bluuebunny/crossref_metadata_2025_split huggingface dataset:
The five digits of the giraffe metatarsal
Authors: Yohe Laurel R , Solounias Nikos 
Published: August 2020

AbstractEvolution has shaped the limbs of hoofed animals in specific ways. In artiodactyls, it is the common assumption that the metatarsal is composed of the fusion of digits III and IV, whereas the other three digits have been lost or are highly reduced. However, evidence from the fossil record and internal morphology of the metatarsal challenges these assumptions. Furthermore, only a few taxonomic groups have been analysed. In giraffes, we discovered that all five digits are present in the adult metatarsal and are highly fused and modified rather than lost. We examined high-resolution micro-computed tomography scans of the metatarsals of two mid and late Miocene giraffid fossils and the extant giraffe and okapi. In all the Giraffidae analysed, we found a combination of four morphologies: (1) four articular facets; (2) four or, in most cases, five separate medullary cavities internally; (3) a clear, small digit I; and (4) in the two fossil taxa of unknown genus, the presence of external elongated grooves where the fusions of digits II and V have taken place. Giraffa and Okapia, the extant Giraffidae, show a difference from all the extinct taxa in having more flattened digits tightly packed together, suggesting convergent highly fused digits despite divergent ecologies and locomotion. These discoveries provide evidence that enhances our understanding of how bones fuse and call into question current hypotheses of digit loss.
Morphological evolution in the ant reproductive caste
Authors: Divieso Raquel , Silva Thiago S R , Pie Marcio R 
Published: August 2020

AbstractThe evolution of eusociality has led to considerable changes in the general hymenopteran body plan. In particular, the evolution of reproductive division of labour caused the worker caste to be largely freed from the demands involved in reproduction. As a consequence, workers were able to evolve highly specialized morphologies for foraging and colony maintenance, whereas the reproductive caste became specialized for reproduction. Despite these important changes, little is known about the general patterns of morphological evolution within the ant reproductive caste. Our goals here were to characterize morphological variation in the ant reproductive caste and to test whether different sexes display variation in their evolutionary rates. We obtained measurements of 897 specimens from a total of 678 ant species. The shapes of the size distributions were similar between sexes, with queens being larger than males in all traits except for eye length. Contrary to the expectation based on Rensch’s rule, although queens were larger, the degree of dimorphism increased with body size. Finally, there was strong evidence for an accelerated tempo of morphological evolution in queens in relation to males. These results represent the first comprehensive treatment of morphological variation in the ant reproductive caste and provide important new insights into their evolution.
Resective surgery prevents progressive cortical thinning in temporal lobe epilepsy
Authors: Galovic Marian , de Tisi Jane , McEvoy Andrew W , Miserocchi Anna , Vos Sjoerd B , Borzi Giuseppe , Cueva Rosillo Juana , Vuong Khue Anh , Nachev Parashkev , Duncan John S , Koepp Matthias J 
Published: August 2020

Abstract
Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal ageing. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning. In this longitudinal case-control neuroimaging study, we included subjects with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural MRI scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to ageing-related cortical thinning in healthy subjects, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 versus healthy volunteers 0.0032 ± 0.0013 mm/year, P &lt; 0.0001) and right (right TLE 0.0198 ± 0.0016 versus healthy volunteers 0.0037 ± 0.0016 mm/year, P &lt; 0.0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = 0.0006) or right (0.0052 ± 0.0020 mm/year, P = 0.0006) anterior temporal lobe. Directly comparing the post- versus presurgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal ageing. Those with postoperative seizures had small areas of continued accelerated thinning after surgery. Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal ageing. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.
Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses
Authors: Béland Louis-Charles , Markovinovic Andrea , Jakovac Hrvoje , De Marchi Fabiola , Bilic Ervina , Mazzini Letizia , Kriz Jasna , Munitic Ivana 
Published: August 2020

Abstract
Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions—excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, non-selective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.
Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer
Authors: Chatterjee Soumya , Chatterjee Annesha , Jana Samir , Dey Subhasis , Roy Himansu , Das Mrinal Kanti , Alam Jahirul , Adhikary Anindya , Chowdhury Abhisek , Biswas Anupam , Manna Debasis , Bhattacharyya Arindam 
Published: August 2020

Abstract
Tumor cells promote immune evasion through upregulation of programmed death-ligand 1 (PD-L1) that binds with programmed cell death protein 1 (PD1) on cytotoxic T cells and promote dysfunction. Though therapeutic efficacy of anti-PD1 antibody has remarkable effects on different type of cancers it is less effective in breast cancer (BC). Hence, more details understanding of PD-L1-mediated immune evasion is necessary. Here, we report BC cells secrete extracellular vesicles in form of exosomes carry PD-L1 and are highly immunosuppressive. Transforming growth factor beta (TGF-β) present in tumor microenvironment orchestrates BC cell secreted exosomal PD-L1 load. Circulating exosomal PD-L1 content is highly correlated with tumor TGF-β level. The later also found to be significantly associated with CD8+CD39+, CD8+PD1+ T-cell phenotype. Recombinant TGF-β1 dose dependently induces PD-L1 expression in Texos in vitro and blocking of TGF-β dimmed exosomal PD-L1 level. PD-L1 knocked down exosomes failed to suppress effector activity of activated CD8 T cells like tumor exosomes. While understanding its effect on T-cell receptor signaling, we found siPD-L1 exosomes failed to block phosphorylation of src family proteins, linker for activation of T cells and phosphoinositide phospholipase Cγ of CD8 T cells more than PD-L1 exosomes. In vivo inhibition of exosome release and TGF-β synergistically attenuates tumor burden by promoting Granzyme and interferon gamma release in tumor tissue depicting rejuvenation of exhausted T cells. Thus, we establish TGF-β as a promoter of exosomal PD-L1 and unveil a mechanism that tumor cells follow to promote CD8 T-cell dysfunction.
Interplay between 5-HT4 Receptors and GABAergic System within CA1 Hippocampal Synaptic Plasticity
Authors: Lecouflet Pierre , Roux Candice M , Potier Brigitte , Leger Marianne , Brunet Elie , Billard Jean-Marie , Schumann-Bard Pascale , Freret Thomas 
Published: August 2020

Abstract
The type 4 serotonin receptor (5-HT4R) is highly involved in cognitive processes such as learning and memory. Behavioral studies have shown a beneficial effect of its activation and conversely reported memory impairments by its blockade. However, how modulation of 5HT4R enables modifications of hippocampal synaptic plasticity remains elusive. To shed light on the mechanisms at work, we investigated the effects of the 5-HT4R agonist RS67333 on long-term potentiation (LTP) within the hippocampal CA1 area. Although high-frequency stimulation-induced LTP remained unaffected by RS67333, the magnitude of LTP induced by theta-burst stimulation was significantly decreased. This effect was blocked by the selective 5-HT4R antagonist RS39604. Further, 5-HT4R-induced decrease in LTP magnitude was fully abolished in the presence of bicuculline, a GABAAR antagonist; hence, demonstrating involvement of GABA neurotransmission. In addition, we showed that the application of a GABABR antagonist, CGP55845, mimicked the effect of 5-HT4R activation, whereas concurrent application of CGP55845 and RS67333 did not elicit an additive inhibition effect on LTP. To conclude, through investigation of theta burst induced functional plasticity, we demonstrated an interplay between 5-HT4R activation and GABAergic neurotransmission within the hippocampal CA1 area.
Vasculitis due to Candidatus Neoehrlichia mikurensis: A Cohort Study of 40 Swedish Patients
Authors: Höper Linnea , Skoog Elisabet , Stenson Martin , Grankvist Anna , Wass Linda , Olsen Björn , Nilsson Kenneth , Mårtensson Andreas , Söderlind Jacob , Sakinis Augustinas , Wennerås Christine 
Published: August 2020

Abstract

Background
Candidatus (Ca.) Neoehrlichia (N.) mikurensis is an emerging tick-borne pathogen of humans that is closely related to Ehrlichia and Anaplasma species. This strict intracellular bacterium escapes detection by routine microbiologic diagnostic methods such as blood culture, leading to considerable under-diagnosis of the infectious disease it causes, neoehrlichiosis.

Methods
Here, we describe the vascular and thromboembolic events afflicting a series of 40 patients diagnosed with neoehrlichiosis in Sweden during a 10-year period (2009–2019).

Results
The majority of the patients (60%) developed vascular events ranging from repeated thrombophlebitis, deep vein thrombosis, pulmonary embolism, transitory ischemic attacks, to arteritis. Younger age was a risk factor for vascular complications. In contrast, there was no difference in the incidence of vascular events between immunosuppressed and immunocompetent patients. However, there were qualitative differences, such that deep vein thrombosis exclusively afflicted the immunosuppressed patients, whereas arteritis was restricted to the immunocompetent persons. We also present the case histories of two patients who developed vasculitis mimicking polyarteritis nodosa and giant cell arteritis. Both were cured by doxycycline treatment.

Conclusions
Ca. N. mikurensis infection should be considered in patients living in tick-endemic areas of Europe and northern Asia who present with atypical vascular and/or thromboembolic events. Early diagnosis and antibiotics targeting this emerging infectious agent can eradicate the infection and prevent the development of new vascular events.
Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor–Containing Regimens
Authors: Leonard Michael A , Cindi Zinhle , Bradford Yuki , Bourgi Kassem , Koethe John , Turner Megan , Norwood Jamison , Woodward Beverly , Erdem Husamettin , Basham Rebecca , Baker Paxton , Rebeiro Peter F , Sterling Timothy R , Hulgan Todd , Daar Eric S , Gulick Roy , Riddler Sharon A , Sinxadi Phumla , Ritchie Marylyn D , Haas David W 
Published: August 2020

Abstract

Background
Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood.

Methods
We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs.

Results
In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex.

Conclusions
Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.
Polyphony of domestic dog whines and vocal cues to body size
Authors: Sibiryakova Olga V , Volodin Ilya A , Volodina Elena V 
Published: August 2020

AbstractIn domestic dogs Canis familiaris, vocal traits have been investigated for barks and growls, and the relationship between individual body size and vocal traits investigated for growls, with less corresponding information for whines. In this study, we examined the frequency and temporal traits of whines of 20 adult companion dogs (9 males, 11 females), ranging in body mass from 3.5 to 70.0 kg and belonging to 16 breeds. Dog whines (26–71 per individual, 824 in total) were recorded in conditioned begging contexts modeled by dog owners. Whines had 3 independent fundamental frequencies: the low, the high and the ultra-high that occurred singly as monophonic calls or simultaneously as 2-voice biphonic or 3-voice polyphonic calls. From the smallest to largest dog, the upper frequency limit varied from 0.24 to 2.13 kHz for the low fundamental frequency, from 2.95 to 10.46 kHz for the high fundamental frequency and from 9.99 to 23.26 kHz for the ultra-high fundamental frequency. Within individuals, the low fundamental frequency was lower in monophonic than in biphonic whines, whereas the high fundamental frequency did not differ between those whine types. All frequency variables of the low, high, and ultra-high fundamental frequencies correlated negatively with dog body mass. For duration, no correlation with body mass was found. We discuss potential production mechanisms and sound sources for each fundamental frequency; point to the acoustic similarity between high-frequency dog whines and rodent ultrasonic calls and hypothesize that ultra-high fundamental frequencies function to allow private, “tete-a-tete” communication between members of social groups.
Columbia spotted frogs (Rana luteiventris) have characteristic skin microbiota that may be shaped by cutaneous skin peptides and the environment
Authors: Loudon A H , Kurtz A , Esposito E , Umile T P , Minbiole K P C , Parfrey L W , Sheafor B A 
Published: August 2020

ABSTRACT
Global amphibian declines due to the fungal pathogen Batrachochytrium dendrobatidis (Bd) have led to questions about how amphibians defend themselves against skin diseases. A total of two amphibian defense mechanisms are antimicrobial peptides (AMPs), a component of amphibian innate immune defense and symbiotic skin bacteria, which can act in synergy. We characterized components of these factors in four populations of Columbia spotted frogs (Rana luteiventris) to investigate their role in disease defense. We surveyed the ability of their AMPs to inhibit Bd, skin bacterial community composition, skin metabolite profiles and presence and intensity of Bd infection. We found that AMPs from R. luteiventris inhibited Bd in bioassays, but inhibition did not correlate with Bd intensity on frogs. R. luteiventris had two prevalent and abundant core bacteria: Rhizobacter and Chryseobacterium. Rhizobacter relative abundance was negatively correlated with AMP's ability to inhibit Bd, but was not associated with Bd status itself. There was no relationship between metabolites and Bd. Bacterial communities and Bd differ by location, which suggests a strong environmental influence. R. luteiventris are dominated by consistent core bacteria, but also house transient bacteria that are site specific. Our emergent hypothesis is that host control and environmental factors shape the microbiota on R. luteiventris.
Carotenoid metabolism in mitochondrial function
Authors: Lu Peiran , Wong Siau Yen , Wu Lei , Lin Dingbo 
Published: August 2020

AbstractMitochondria are highly dynamic organelles that are found in most eukaryotic organisms. It is broadly accepted that mitochondria originally evolved from prokaryotic bacteria, e.g. proteobacteria. The mitochondrion has its independent genome that encodes 37 genes, including 13 genes for oxidative phosphorylation. Accumulative evidence demonstrates that mitochondria are not only the powerhouse of the cells by supplying adenosine triphosphate, but also exert roles as signalling organelles in the cell fate and function. Numerous factors can affect mitochondria structurally and functionally. Carotenoids are a large group of fat-soluble pigments commonly found in our diets. Recently, much attention has been paid in carotenoids as dietary bioactives in mitochondrial structure and function in human health and disease, though the mechanistic research is limited. Here, we update the recent progress in mitochondrial functioning as signalling organelles in human health and disease, summarize the potential roles of carotenoids in regulation of mitochondrial redox homeostasis, biogenesis, and mitophagy, and discuss the possible approaches for future research in carotenoid regulation of mitochondrial function.
Alterations of Lipid Metabolism With Age and Weight in Companion Dogs
Authors: Hoffman Jessica M , Kiklevich J Veronika , Klavins Kristaps , Valencak Teresa G , Austad Steven N 
Published: August 2020

AbstractThe companion dog has recently been promoted as powerful translational model of aging. However, while dogs share environments with their human owners and develop many of the same age-related morbidities, little is known about the underlying mechanisms that drive their health and longevity. In addition, dogs have a well described phenotypic pattern in which small dogs live significantly longer than large dogs, such that weight can be used as a crude proxy for longevity. To investigate this pattern, we completed a small lipidomics study on 41 dogs in the Birmingham, Alabama, United States, area to determine individual circulating lipids that were associated with age and body weight. We discovered that sphingomyelins were significantly higher in large, short-lived dogs, independent of age, and triglycerides were higher in older dogs of all sizes. Our results point towards physiological differences that may explain a portion of the variation in longevity seen in companion dogs.