bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of evolutionary selection on dynamic behavior of MCAK protein
Authors: Limbu Shiwani 
Published: December 2020

AbstractKinesins of class 13 (kinesin-13s), also known as KinI family proteins, are non-motile microtubule binding kinesin proteins. Mitotic centromere-associated kinesin (MCAK), a member of KinI family protein, diffuses along the microtubule and plays a key role in microtubule depolymerization. Here we have demonstrated the role of evolutionary selection in MCAK protein coding region in regulating its dynamics associated with microtubule binding and stability. Our results indicate that evolutionary selection within MCAK motor domain at amino acid position 440 in carnivora and artiodactyla order results in significant change in the dynamics ofα – helixand loop 11, indicating its likely impact on changing the microtubule binding and depolymerization process. Furthermore, evolutionary selections at amino acid position 600, 617 and 698 are likely to affect MCAK stability. A deeper understanding of evolutionary selections in MCAK can reveal the mechanism associated with change in microtubule dynamics within eutherian mammals.
Handling and accuracy of four rapid antigen tests for the diagnosis of SARS-CoV-2 compared to RT-qPCR
Authors: Olearo Flaminia , Nörz Dominik , Heinrich Fabian , Sutter Jan Peter , Rödel Kevin , Schultze Alexander , Zur Wiesch Julian Schulze , Braun Platon , Oesterreich Lisa , Kreuels Benno , Wichmann Dominic , Aepfelbacher Martin , Pfefferle Susanne , Lütgehetmann Marc 
Published: December 2020

AbstractBackgroundSARS-CoV-2 molecular diagnostics is facing material shortages and long turnaround times due to exponential increase of testing demand.ObjectiveWe evaluated the analytic performance and handling of four rapid Antigen Point of Care Tests (AgPOCTs) I-IV (Distributors: (I) Roche, (II) Abbott, (III) MEDsan and (IV) Siemens).Methods100 RT-PCR negative and 84 RT-PCR positive oropharyngeal swabs were prospectively collected and used to determine performance and accuracy of these AgPOCTs. Handling was evaluated by 10 healthcare workers/users through a questionnaire.ResultsThe median duration from symptom onset to sampling was 6 days (IQR 2-12 days). The overall relative sensitivity was 49.4%, 44.6%, 45.8% and 54.9 % for tests I, II, III and IV, respectively. In the high viral load subgroup (containing >106copies of SARS-CoV-2 /swab, n=26), AgPOCTs reached sensitivities of 92.3% or more (range 92.3%-100%). Specificity was 100% for tests I, II and IV and 97% for test III. Regarding handling, test I obtained the overall highest scores, while test II was considered to have the most convenient components. Of note, users considered all assays, with the exception of test I, to pose a significant risk for contamination by drips or spills.DiscussionBesides some differences in sensitivity and handling, all four AgPOCTs showed acceptable performance in high viral load samples. However, due to the significantly lower sensitivity compared to RT-qPCR, a careful consideration of pro and cons of AgPOCT has to be taken into account before clinical implementation.
Source-sink dynamics can maintain mismatched range and bioclimatic limits even at large spatial scales
Authors: Goel Nikunj , Keitt Timothy H. 
Published: December 2020

AbstractBioclimatic models assume that at broad spatial scales, climate is the primary determinant of species distribution. Meanwhile, processes such as source-sink dynamics can be ignored because they are thought to manifest at length scales comparable to species mean dispersal distance. We present a reaction-diffusion model to show species can use sink patches near the bioclimatic (or niche) limit as stepping-stones to occupy sinks much further than the mean dispersal distance, thereby extending the distribution far beyond the bioclimatic envelope. This mismatch between geographical and bioclimatic limits is mediated by the shape of the bioclimatic limit and may be significant for low growth sensitivity and fast dispersal life strategy. These findings challenge one of the core assumptions of the bioclimatic models. Therefore, we advocate that biogeographers consider the role of dispersal when using bioclimatic models to generate inferences about the ecological and evolutionary processes that determine the distribution of biota.
DIFFERENTIAL EXPRESSION OF CB1 CANNABINOID RECEPTOR AND CANNABINOID RECEPTOR INTERACTING PROTEIN 1A IN LABOR
Authors: Kozakiewicz Melissa L. , Zhang Jie , Leone-Kabler Sandra , Yamaleyeva Liliya M. , Brost Brian C. , Howlett Allyn C. 
Published: December 2020

AbstractBackgroundThe endocannabinoid system is present in multiple organ systems and is involved in smooth muscle regulation, immune function, neuroendocrine modulation and metabolism of tissues. Limited data are available regarding the presence and role of this system in reproductive tissues. Components of the endocannabinoid system have been identified in myometrial and placental tissues. However, no study has investigated differential expression of the endocannabinoid system in labor.ObjectivesThe purpose of this study was to identify and quantify two components of the endocannabinoid system, the CB1 cannabinoid receptor and cannabinoid receptor interacting protein 1a, in uterine and placental tissues, and to determine if there is differential expression in tissues exposed to labor. We hypothesized that CB1 cannabinoid receptor concentration would be altered in uterine and placental tissue exposed to labor as compared to tissues not exposed to labor.Study DesignUterine and placental tissue samples were collected in nine laboring and 11 non-laboring women undergoing cesarean delivery. CB1 cannabinoid receptor and cannabinoid receptor interacting protein 1a presence and quantification were evaluated using western blot and real-time quantitative polymerase chain reaction. Statistical comparisons of laboring and non-laboring subjects were made for uterine and placental tissue using a Mann-Whitney test.ResultsThe protein abundance of CB1 cannabinoid receptor in uterine tissue was significantly lower in tissues exposed to labor (p = 0.01). The protein abundance of cannabinoid receptor interacting protein 1a was lower in uterine tissue exposed to labor but did not reach statistical significance (p = 0.06). mRNA expression of CB1 cannabinoid receptor (p = 0.20) and cannabinoid receptor interacting protein 1a (p = 0.63) did not differ in labored compared to non-labored uterine tissues.ConclusionsOur findings of diminished protein density of CB1 cannabinoid receptor in uterine tissue exposed to labor support the hypothesis that the endocannabinoid system plays a role in parturition. Our data add to the growing body of evidence indicating the endocannabinoid system is of importance for successful reproduction and support the need for additional research investigating this complex system as it pertains to labor.
Tau-mediated axonal degeneration is prevented by activation of the WldSpathway
Authors: Stubbs Katy , Sealey Megan , Moreno Miguel Ramirez , Perry V Hugh , Newman Tracey A , Mudher Amritpal 
Published: December 2020

AbstractTauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau. The neuronal changes evident in Tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by expression of WldS. In aDrosophilamodel of tauopathy in which expression of human Tau protein (hTau0N3R) leads to progressive age-dependent phenotypes, activation of the pathway downstream of WldScompletely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldSwas activated several weeks after hTau-mediated degeneration had become established. In contrast, WldSexpression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in hTau0N3R–expressing larvae. This collectively implies that the pathway mediating the protective effect of WldSintersects with the mechanism(s) of degeneration initiated by hTau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.
A slow-exchange conformational switch regulates off-target cleavage by high-fidelity Cas9
Authors: De Paula Viviane S. , Dubey Abhinav , Arthanari Haribabu , Sgourakis Nikolaos G. 
Published: December 2020

AbstractThe Cas9 endonuclease is broadly used for genome engineering applications by programming its single-guide RNA, where high specificity is required. Although mechanistic understanding of DNA cleavage in the CRISPR-Cas9 system has been guided by crystallographic structures and single-molecule FRET experiments, the role of conformational plasticity within its DNA recognition lobe (REC) for target accuracy remains elusive. Through NMR analysis of milliseconds-timescale dynamics, we show that the REC3 domain exchanges between a major, closed and a minor, open conformation. We find that a single mutation in the HiFi Cas9 variant (R691A) increases conformational dynamics in REC3, eliciting a global transition to the open conformation which is regulated by an intramolecular salt-bridge network. These observations suggest a mechanism for reduced off-target recognition by switching on a global conformational exchange process to allow REC3 scanning for proper base pairing. Our data establish a framework for rational engineering Cas9 variants with improved target discrimination.
A new hypothesis for type 1 diabetes risk: The at-risk allele at rs3842753 associates with increased beta cellINSmRNA in a meta-analysis of single cell RNA sequencing data
Authors: Wang Su , Flibotte Stephane , Camunas-Soler Joan , MacDonald Patrick E. , Johnson James D. 
Published: December 2020

ABSTRACTType 1 diabetes is characterized by the autoimmune destruction of insulin secreting β cells. Genetic variations upstream at the insulin (INS) locus contribute to ~10% of type 1 diabetes heritable risk. Multiple studies showed an association between rs3842753 C/C genotype and type 1 diabetes susceptibility, but the molecular mechanisms remain unclear. To date, no large-scale studies have looked at the effect of genetic variation at rs3842753 onINSmRNA at the single cell level. We aligned all human islet single cell RNA sequencing datasets available to us in 2020 to the reference genome GRCh38.98 and genotyped rs3842753, integrating 2315 β cells and 1223 β-like cells from 13 A/A protected donors, 23 A/C heterozygous donors, and 35 C/C at-risk donors, including adults without diabetes and with type 2 diabetes.INSexpression mean and variance were significantly higher in single β cells from females compared with males. Comparing across β cells and β-like cells, we found that rs3842753 C containing cells (either homozygous or heterozygous) had the highestINSexpression. We also found that β cells with the rs3842753 C allele had significantly higher ER stress marker gene expression compared to the A/A homozygous genotype. These findings support the emerging concept that inherited risk of type 1 diabetes may be associated with inborn, persistent elevated insulin production which may lead to β cell ER stress and fragility.
Plasma S1P links to hypertension and biomarkers of inflammation and cardiovascular disease – findings from a translational investigation
Authors: Jujic Amra , Matthes Frank , Vanherle Lotte , Petzka Henning , Orho-Melander Marju , Nilsson Peter M , Magnusson Martin , Meissner Anja 
Published: December 2020

AbstractSphingosine-1-phosphate (S1P) is an important regulator of immune cell trafficking and vascular dysfunction contributing to the development and progression of overt hypertension. Although targeting S1P signaling revealed therapeutic potential in different experimental hypertension studies, validations of S1P-blood pressure (BP) associations in humans are lacking. In a translational approach, we explored the associations between plasma S1P and BP in a family-based study cohort (Malmö Offspring (MOS) study; N=1026), and in a longitudinally conducted murine hypertension cohort.In MOS, linear multivariate regression analyses showed that plasma S1P associates with increased systolic BP (β=1.06, P=0.015). Study subjects with systolic BP ≥140 mmHg presented with significantly higher S1P plasma concentrations compared to subjects with BP <120 mmHg independent of age and sex. The S1P-BP association was validated in a murine model where plasma S1P increased with systolic BP (r=0.7018, R2=0.4925; P<0.0001). In a sub-sample of MOS (N=444), proteomic profiling for markers of inflammation, metabolism and cardiovascular disease using proximity Extension Assays revealed multiple significant S1P associations, some of them with marked sex-specificity.In vitroandex vivovalidation of identified S1P associations disclosed augmented expression of different vascular dysfunction and inflammation markers in response to S1P.Our translational findings show a link between plasma S1P and systolic BP as well as several inflammation and cardiovascular disease markers and suggest S1P’s biomarker potential. This encourages further studies to investigate its predictive capacity for hypertensive disease or the therapeutic potential of its signaling axis.
Evolution during primary HIV infection does not require adaptive immune selection
Authors: Swan David A , Rolland Morgane , Herbeck Joshua , Schiffer Joshua T , Reeves Daniel B 
Published: December 2020

AbstractModern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we developed multiple within-host phylodynamic (wi-phy) models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The most parsimonious and accurate model required no positive selection, suggesting that the host adaptive immune system reduces viral load, but does not drive observed viral evolution. Rather, random genetic drift primarily dictates fitness changes. These results hold during early infection, and even during chronic infection when selection has been observed, viral fitness distributions are not largely different from in vitro distributions that emerge without adaptive immunity. These results highlight how phylogenetic inference must consider complex viral and immune-cell population dynamics to gain accurate mechanistic insights.One sentence summaryThrough the lens of a unified population and phylodynamic model, current data show the first wave of HIV mutations are not driven by selection by the adaptive immune system.
Evolutionary loss of inflammasomes in carnivores to facilitate carriage of zoonotic infections
Authors: Digby Z. , Rooney J. , Boyle J.P. , Bibo-Verdugo B. , Pickering R. , Webster S.J. , Monie T.P. , Hopkins L.J. , Kayagaki N. , Salvesen G.S. , Warming S. , Weinert L. , Bryant C.E. 
Published: December 2020

SummaryZoonotic infections, such as COVID-19, reside in animal hosts before jumping species to humans. The Carnivora, like mink, carry many zoonoses yet how diversity in host immune genes across species impact upon pathogen carriage are poorly understood. Here we describe a progressive evolutionary downregulation of pathogen sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerisation domain leucine rich repeat receptors (NLRs), acquisition of a unique caspase−1/−4 effector fusion protein that processes gasdermin D pore formation without inducing lytic cell death and the formation of an NLRP3-caspase-8 containing inflammasome that inefficiently processes interleukin-1β (IL-1β). Inflammasomes regulate gut immunity, but the carnivorous diet is antimicrobial suggesting a tolerance to the loss of these immune pathways. The consequences of systemic inflammasome downregulation, however, can reduce the host sensing of specific pathogens such that they can reside undetected in the Carnivora.
Following The Niche: Reconstructing 32,000 Years Of Niche Dynamics In Four European Ungulate Species
Authors: Leonardi Michela , Boschin Francesco , Boscato Paolo , Manica Andrea 
Published: December 2020

AbstractAn understanding of how ecological niches can change through time is key to predicting the effect of future global change. Past climatic fluctuations provide a natural experiment to assess the extent to which species can change their niche. Here we use an extensive archaeological database to formally test whether the niche of four European ungulates changed between 40 and 8 kya (i.e. before major anthropogenic habitat modification and excluding the confounding effect of domestication). We find that niche change depended on habitat. Horse and aurochs, which are adapted to open environment, changed their niche after the Last Glacial Maximum, and it is unclear whether this was the result of adaptation, or an expansion of the realized niche as a response to the extinction of other megafauna (competitors and predators) that shared the same habitat preferences. On the other hand, red deer and wild boar, which prefer close and semi-close habitats, did not change their niche during the same period; possibly because these habitats have experienced fewer extinctions. Irrespective of the mechanism that might have led to the observed niche changes, the fact that large mammals with long generation times can change their niche over the time period of thousands of years cautions against assuming a constant niche when predicting the future.Significance statementWhen predicting species responses to future change, it is often assumed that their habitat preferences (i.e. their niche) will not change. However, it is strongly debated whether this is reasonable. Here we show that two out of four species of large European ungulates changed their niche following the Last Glacial Maximum, possibly as a response to the reorganization of animal communities that resulted from numerous megafauna extinctions. This finding cautions against the assumption of a constant niche, highlighting that, to predict the future, we will ultimately need to understand the mechanisms that underpin the success of a given species under different climatic conditions.
Adverse Social Experiences in Adolescent Rats Results in Persisting Sex-Dependent Effects on Alcohol-Seeking Behavior
Authors: Surakka Akseli , Vengeliene Valentina , Skorodumov Ivan , Meinhardt Marcus , Hansson Anita C. , Spanagel Rainer 
Published: December 2020

AbstractBackgroundAccumulating clinical evidence suggests women with prior exposure to adverse childhood experiences are more susceptible to alcohol relapse and other health-related issues. Yet, preclinical studies investigating sex-dependent effects of adolescent adverse social experiences (ASEs) on later alcohol-seeking behavior are lacking. This is mainly due to a lack of valid animal models and a shortage of studies comparing sexes. Therefore, we sought to investigate the sex-dependent effects of ASE on adult alcohol-seeking behavior, locomotion and reward sensitivity in both male and female rats.MethodsWe recently developed a rat model for adolescent peer-rejection which allows us to study the long-term consequences of ASEs. Peer-rejection interferes with adolescent rats‘ability to engage in adequate and reciprocal play behaviors that result in persistent dysregulation of social and pain-related behavior. Adolescent Wistar rats were reared from postnatal day (pd) 21 to pd 50 either within a group of Fischer 344 rats (ASE) or with Wistar rats (control). Adult male and female rats were tested in the reinstatement paradigm for cue-induced alcohol-seeking behavior, circadian locomotor activity, and sucrose consumption in adulthood long-after the termination of the peer-rejection condition.ResultsPeer-rejection induced persistent sex-dependent changes to cue-induced reinstatement. Females showed an increased reinstatement effect while peer-rejected males demonstrated a decrease. No differences were observed in circadian locomotor activity or reward sensitivity to sucrose.ConclusionsPeer-rejection has lasting sex-dependent consequences on alcohol-seeking behavior without affecting locomotion or sweet reward sensitivity. Our results suggest that peer-rejected female rats represent a vulnerable population to study relapse-like behaviors similar to clinical findings. While males seem to buffer the peer-rejection effect and demonstrate resilience to later-life alcohol-seeking behaviors, measured by the reinstatement effect. Finally, we provide a novel approach to investigate the molecular and neurobiological underpinnings of ASEs on alcohol and other drug-seeking behaviors.
Evolution-inspired dissection of caspase activities enables the redesign of caspase-4 into an LPS sensing interleukin-1 converting enzyme
Authors: Devant Pascal , Cao Anh , Kagan Jonathan C. 
Published: December 2020

AbstractInnate immune signaling pathways comprise multiple proteins that promote inflammation. This multistep means of information transfer suggests that complexity is a prerequisite for pathway design. Herein, we examined this possibility by studying caspases that regulate inflammasome-dependent inflammation. Several caspases differ in their ability to recognize bacterial LPS and cleave interleukin-1β (IL-1β). No caspase is known to contain both activities, yet distinct caspases with complementary activities bookend an LPS-induced pathway to IL-1β cleavage. Using unique caspases present in carnivorans as a guide, we identified molecular determinants of IL-1β cleavage specificity within caspase-1. This knowledge enabled the redesign of human caspase-4 to operate as a one-protein signaling pathway, which intrinsically links LPS detection to IL-1β cleavage and release, independent of inflammasomes. Strikingly, cat caspase-4 displays the activities of redesigned human caspase-4. These findings illustrate natural signaling pathway diversity and highlight how multistep innate immune pathways can be condensed into a single protein.