North American Arctic against strong headwinds. Wind support might be less important for individuals flying eastwards, because their autumn migration journey will be shorter. Our study suggests that individuals of a species with low site fidelity choose their breeding site opportunistically based on the prevailing wind conditions.
Calcified gill filaments increase respiratory function in fishes
Authors: Turko Andy J. , Cisternino Bianca , Wright Patricia A.
Published: February 2020

The morphology of fish gills is closely linked to aerobic capacity and tolerance of environmental stressors such as hypoxia. The importance of gill surface area is well studied, but little is known about how the mechanical properties of gill tissues determine function. In some fishes, the bases of the gill filaments are surrounded by a calcified ‘sheath' of unknown function. We tested two non-exclusive hypotheses: (i) calcified gill filaments enhance water flow through the gill basket, improving aquatic respiratory function, and (ii) in amphibious fishes, calcification provides support for gills out of water. In a survey of more than 100 species of killifishes and related orders, we found filament calcification was widespread and thus probably arose before the evolution of amphibious lifestyles in killifishes. Calcification also did not differ between amphibious and fully aquatic species, but terrestrial acclimation caused calcium deposition on the filaments of the killifishKryptolebias marmoratus, suggesting a possible structural role when out of water. We found strong evidence supporting a role for filament calcification in enhancing aquatic respiratory function. First, acclimation to increased respiratory demands (hypoxia, elevated temperatures) induced calcium deposition on the filaments ofK. marmoratus. Next, gentle removal of filament calcification decreased branchial resistance to water flow, indicating disruption of gill basket positioning. Thus, the mechanical properties of the gill filaments appear to play an important and previously unappreciated role in determining fish respiratory function.
Substantially adaptive potential in polyploid cyprinid fishes: evidence from biogeographic, phylogenetic and genomic studies
Authors: Li Xinxin , Guo Baocheng
Published: February 2020

Whole genome duplication (WGD) is commonly believed to play key roles in vertebrate evolution. However, nowadays polyploidy exists in a few fish, amphibian and reptile groups only, and seems to be an evolutionary dead end in vertebrates. We investigate the evolutionary significance of polyploidization in Cyprinidae—a fish family that contains more polyploid species than any other vertebrate group—with integrated biogeographic, phylogenetic and genomic analyses. First, polyploid species are found to be significantly frequent in areas of higher altitude and lower mean annual temperature compared with diploid species in Cyprinidae. Second, a polyploidy-related diversification rate shift is observed in Cyprinidae. This increased net diversification rate is only seen in three polyploid lineages, and other polyploid lineages have similar net diversification rate as well as diploid lineages in Cyprinidae. Interestingly, significant ‘lag times’ existed between polyploidization and radiation in Cyprinidae. Multiple polyploid lineages were established approximately 15 Ma through recurrent allopolyploidization events, but the net diversification rate did not start to increase until approximately 5 Ma—long after polyploidization events. Environmental changes associated with the continuous uplift of the Tibetan Plateau and climate change have probably promoted the initial establishment and subsequent radiation of polyploidy in Cyprinidae. Finally, the unique retention of duplicated genes in polyploid cyprinids adapted to harsh environments is found. Taken together, our results suggest that polyploidy in Cyprinidae is far more than an evolutionary dead end, but rather shows substantially adaptive potential. Polyploid cyprinids thus constitute an ideal model system for unveiling largely unexplored consequences of WGD in vertebrates, from genomic evolution to species diversification.
Sphingobacterium cavernae sp. nov., a novel bacterium isolated from soil sampled at Tiandong Cave
Authors: Zhou Xing-Kui , Huang Ying , Li Miao , Zhang Xiao-Fei , Wei Yu-Qian , Cha Qi-Yan , Zhang Ti-Kun , Wang Xue-Jian , Liu Jian-Jin , Liu Zi-Yi , Qin Shi-Chun , Mo Ming He
Published: February 2020

A Gram-stain-negative, non-motile and rod-shaped bacterium, designated strain 5.0403-2T, was isolated from a cave soil sample collected from Tiandong Cave, Guizhou Province, south-west PR China. Cells showed positive oxidase and catalase reactions. The predominant isoprenoid quinone was MK-7. The major fatty acids were identified as iso-C15 : 0, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), iso-C17 : 0 3OH and summed feature 9 (iso-C17 : 1 ω9c or C16 : 0 10-methyl). The cellular polar lipids contained phosphatidylethanolamine, one unidentified phospholipid, three unidentified phosphoglycolipids and four unidentified lipids. The genomic DNA G+C content was 36.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 5.0403-2T should be assigned to the genus

Sphingobacterium

. Results of 16S rRNA gene sequence similarity analysis showed that strain 5.0403-2T was most similar to

Sphingobacterium bovisgrunnientis

KCTC 52685T (98.7 %),

Sphingobacterium composti

KCTC 12578T (98.0 %) and

Sphingobacterium alimentarium

DSM 22362T (97.3 %) and less than 95.0 % similar to other species of the genus

Sphingobacterium

. The average nucleotide identity values between strain 5.0403-2T and

S. bovisgrunnientis

KCTC 52685T,

S. composti

KCTC 12578T and

S. alimentarium

DSM 22362T were 94.2, 82.3 and 77.2 % respectively. The digitalDNA–DNA hybridization values between strain 5.0403-2T and

S. bovisgrunnientis

KCTC 52685T,

S. composti

KCTC 12578T and

S. alimentarium

DSM 22362T were 68.4, 25.6 and 20.7 %. These results indicated that the isolate represented a novel genomic species. The polyphasic taxonomic characteristics indicated that strain 5.0304-2T represents a novel species of the genus

Sphingobacterium

, for which the name Sphingobacterium cavernae sp. nov. (type strain 5.0403–2T=KCTC 62981T=CCTCC AB 2019257T) is proposed.
Epigenetic immune-modulation by Histone Deacetylase Activity (HDAC) of tissue and organ regeneration inXenopus laevis
Authors: Pentagna Nathalia , dos Santos Felipe Soares , de Almeida Fernanda Martins , Abreu José Garcia , Levin Michael , Carneiro Katia
Published: February 2020

In the present work we propose to shed light on the epigenetic control of immune mechanisms involved duringXenopustail regeneration. Here we show that the first 24 hour post amputation (hpa), which exclusively encompasses the first wave of myeloid differentiation, are crucial to epigenetically modulate the regenerative ability ofXenopustadpoles. During this developmental window, HDAC activity was shown to be necessary for the proper establishment of myeloid cells dynamics in the regenerative bud, mainly contributing to modulate the behavior of monocytes/macrophages and neutrophils as well the mRNA expression pattern of the main myeloid markers, such as LURP, MPOX, Spib and mmp7. In addition, we functionally bridge the spatial and temporal dynamics of lipid droplets, the main platform of lipid mediators synthesis in myeloid cells during the inflammatory response, and the regenerative ability ofXenopustadpoles showing that 15-LOX activity is a key player during tail regeneration. Taken together our results support a role for the epigenetic control of inflammatory response during tissue and organ regeneration, which may positively impact translational approaches for regenerative medicine.

Summary statement

We propose that Epigenetic mechanisms HDAC-dependent can control myeloid cells behavior upon tissue injury and that HDAC inhibitors may be used for tissue regeneration in translational studies.
Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling
Authors: Amar Megha , Pramod Akula Bala , Yu Nam-Kyung , Herrera Victor Munive , Qiu Lily R. , Moran-Losada Patricia , Zhang Pan , Trujillo Cleber A. , Ellegood Jacob , Urresti Jorge , Chau Kevin , Diedrich Jolene , Chen Jiaye , Gutierrez Jessica , Sebat Jonathan , Ramanathan Dhakshin , Lerch Jason P. , Yates John R. , Muotri Alysson R. , Iakoucheva Lilia M.
Published: February 2020

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Autism Spectrum Disorder (ASD) and Developmental Delay (DD). To investigate howCul3mutations impact brain development, we generated haploinsufficientCul3mouse model using CRISPR/Cas9 genome engineering.Cul3mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions ofCul3mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers ofCul3functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced inCul3mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified neuronal cytoskeleton and Rho signaling as primary targets ofCul3mutation during early brain development.
A Cohort Study: Evaluating Self-Efficacy in Adolescents Attending a Tailored Youth-Informed Breastfeeding Program
Authors: Cantin Christina M. , Peterson Wendy E. , Agarwal Amisha , Hamid Jemila S. , Stortini Bianca , Fleming Nathalie
Published: February 2020

Adolescents (≤19 years of age) have lower rates of breastfeeding (BF) compared to older mothers. BF self-efficacy (SE), defined as a mother’s confidence in her ability to breastfeed her infant, has been identified as an important factor influencing BF outcomes. An innovative youth-informed BF program for young women was designed and implemented, which included staff training, a prenatal BF class and BF peer support. The objective of this cohort study was to evaluate the effectiveness of the program in improving young mother’s BF SE.

Participants were pregnant adolescents recruited from a large urban non-profit social service outreach centre. The Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF) was administered to participants before and after participating in the BF program. BSES-SF scores were summed to determine a composite score and compared descriptively using mean score. Un-aggregated, item-by-item, comparison of pre-vs post-BF program scores were also compared to examine improvements in SE. A total of 20 adolescent mothers (mean age = 16.6) attended the BF program. An increase in the total BSES-SF score was observed based on descriptively comparing the mean pre vs post intervention.

Prenatal education and peer support adapted to the needs of adolescent mothers was associated with increased BSES-SF. These results are promising given that clients attending programs at this agency have low-income, low educational attainment, variable family support, housing instability, and are at-risk for not breastfeeding. Future studies with larger cohort are required to further validate and establish generalizability, as well as to determine the effect on BF duration rates.
Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP)
Authors: Wan Suxin , Yi Qingjie , Fan Shibing , Lv Jinglong , Zhang Xianxiang , Guo Lian , Lang Chunhui , Xiao Qing , Xiao Kaihu , Yi Zhengjun , Qiang Mao , Xiang Jianglin , Zhang Bangshuo , Chen Yongping
Published: February 2020

Background

To explore the cellular immunity and cytokines status of NCP patients and to predict the correlation between the cellular immunity levels, cytokines and the severity of patients.

Methods

123 NCP patients were divided into mild and severe groups. Peripheral blood was collected, lymphocyte subsets and cytokines were detected. Correlation analysis was performed on the lymphocyte subsets and cytokines, and the differences between the indexes of the two groups were analyzed.

Results

102 mild and 21 severe patients were included. Lymphocyte subsets were reduced in two groups. The proportion of CD8 + T reduction in the mild and severe group was 28.43% and 61.9%, respectively; The proportion of B cell reduction was 25.49% and 28.57%; The proportion of NK cell reduction was 34.31% and 47.62%; The detection value of IL-6 was 0 in 55.88% of the mild group, mild group has a significantly lower proportion of patients with IL-6 higher than normal than severe group; There was no significant linear correlation between the lymphocyte subsets and cytokines, while significant differences were noticed between the two groups in CD4 + T, CD8 + T, IL-6 and IL-10.

Conclusions

Low levels of CD4+T and CD8+T are common in severe NCP. IL-6 and IL-10 levels were higher in severe patients. T cell subsets and cytokines can be used as one of the basis for predicting the transition from mild to severe. Large number of samples are still needed to confirm the “warning value” of CD4 + T, CD8 + T IL-6 and IL-10.
Protein-carbohydrate ingestion alters Vps34 cellular localization independent of changes in kinase activity in human skeletal muscle
Authors: Hodson Nathan , Dent Jessica R. , Song Zhe , O’Leary Mary F. , Nicholson Thomas , Jones Simon W. , Murray James T. , Jeromson Stewart , Hamilton D. Lee , Breen Leigh , Philp Andrew
Published: February 2020

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell size and growth in response to nutrients, however, the mechanisms by which nutrient levels are sensed by mTORC1 in human skeletal muscle are yet to be fully elucidated. The Class III PI3Kinase Vps34 has recently been proposed as a sensor essential for mTORC1 activation following nutrient stimulation. We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (age – 21 ± 0.5yrs, mean ± SEM) ingested a PRO-CHO beverage containing 20/44/1g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1h and 3h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean±SEM) - 0.273±0.021, 1h - 0.347±0.022, Pearson’s Coefficient (r)) where it co-localized with mTOR (PRE – 0.312±0.018, 1h – 0.348±0.024, Pearson’s Coefficient (r))). These alterations occurred in parallel to an increase in S6K1 kinase activity – 941±164% of PRE at 1h post-feeding). Subsequentin vitroexperiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1in vitro. However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activityper semay be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.
Ubiquitin ligase component LRS1 and transcription factor CrHy5 act as a light switch for photoprotection inChlamydomonas
Authors: Lämmermann Nina , Wulf Donat , Chang Kwang Suk , Wichmann Julian , Jang Junhwan , Jin EonSeon , Bräutigam Andrea , Wobbe Lutz , Kruse Olaf
Published: February 2020

Survival under excess light conditions requires the light-induced accumulation of protein LHCSR3 and other photoprotection factors, to enable efficient energy-dependent quenching in the green microalgaChlamydomonas reinhardtii. Here, we demonstrate that the high light-tolerant phenotype of mutanthit1is caused by a de-repression of promoters belonging to photoprotection genes, which in turn results from an inactivation of the E3 ubiquitin ligase substrate adaptor LRS1. Transcriptome analyses ofhit1revealed massive alterations of gene expression modulation as a consequence of perturbed LRS1 function, indicating its role as a crown regulator. In conjunction with random forest-based network modeling, these transcriptome analyses predicted that LRS1 controls photoprotection gene expression via an algal HY5 homolog as its prime transcription factor target. CrHY5 binds to T-box elements present in the promoters of these genes and its inactivation in thehit1mutant via CRISPR-Cas9 genome editing, confirmed the regulatory connection between LRS1 and CrHY5, predicted by the network analysis.
Arid1aloss potentiates pancreatic β-cell regeneration through activation of EGF signaling
Authors: Celen Cemre , Chuang Jen-Chieh , Shen Shunli , Otto Jordan E. , Collings Clayton K. , Luo Xin , Li Lin , Wang Yunguan , Wang Zixi , Jia Yuemeng , Sun Xuxu , Nassour Ibrahim , Park Jiyoung , Ghaben Alexandra , Wang Tao , Wang Sam C. , Scherer Philipp E. , Kadoch Cigall , Zhu Hao
Published: February 2020

The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration.Arid1ais highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-bodyArid1aknockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that β-cell specificArid1adeletion could potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling. Functionally,ERBB3overexpression in β-cells was sufficient to protect against diabetes, and chemical inhibition of ERBB or NR4A was able to block increased regeneration associated withArid1aloss. mSWI/SNF complex activity is a barrier to β-cell regeneration in physiologic and disease states.
Reduced language lateralization in autism and the broader autism phenotype as assessed with robust individual-subjects analyses
Authors: Jouravlev Olessia , Kell Alexander J.E. , Mineroff Zachary , Haskins A.J. , Ayyash Dima , Kanwisher Nancy , Fedorenko Evelina
Published: February 2020

One of the few replicated functional brain differences between individuals with autism spectrum disorders (ASD) and neurotypical (NT) controls is reduced language lateralization. However, most prior reports relied on comparisons of group-level activation maps or functional markers that had not been validated at the individual-subject level, and/or used tasks that do not isolate language processing from other cognitive processes, complicating interpretation. Furthermore, few prior studies have examined functional responses in other functional networks, as needed to determine the selectivity of the effect. Using fMRI, we compared language lateralization between 28 ASD participants and carefully pairwise-matched controls, with the language regions defined individually with a well-validated language localizer. ASD participants showed less lateralized responses due to stronger right hemisphere activations. Further, this effect did not stem from a ubiquitous reduction in lateralization across the brain: ASD participants did not differ from controls in the lateralization of two other large-scale networks—the Theory of Mind network and the Multiple Demand network. Finally, in an exploratory study, we tested whether reduced language lateralization may also be present in NT individuals with high autistic trait load. Indeed, autistic trait load in a large set of NT participants (n=189) was associated with less lateralized language activations. These results suggest that reduced language lateralization is a robust and spatially selective neural marker of autism, present in individuals with ASD, but also in NT individuals with higher genetic liability for ASD, in line with a continuum model of underlying genetic risk.
Vegetative nuclear positioning is required for calcium and ROS signaling in Arabidopsis pollen tubes
Authors: Moser Morgan , Kirkpatrick Andrew , Groves Norman Reid , Meier Iris
Published: February 2020

Efficient transport and delivery of sperm cells (SCs) is vital for angiosperm plant fertility. InArabidopsis thaliana, SCs are transported through the growing pollen tube by a connection with the vegetative nucleus (VN). During pollen tube growth, the VN leads the way and maintains a fixed distance from the pollen tube tip, while the SCs lag behind the VN. Upon reception at the ovule, the pollen tube bursts and the SCs are released for fertilization. In pollen tubes of Arabidopsis mutantswit12andwifi, deficient in the outer nuclear membrane component of a plant LINC complex, the SCs precede the VN and the VN falls behind. Subsequently, pollen tubes frequently fail to burst upon reception. In this study, we sought to determine if the pollen tube reception defect observed inwit12andwifiis due to decreased sensitivity to reactive oxygen species (ROS). Here we show thatwit12andwifiare hyposensitive to exogenous H2O2, and that this hyposensitivity is correlated with decreased proximity of the VN to the pollen tube tip. Additionally, we report the first instance of nuclear Ca2+spikes in growing pollen tubes, which are disrupted in thewit12mutant. In thewit12mutant, nuclear Ca2+spikes are reduced in response to exogenous ROS, but these spikes are not correlated with pollen tube burst. This study finds that VN proximity to the pollen tube tip is required for both response to exogenous ROS, as well as internal nuclear Ca2+fluctuations.

Mutants deficient in outer nuclear membrane proteins display defects in reactive oxygen species-induced pollen tube burst and nuclear Ca2+signatures that correlate with the position of the vegetative nucleus.
Mechanics regulate human embryonic stem cell self-organization to specify mesoderm
Authors: Muncie Jonathon M. , Ayad Nadia M.E. , Lakins Johnathon N. , Weaver Valerie M.
Published: February 2020

Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level force. Whether cell tension regulates development by directly influencing morphogen signaling remains unclear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization that motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that enhance cell-cell interactions to direct the self-organization of cultured hESCs into “gastrulation-like” nodes. Tissue geometries that generate local nodes of high cell-cell tension and induce these self-organized tissue nodes drive BMP4-dependent gastrulation by enhancing phosphorylation and nuclear translocation of β-catenin to promote Wnt signaling and mesoderm specification. The findings underscore the interplay between tissue organization, cell tension, and morphogen-dependent differentiation, and demonstrate that cell- and tissue-level forces directly regulate cell fate specification in early human development.

Graphical Abstract

Highlights

Substrates that enhance cell-cell adhesion promote hESC self-organization

Tissue nodes exhibiting high tension are predisposed to gastrulation induction

Colony geometry dictates the localization of tension nodes to specify mesoderm

Tension activates β-catenin and stimulates Wnt signaling to induce mesoderm

In Brief

Engineered substrates that promote cell-cell adhesion and reconstitute epiblast tissue organization facilitate “gastrulation-like” morphogenesis in cultured hESCs. Tissue geometries that foster localized regions of high cell-cell tension potentiate BMP4-dependent mesoderm specification by enhancing phosphorylation and nuclear translocation of β-catenin to promote Wnt signaling.
Evidence that ion conduction in 5-HT3Areceptors proceeds through lateral portals in the cytosol
Authors: Stuebler Antonia G. , Jansen Michaela
Published: February 2020

The intracellular domain of the serotonin type 3A receptor, a pentameric ligand-gated ion channel, is crucial for regulating conductance. However, the specific ion conduction pathway through this domain is less clear. The intracellular domain starts with a short loop after the third transmembrane segment, followed by a short α-helical segment, a large unstructured loop, and finally the membrane-associated MA-helix that continues into the last transmembrane segment. The MA-helices from all five subunits form the extension of the transmembrane ion channel and shape what has been described as a “closed vestibule”, with their lateral portals obstructed by loops and their cytosolic ends forming a tight hydrophobic constriction. The question remains whether the lateral portals or cytosolic constriction conduct ions upon channel opening. In the present study, we used disulfide bond formation between pairs of engineered cysteines to probe the proximity and mobility of segments of the MA-helices most distal to the membrane bilayer. Our results indicate that the proximity and orientation for cysteine pairs at I409C/R410C, in close proximity to the lateral windows, and L402C/L403C, at the cytosolic ends of the MA-helices, are conducive for disulfide bond formation. While conformational changes associated with gating promote crosslinking for I409C/R410C, which in turn decreases channel currents, crosslinking of L402C/L403C is functionally silent in macroscopic currents. These results support the hypothesis that concerted conformational changes open the lateral portals for ion conduction, rendering ion conduction through the vertical portal unlikely.

Significance

The intracellular domain (ICD) of pentameric ligand-gated ion channels (pLGICs) is the most diverse domain within receptors of the Cys-loop superfamily. Despite being the least understood domain of pLGICs, its impact on ion-channel function and contribution to the cytosolic exit pathway of the channel have been investigated. X-ray and cryo-EM structures have captured the structured segments of the ICD of 5-HT3Areceptors in different conformational states with lower resolution of the ICD as compared to the other domains. Here, we provide experimentally derived evidence for the importance of the differential mobility of the cytosolic segment of the MA-helices, which supports the existence of lateral portals as opposed to a vertical pathway for 5-HT3Areceptors.
Assessment of the Prevalence of Pulmonary Tuberculosis Patients at Nakfa Hospital from 2014-2019, Eritrea
Authors: Kesete Yafet
Published: February 2020

Background

Tuberculosis, an infectious disease, is one of the top 10 causes of death, and the leading cause from a single infectious agent M. tuberculosis. According to recent WHO estimate report, at least 3100 new TB cases occur every year in Eritrea. However, very little information is available in Eritrea related to area specific prevalence of tuberculosis and risk factors attributed to it. This is a retrospective study aimed to assess the prevalence of tuberculosis disease among patients attending at Nakfa Hospital, Eritrea.

Methods

A retrospective study was conducted on patients visiting Nakfa Hospital, 221km north of Asmara, Eritrea from April 2014 to March 2019. Data was extracted from secondary data sources like patient admission records and laboratory registers at Nakfa Hospital.

Results

A total of 1100 patients were examined for tuberculosis using acid fast staining test. The overall prevalence of smear positive pulmonary TB cases was 7.8% (86 cases out of 1100). Females (8.2%) were more prone to have a positive Tuberculosis smear than males (7.4%). According to severity of infection, 38(3.5%) of subjects were +1 positive, whereas 23(2.1%) and 24(2.2%) of patients were +2 and +3 positives respectively. The highest prevalence of pulmonary TB was observed in the adult age group of 41-60 years (11%) and a comparatively higher number of cases was recorded in age group 21-40 years (8.3%). Adults aged between 41 to 60 had a two times more likelihood to be infected with Tuberculosis than those aged below 20 years old. Moreover, pulmonary tuberculosis was highly prevalent among middle age (20-60) than any other age class in all study years (2014-2019). The pulmonary TB cases were highly predominant during the year 2014 which was 16.8% (19 of 113 subjects) whereas the almost a quarter of it (4.5%) was recorded in following year. Based on locality, the highest rate of infection was observed in Adobha (25%), a town at border of Sudan and Eritrea, in which patients who came from Adobha had 4 times more likelihood to be infected than those from Nakfa town.

Conclusion

This study showed Nakfa subzone has relatively increased prevalence of smear positive pulmonary tuberculosis than the average WHO estimate for the country. Therefore, appropriate policies and strategies for prevention, targeted detection of cases and treatment are required to reinforce Tuberculosis control programs.
Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes
Authors: Murley Alexander G. , Rouse Matthew A. , Coyle-Gilchrist Ian , Jones P Simon , Li Win , Wiggins Julie , Lansdall Claire , Rodriguez Patricia Vazquez , Wilcox Alicia , Patterson Karalyn , Rowe James B.
Published: February 2020

Objective

To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of syndrome subtype.

Method

We used a transdiagnostic approach to survival in an epidemiological cohort, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (n=64), non-fluent variant primary progressive aphasia (n=36), semantic variant primary progressive aphasia (n=25), progressive supranuclear palsy (n=101) and corticobasal syndrome (n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression we identified the association between each of these dimensions and functionally independent survival (time from clinical assessment to care home admission), and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups.

Results

Behavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis.

Conclusion

Our results may help individualised prognostication and planning of disease-modifying trials and support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.
Optimal timing for cancer screening and adaptive surveillance using mathematical modeling
Authors: Curtius Kit , Dewanji Anup , Hazelton William D. , Rubenstein Joel H. , Luebeck E. Georg
Published: February 2020

Cancer screening and early detection efforts have been partially successful in reducing incidence and mortality but many improvements are needed. Although current medical practice is mostly informed by epidemiological studies, the decisions for guidelines are ultimately madead hoc. We propose that quantitative optimization of protocols can potentially increase screening success and reduce overdiagnosis. Mathematical modeling of the stochastic process of cancer evolution can be used to derive and to optimize the timing of clinical screens so that the probability is maximal that a patient is screened within a certain “window of opportunity” for intervention when early cancer development may be observable. Alternative to a strictly empirical approach, or microsimulations of a multitude of possible scenarios, biologically-based mechanistic modeling can be used for predicting when best to screen and begin adaptive surveillance. We introduce a methodology for optimizing screening, assessing potential risks, and quantifying associated costs to healthcare using multiscale models. As a case study in Barrett’s esophagus (BE), we applied our methods for a model of esophageal adenocarcinoma (EAC) that was previously calibrated to US cancer registry data. We found optimal screening ages for patients with symptomatic gastroesophageal reflux disease to be older (58 for men, 64 for women) than what is currently recommended (age > 50 years). These ages are in a cost-effective range to start screening and were independently validated by data used in current guidelines. Our framework captures critical aspects of cancer evolution within BE patients for a more personalized screening design.

Significance

Our study demonstrates how mathematical modeling of cancer evolution can be used to optimize screening regimes. Surveillance regimes could also be improved if they were based on these models.

Graphical Abstract
A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
Authors: López de Maturana E , Rodríguez JA , Alonso L , Lao O , Molina-Montes E , Martín-Antoniano I , Gómez-Rubio P , Lawlor RT , Carrato A , Hidalgo M , Iglesias M , Molero X , Löhr M , Michalski CW , Perea J , O’Rorke M , Barberà VM , Tardón A , Farré A , Muñoz-Bellvís L , Crnogorac-Jurcevic T , Domínguez-Muñoz E , Gress T , Greenhalf W , Sharp L , Arnes L , Cecchini Ll , Balsells J , Costello E , Ilzarbe L , Kleeff J , Kong B , Márquez M , Mora J , O’Driscoll D , Scarpa A , Ye W , Yu J ,   PanGenEU Investigators, García-Closas M , Kogevinas M , Rothman N , Silverman D ,   SBC/EPICURO Investigators, Albanes D , Arslan AA , Beane-Freeman L , Bracci PM , Brennan P , Bueno-de-Mesquita B , Buring J , Canzian F , Du M , Gallinger S , Gaziano JM , Goodman PJ , Gunter M , LeMarchand L , Li D , Neale RE , Peters U , Petersen GM , Risch HA , Sánchez MJ , Shu XO , Thornquist MD , Visvanathan K , Zheng W , Chanock S , Easton D , Wolpin BM , Stolzenberg-Solomon RZ , Klein AP , Amundadottir LT , Marti-Renom MA , Real FX , Malats N
Published: February 2020

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D) to gain additional insight into the inherited basis of PC.In-silicofunctional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We replicated 17/40 previous PC-GWAS hits and identified novel variants with potential biological functions. The spatial autocorrelation approach prioritized low MAF variants not detected by GWAS. These were further expanded via 3D interactions to 54 target regions with high functional relevance. This multi-step strategy, combined with an in-depthin-silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
read_haps: using read haplotypes to detect same species contamination in DNA sequences
Authors: Eggertsson Hannes P. , Halldorsson Bjarni V.
Published: February 2020

Motivation

Data analysis is requisite on reliable data. In genetics this includes verifying that the sample is not contaminated with another, a problem ubiquitous in biology.

Results

In human, and other diploid species, DNA contamination from the same species can be found by the presence of three haplotypes between polymorphic SNPs. read_haps is a tool that detects sample contamination from short read whole genome sequencing data.

Availability

github.com/DecodeGenetics/read_haps

Contact

bjarni.halldorsson@decode.is
Design and fabrication of recombinant reflectin-based Bragg reflectors: bio-design engineering and photoisomerism induced wavelength modulation
Authors: Wolde-Michael Emmanuel , Roberts Aled D , Heyes Derren J , Dumanli Ahu G , Blaker Jonny J , Takano Eriko , Scrutton Nigel S
Published: February 2020

The remarkable camouflage capabilities of cephalopods have inspired many to develop dynamic optical materials which exploit certain design principles and/or material properties from cephalopod dermal cells. Here, the angle-dependent optical properties of various single-layer reflectin thin-films are characterized within the UV-Vis-NIR regions. Following this, the design and fabrication of the first bio-inspired reflectin-based Bragg reflector is described, which was found to conserve the optical properties of single layer films but exhibit a unique characteristic; reduced angle-dependent reflectivity. Finally, a novel method of controlling reflectin thin-film optical properties is introduced; visible light-induced photoisomerism, representing a new class of reflectin-based optical materials.
Selective LXR agonist, DMHCA, corrects the retina-bone marrow axis in type 2 diabetes
Authors: Vieira Cristiano P. , Fortmann Seth D. , Hossain Masroor , Longhini Ana Leda , Hammer Sandra S. , Asare-Bediako Bright , Crossman David K. , Sielski Micheli S. , Adu-Agyeiwaah Yvonne , Dupont Mariana , Floyd Jason L. , Calzi Sergio Li , Lydic Todd , Welner Robert S , Blanchard Gary J. , Busik Julia V. , Grant Maria B.
Published: February 2020

In diabetic dyslipidemia, cholesterol accumulates in the plasma membrane, decreasing fluidity and thereby suppressing the ability of cells to transduce ligand-activated signaling pathways. Liver X receptors (LXRs) are the main cellular mechanism by which intracellular cholesterol is regulated and play important roles in inflammation and disease pathogenesis. N,N-dimethyl-3β-hydroxy-cholenamide (DMHCA), a selective LXR agonist, specifically activates the cholesterol efflux arm of the LXR pathway without stimulating triglyceride synthesis. Thus, DMHCA possesses superior clinical potential as a cholesterol lowering agent than current LXR pan-agonist. In this study, we use a multi-systems approach to understand the effects and molecular mechanisms of DMHCA treatment in type 2 diabetic db/db mice and human -derived circulating angiogenic cells (CACs), which are vascular reparative cells. We find that DMHCA is sufficient to correct the retina-bone marrow (BM) axis in diabetes, thereby restoring retinal structure, function, and cholesterol homeostasis, rejuvenating membrane fluidity in circulating vascular reparative cells, hampering systemic inflammation, and correcting BM dysfunction. Using single-cell RNA-seq on lineage-sca1+cKit+(LSK) hematopoietic stem cells (HSCs) from untreated and DMHCA-treated diabetic mice, we provide novel insights into hematopoiesis and reveal DMHCA’s mechanism of action in correcting diabetic HSCs by reducing myeloidosis and increasing CACs and erythrocyte progenitors. Taken together, these findings demonstrate the broad and pleiotropic effects of DMHCA treatment, which has exciting potential to correct the retina-BM axis in diabetic subjects.
IGF-I Governs Cortical Inhibitory Synaptic Plasticity By Astrocyte Activation
Authors: Noriega-Prieto José Antonio , Maglio Laura Eva , Zegarra-Valdivia Jonathan A. , Pignatelli Jaime , Fernandez Ana M. , Martinez-Rachadell Laura , Fernandes Jansen , Núñez Ángel , Araque Alfonso , Alemán Ignacio Torres , de Sevilla David Fernández
Published: February 2020

Insulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology and pathology. While the direct effects of IGF-I in neurons have been extensively studied, the astrocyte involvement in IGF-I signaling and the consequences on synaptic plasticity and animal behavior remain unknown. Here we show that IGF-I induces the long-term depression (LTD) of inhibitory synaptic transmission in the mouse barrel cortex. This LTD requires the activation of the IGF-I receptor (IGF-IR) in astrocytes, which stimulates astrocyte Ca2+signaling and the release of ATP/adenosine that in turn activates A2Aadenosine receptors at presynaptic inhibitory terminals. Specific deletion of IGF-IR in cortical astrocytes (IGF-IR-/-) impaired the behavioral performance in a whisker discrimination task. These results show novel mechanisms and functional consequences of IGF-I signaling on cortical inhibitory synaptic plasticity and animal behavior, revealing astrocytes as key elements in these processes.
Multimodal finger-printing of the human precentral cortex forming the motor hand knob
Authors: Dubbioso Raffaele , Madsen Kristoffer Hougaard , Thielscher Axel , Siebner Hartwig Roman
Published: February 2020

Transcranial magnetic stimulation (TMS) of the precentral hand knob can evoke motor evoked potentials (MEP) in contralateral hand muscles. Biophysical modelling points to the dorsal premotor cortex (PMd) in the superficial crown-lip region as primary site of TMS-induced neuronal excitation. Here, we used a sulcus-aligned MRI-informed TMS mapping approach to determine the optimal site (hotspot) for evoking MEPs in the precentral hand knob. Individual precentral hotspot location varied along the rostro-caudal axis. Individuals with a more rostral location had longer MEP latencies. Spatiotemporal “hotspot rostrality” was associated with higher precentral myelin-related signals, stronger movement-related activation of PMd in the precentral crown, and higher temporal precision during paced finger tapping. Together, our multimodal mapping approach provides first-time evidence for behaviourally relevant, structural and functional phenotypic variation in the crown of human precentral motor hand knob. The results have important implications for physiological and interventional TMS studies targeting the precentral hand knob.
Recognition of A Highly Conserved DSRCPTQ Epitope in Envelope Protein of Zika Virus Throughin silicoApproaches
Authors: Rahman Anisur , Hossain Md. Iqbal , Tamanna Saheda , Ullah Md Neamat
Published: February 2020

The recurrent and recent outbreak of Zika Virus (ZIKV) has turned into global concern as yet there is no appropriate preventive measure been found. Situation getting worse as this virus also associates with several birth defects in neonatal such as primary microcephaly as well as many other neurological disorders. ZIKV adopts a wide host range which has hastened its expansion more recklessly. Hence, now there is an acute demand for developing a preventive vaccine against ZIKV. Immunoinformatic techniques have been employed in this study to pick out a highly conserved versatile antigenic B-cell linear epitope for all strains of ZIKV. Capsid protein (C), Membrane Glycoprotein Precursor (PrM), envelope protein (E) and RNA-dependent RNA Polymerase (NS5) have investigated by the implementation of sequence analysis and different epitope prediction methods. Some potential linear peptides have been recognized and tested for hydrophilicity and conservancy. Peptide with best antigenic properties was selected as ultimate final epitope and further structural exploration revealed its compatible position in protein 3D structure. Being fully conserved in all strains of ZIKV and its position in Envelope protein suggested epitope DSRCPTQ can be a quantum leap in the advancement of ZIKV prevention. However, extensivein vitroplusin vivoexperimentations are needed to be clarified about the real potency of the selected epitope.
A genome-wide screen for genes affecting spontaneous direct-repeat recombination inSaccharomyces cerevisiae
Authors: Novarina Daniele , Desai Ridhdhi , Vaisica Jessica A. , Ou Jiongwen , Bellaoui Mohammed , Brown Grant W. , Chang Michael
Published: February 2020

Homologous recombination is an important mechanism for genome integrity maintenance, and several homologous recombination genes are mutated in various cancers and cancer-prone syndromes. However, since in some cases homologous recombination can lead to mutagenic outcomes, this pathway must be tightly regulated, and mitotic hyper-recombination is a hallmark of genomic instability. We performed two screens inSaccharomyces cerevisiaefor genes that, when deleted, cause hyper-recombination between direct repeats. One was performed with the classical patch and replica-plating method. The other was performed with a high-throughput replica-pinning technique that was designed to detect low-frequency events. This approach allowed us to validate the high-throughput replica-pinning methodology independently of the replicative aging context in which it was developed. Furthermore, by combining the two approaches, we were able to identify and validate 35 genes whose deletion causes elevated spontaneous direct-repeat recombination. Among these are mismatch repair genes, the Sgs1-Top3-Rmi1 complex, the RNase H2 complex, genes involved in the oxidative stress response, and a number of other DNA replication, repair and recombination genes. Since several of our hits are evolutionary conserved, and repeated elements constitute a significant fraction of mammalian genomes, our work might be relevant for understanding genome integrity maintenance in humans.