julilili42/papers huggingface dataset:
Hyaenidae (Carnivora) from the Late Miocene hominid locality of Hammerschmiede (Bavaria, Germany)
2021-12-05

The present paper deals with new hyaenid material from the locality of Hammerschmiede (Bavaria, Germany). The described specimens are attributed to two forms: most of the specimens belong to the species Thalassictis montadai, whereas one I3 is attributed to a large bone-cracking hyena. The material comes from the layers HAM 5 (11.62 Ma) and HAM 6 (slightly younger than 11.44 Ma) of Hammerschmiede (base of Late Miocene). The species Thalassictis montadai is well-known from late Aragonian and early Vallesian localities of central and southern Europe and west Asia. The presented material enables us to make a short review of the state-of-the-art about the fossil record of this species and to discuss its intraspecific variability. A gradual replacement of Thalassictis montadai, Thalassictis robusta and Hyaenictitherium wongii in Europe is demonstrated, until the arrival of canids during the latest Miocene. Additionally, the upper incisor of the large hyaenid creates some interesting questions concerning the first appearance of the crocutoid hyenas in the fossil record and their dominance over the percrocutoids.
Comparative magnitude and persistence of SARS-CoV-2 vaccination responses on a population level in Germany
2021-12-05

Abstract Background While SARS-CoV-2 vaccinations were successful in decreasing COVID-19 caseloads, recent increases in SARS-CoV-2 infections have led to questions about duration and quality of the subsequent immune response. While numerous studies have been published on immune responses triggered by vaccination, these often focused on the initial peak response generated in specific population subgroups (e.g. healthcare workers or immunocompromised individuals) and have often only examined the effects of one or two different immunisation schemes. Methods and Findings We analysed serum samples from participants of a large German seroprevalence study (MuSPAD) who had received all available vaccines and dose schedules (mRNA-1273, BNT162b2, AZD1222, Ad26.CoV2S.2 or a combination of AZD1222 plus either mRNA-1273 or BNT162b2). Antibody titers against various SARS-CoV-2 antigens and ACE2 binding inhibition against SARS-CoV-2 wild-type and the Alpha, Beta, Gamma and Delta variants of concern were analysed using a previously published multiplex immunoassay MULTICOV-AB and an ACE2-RBD competition assay. Among the different vaccines and their dosing regimens, homologous mRNA-based or heterologous prime-boost vaccination produced significantly higher antibody responses than vector-based homologous vaccination. Ad26.CoV2S.2 performance was significantly reduced, even compared to AZD1222, with 91.67% of samples being considered non-responsive forACE2 binding inhibition. mRNA-based vaccination induced a higher ratio of RBD- and S1-targeting antibodies than vector-based vaccination, which resulted in an increased proportion of S2-targeting antibodies. Previously infected individuals had a robust immune response once vaccinated, regardless of which vaccine they received. When examining antibody kinetics post-vaccination after homologous immunisation regimens, both titers and ACE2 binding inhibition peaked approximately 28 days post-vaccination and then decreased as time increased. Conclusions As one of the first and largest population-based studies to examine vaccine responses for all currently available immunisation schemes in Germany, we found that homologous mRNA or heterologous vaccination elicited the highest immune responses. The high percentage of non-responders for Ad26.CoV2.S requires further investigation and suggests that a booster dose with an mRNA-based vaccine may be necessary. The high responses seen in recovered and vaccinated individuals could aid future dose allocation, should shortages arise for certain manufacturers. Given the role of RBD- and S1-specific antibodies in neutralising SARS-CoV-2, their relative over-representation after mRNA vaccination may explain why mRNA vaccines have an increased efficacy compared to vector-based formulations. Further investigation on these differences will be of particular interest for vaccine development and efficacy, especially for the next-generation of vector-based vaccines.
Project-based engineering learning in college: associations with self-efficacy, effort regulation, interest, skills, and performance
2021-12-05

Abstract This quantitative study examined student participation in an introductory project-based engineering course offered in fully face-to-face and hybrid course modes ( N = 160). This course attempted to counteract trends of decreased student motivation and high attrition rates among engineering majors. Mixed-design analysis of variance examined differences in motivational constructs including student self-efficacy, effort regulation, and interest in engineering, as well as engineering skills throughout the course and across instructional modes. None of the motivational constructs were associated with significant decreases throughout the course nor with differences across instructional modes. However, students’ engineering skills increased throughout the course with no significant differences across course modalities. Furthermore, interest in engineering and effort regulation were positively associated with course performance. The instructional modality was not significantly associated with course performance. Overall, this study provides an example of a project-based introductory engineering course which may help maintain student motivation and foster student success in engineering.
Palaeoecological and genetic analyses of Late Pleistocene bears in Asiatic Russia
2021-12-05

Brown bears are one of the few large carnivore species that survived the final Pleistocene wave of extinctions, perhaps in part owing to their wide ecological plasticity, variety of forms and polyphagia. Although the brown bear has become a well‐studied system, many questions remain regarding the ecological, trophic and genetic diversity throughout their distribution. For example, knowledge about Asiatic Russian brown bears from the Late Pleistocene arctic tundra steppe, an ecosystem with no analogue in modern times, is sparse. Here we compared diets, morphometry and genetic affinities of Late Pleistocene bears based on broadly sampled subfossil remains from Asiatic Russia. Collecting sites included the Ural Mountains, the lower reaches of the Irtysh River, the upper reaches of the Ob River, the Altai Mountains of western Siberia, the Indigirka–Kolyma Lowlands and northwestern Chukotka. An extremely large bear specimen from the middle Indigirka (41 090 14 C a BP) that lived in landscapes of treeless shrubs and wet meadows had a diet composed principally of large herbivorous mammals. A bear from western Chukotka (25 880 14 C a BP), much smaller in size, had a diet close to that of modern brown bears. These two Late Pleistocene NE Russian brown bears may comprise a previously undiscovered, but extinct, genetic lineage. At the end of the Pleistocene (MIS 3 and MIS 2), the brown bears from the Ob River Valley and Urals lived in periglacial forest‐steppes and those from the southern Urals in conditions of periglacial steppe. Brown bears from the Ob River valley and Urals, as well as ancient Altai bears, were characterized by a varied diet, from polyphagia to vegetarianism. In living brown bears, the proportions of different dietary foods are primarily related to food availability, which depends on the geographical zone and climatic conditions. We conclude that the same was true for Late Pleistocene brown bears of NE Siberia.
Association between Immune-Related Adverse Events and Survival in 319 Stage IV Melanoma Patients Treated with PD-1-Based Immunotherapy: An Approach Based on Clinical Chemistry
2021-12-06

(1) Background: Immune checkpoint inhibitors have improved the prognosis of patients with advanced melanoma. Published data suggested that the objective response rates appear to be superior in patients who developed immune-related adverse events (irAEs). (2) The primary aim of this cohort study was to evaluate the association between irAEs and disease control rate in patients with stage IV melanoma treated with first-line PD-1-based immunotherapy. (3) Among 319 patients, 53% experienced at least one irAE. A higher percentage of patients with irAEs had disease control compared to those without irAEs (69.8% vs. 49.3%). In multivariate analysis, development of grade 3 and 4 irAEs was significantly associated with a protective effect for the outcome primary resistance (OR: 0.40 95% CI 0.23–0.70, p = 0.001). The presence of any grade irAEs was significantly associated with longer OS (irAEs grade 1–2 HRadj: 0.61 95% CI: 0.4–0.93, p = 0.02, irAEs grade 3–4 HRadj: 0.55 95% CI 0.31–0.99, p = 0.04), but not with PFS (irAEs grade 1–2 HRadj: 1.21 95% CI: 0.91–1.79, p = 0.16, irAEs grade 3–4 HRadj: 1.14 95% CI 0.83–2.02, p = 0.24). (4) The presence of irAEs with laboratorial expression is positively associated with response and OS, suggesting that irAEs might be a predictive factor in this setting.
Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 associated with Developmental and Epileptic Encephalopathy and Autism Spectrum Disorder
2021-12-06

Abstract Objective Fibroblast growth factor 12 (FGF12) may represent an important modulator of neuronal network activity and has been associated with developmental and epileptic encephalopathy (DEE). We sought to identify the underlying pathomechanism of FGF12-related disorders. Methods Patients with pathogenic variants in FGF12 were identified through published case reports, GeneMatcher and whole exome sequencing of own case collections. The functional consequences of two missense variants and two copy number variants (CNVs) were studied by co-expression of wild-type and mutant FGF12 in neuronal-like cells (ND7/23) with the sodium channels Na V 1.2 or Na V 1.6, including their functional active beta-1 and beta-2 sodium channel subunits ( SCN1B and SCN2B ). Results Four variants in FGF12 were identified for functional analysis: one novel FGF12 variant in a patient with autism spectrum disorder and three variants from previously published patients affected by developmental and epileptic encephalopathy (DEE). We demonstrate the differential regulating effects of wildtype and mutant FGF12 on Na V 1.2 and Na V 1.6 channels. Here, FGF12 variants lead to a complex kinetic influence on Nav1.2 and Nav 1.6, including loss- as well as gain-of function changes in fast inactivation as well as loss-of function changes in slow inactivation. Interpretation For the first time, we could demonstrate the detailed regulating effect of FGF12 on Na V 1.2 and Na V 1.6 and confirmed the complex effect of FGF12 on neuronal network activity. Our findings expand the phenotypic spectrum related to FGF12 variants and elucidate the underlying pathomechanism. Specific variants in FGF12-associated disorders may be amenable to precision treatment with sodium channel blockers.
Imidacloprid - Induced Pathophysiological Damage in the Midgut of Locusta Migratoria (Orthoptera: Acrididae) in the Field
2021-12-06

Abstract Neonicotinoids are modern insecticides widely used in agriculture worldwide. Their impact on target (nervous system) and non-target (midgut) tissues has been well studied in beneficial insects including honeybees. However, their effects on pest insects on the field are comparably rarely described. Here, we have studied the effects of the neonicotinoid imidacloprid on the midgut of the pest insect Locusta migratoria caught in the field. We found that in the midgut of imidacloprid-exposed locusts the activity of enzymes involved in reactive oxygen metabolism was perturbed. By contrast, the activity of P450 enzymes that have been shown to be activated in a detoxification response and that were also reported to produce reactive oxygen species was elevated. Probably as a consequence, markers of oxidative stress including protein carbonylation and lipid peroxidation accumulated in midgut samples of these locusts. Histological analyses revealed that their midgut epithelium is disorganized and that the brush border of the epithelial cells is markedly reduced. Indeed, microvilli are significantly shorter, misshapen and possibly non-functional in imidacloprid-treated locusts. We hypothesize that imidacloprid induces oxidative stress in the locust midgut, thereby changing the shape of midgut epithelial cells and probably in turn compromising their physiological function. Presumably, these effects reduce the survival rate of imidacloprid-treated locusts and the damage they cause in the field.
Diminishing Domain Bias by Leveraging Domain Labels in Object Detection on UAVs
2021-12-06

Object detection from Unmanned Aerial Vehicles (UAVs) is of great importance in many aerial vision-based applications. Despite the great success of generic object detection methods, a significant performance drop is observed when applied to images captured by UAVs. This is due to large variations in imaging conditions, such as varying altitudes, dynamically changing viewing angles, and different capture times. These variations lead to domain imbalances and, thus, trained models suffering from domain bias. We demonstrate that domain knowledge is a valuable source of information and thus propose domain-aware object detectors by using freely accessible sensor data. By splitting the model into cross-domain and domain-specific parts, substantial performance improvements are achieved on multiple data sets across various models and metrics without changing the architecture. In particular, we achieve a new state-of-the-art performance on UAVDT for embedded real-time detectors. Furthermore, we create a new airborne image data set by annotating 13,713 objects in 2,900 images featuring precise altitude and viewing angle annotations.
Removing Inter-Experimental Variability from Functional Data in Systems Neuroscience
2021-12-06

Integrating data from multiple experiments is common practice in systems neuroscience but it requires inter-experimental variability to be negligible compared to the biological signal of interest. This requirement is rarely fulfilled; systematic changes between experiments can drastically affect the outcome of complex analysis pipelines. Modern machine learning approaches designed to adapt models across multiple data domains offer flexible ways of removing inter-experimental variability where classical statistical methods often fail. While applications of these methods have been mostly limited to single-cell genomics, in this work, we develop a theoretical framework for domain adaptation in systems neuroscience. We implement this in an adversarial optimization scheme that removes inter-experimental variability while preserving the biological signal. We compare our method to previous approaches on a large-scale dataset of two-photon imaging recordings of retinal bipolar cell responses to visual stimuli. This dataset provides a unique benchmark as it contains biological signal from well-defined cell types that is obscured by large inter-experimental variability. In a supervised setting, we compare the generalization performance of cell type classifiers across experiments, which we validate with anatomical cell type distributions from electron microscopy data. In an unsupervised setting, we remove inter-experimental variability from data which can then be fed into arbitrary downstream analyses. In both settings, we find that our method achieves the best trade-off between removing inter-experimental variability and preserving biological signal. Thus, we offer a flexible approach to remove inter-experimental variability and integrate datasets across experiments in systems neuroscience. Code available at https://github.com/eulerlab/rave.
Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia
2021-12-07

Abstract The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in therapeutic approaches, at least in monogenic disease, demand a proper definition of these predementia stages. It has become clear that a consensus lexicon is needed to comprehensively describe the stages that anticipate dementia. The goal of the present work is to review existing literature on the preclinical and prodromal phases of FTD, providing recommendations to address the unmet questions, therefore laying out a strategy for operationalizing and better characterizing these presymptomatic disease stages.
The Role of Physical Activity in Nonalcoholic and Metabolic Dysfunction Associated Fatty Liver Disease
2021-12-07

Sedentary behavior constitutes a pandemic health threat contributing to the pathophysiology of obesity and type 2 diabetes (T2D). Sedentarism is further associated with liver disease and particularly with nonalcoholic/metabolic dysfunction associated fatty liver disease (NAFLD/MAFLD). Insulin resistance (IR) represents an early pathophysiologic key element of NAFLD/MAFLD, prediabetes and T2D. Current treatment guidelines recommend regular physical activity. There is evidence, that physical exercise has impact on a variety of molecular pathways, such as AMP-activated protein kinase and insulin signaling as well as glucose transporter 4 translocation, modulating insulin action, cellular substrate flow and in particular ectopic lipid and glycogen storage in a positive manner. Therefore, physical exercise can lead to substantial clinical benefit in persons with diabetes and/or NAFLD/MAFLD. However, experience from long term observational studies shows that the patients’ motivation to exercise regularly appears to be a major limitation. Strategies to integrate everyday physical activity (i.e., nonexercise activity thermogenesis) in lifestyle treatment schedules might be a promising approach. This review aggregates evidence on the impact of regular physical activity on selected molecular mechanisms as well as clinical outcomes of patients suffering from IR and NAFLD/MAFLD.
Successful treatment with azacitidine in VEXAS syndrome with prominent myofasciitis
2021-12-07

Dear Editor, The recently defined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome summarizes late-onset inflammatory conditions such as Sweet's syndrome with overlapping haematological features due to somatic variants in UBA1 [1]. To date, data on effective therapies other than glucocorticoids are scarce. Our patient first presented with non-pruritic tender lesions (Fig. 1A and B) at age 60. The histopathologically confirmed neutrophilic dermatosis was not responding to a wide range of treatments, including hydroxychloroquine, methotrexate, ciclosporin, azathioprine, infliximab, adalimumab, ustekinumab, and apremilast. Only prednisolone was effective, but high doses were needed to prevent relapse. Ten years later, the patient was admitted with limb swelling and myalgias accompanied by pronounced fatigue and recurrent fevers. Physical examination revealed massive limb oedema leading to weight gain of 25 kg (Fig. 1C). Laboratory exams showed anaemia (haemoglobin min. 5.9 g/dl), thrombocytopenia (min. 90 G/l), and undulating white...
TGF-β Induction of miR-143/145 Is Associated to Exercise Response by Influencing Differentiation and Insulin Signaling Molecules in Human Skeletal Muscle
2021-12-07

Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or &lt;+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned IRS1 suppression by miR-143-3p.
Case Report: Catatonia Associated With Post-traumatic Stress Disorder
2021-12-07

We report here about a 12-year-old female patient who had two life-threatening accidents that led to post-traumatic stress disorder associated with catatonia. She had closed eyes, had urinary and fecal incontinence, and had been in an abnormal position for one and half month. Moreover, she had complications such as dehydration, malunion of the fractured arm, and deformities in hand and foot. After detailed psychiatric examination, neurological assessment, and laboratory investigation, the patient received successful treatment in the form of benzodiazepine injections, intravenous fluid, oral antidepressants, and six sessions of electroconvulsive therapy (ECT). We discuss the pathophysiology of catatonia, which remains elusive, and recommend evaluating catatonic children for any possible trauma during psychiatry assessment.
Transcript-Specific Loss-of-Function Variants in VPS16 Are Enriched in Patients With Dystonia
2021-12-07

Our data provide strong evidence for <i>VPS16</i> pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.