julilili42/papers huggingface dataset:
KPNB1 modulates the Machado–Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP
2022-07-06

Abstract Machado–Joseph disease (MJD) is characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Despite its primarily cytoplasmic localization, polyQ-expanded ataxin-3 accumulates in the nucleus and forms intranuclear aggregates in the affected neurons. Due to these histopathological hallmarks, the nucleocytoplasmic transport machinery has garnered attention as an important disease relevant mechanism. Here, we report on MJD cell model-based analysis of the nuclear transport receptor karyopherin subunit beta-1 (KPNB1) and its implications in the molecular pathogenesis of MJD. Although directly interacting with both wild-type and polyQ-expanded ataxin-3, modulating KPNB1 did not alter the intracellular localization of ataxin-3. Instead, overexpression of KPNB1 reduced ataxin-3 protein levels and the aggregate load, thereby improving cell viability. On the other hand, its knockdown and inhibition resulted in the accumulation of soluble and insoluble ataxin-3. Interestingly, the reduction of ataxin-3 was apparently based on protein fragmentation independent of the classical MJD-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments identified mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1. We confirmed reduction of KPNB1 protein levels in MJD by analyzing two MJD transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from MJD patients. Our results reveal a yet undescribed regulatory function of KPNB1 in controlling the turnover of ataxin-3, thereby highlighting a new potential target of therapeutic value for MJD.
A simple method for generating arbitrary Gaussian noise and compensating filter properties of a stimulator to measure the frequency response function of a mechanosensory sensillum
2022-07-06

Abstract Gaussian noise is one of the principal inputs used for studying biological systems, especially sensory and neuronal systems. Because of the inherent nonlinearities of these systems, the properties of the noise strongly influence the outcome of the analysis. We show for the case of an insect filiform sensillum, a simple mechanoreceptor with a single sensory cell, that changes in noise amplitude and spectral properties affect the linear transfer function of the sensillum. We then explain how to use the inverse fast Fourier transform to generate Gaussian noise with an arbitrary frequency spectrum, including band-limited white noise with a perfectly sharp roll-off edge. Finally, we demonstrate a straightforward procedure for compensating filter properties of a stimulator in order to produce a proper band-limited Gaussian white noise stimulus. Using this approach one can generate well defined Gaussian noise stimulus that can be adapted to any particular application.
Motivated by Agility, Hampered by Switching: A Boundary Perspective
2022-07-06

While agile working methods become more and more important in practice, the implications from applying this new work form are largely underexplored. In this paper, we contribute to the literature on the downstream effects of agile working methods from a Job-Demand-Control perspective. Our moderated mediation model suggests that agile working methods increase employees’ intrinsic task motivation through role clarity. Furthermore, we argue that this indirect effect diminishes with the frequency of switching projects. We find empirical evidence for both hypotheses using data from a field study in a manufacturing company with 206 observations of 103 employees, who were surveyed in terms of their experience with working in agile and traditional projects.
A Sizable Advantage: Environmental and Social Sustainability Implications of Gender Diversity
2022-07-06

We study the effect of board gender diversity on environmental and social performance of firms. Our model complements existing literature in the field of corporate governance and sustainability by hypothesizing a direct positive effect of board gender diversity on environmental and social performance. We further argue that this direct effect is moderated by firm size such that the effect of board gender diversity on environmental and social performance is larger for smaller firms. We find evidence for our hypotheses when using board gender quotas as the empirical setting for our identification strategy. Our results of a staggered difference-in-differences approach with 2,981 firm-year observations of 511 firms in eight European countries with mandatory board gender quotas provide tentative evidence of a direct effect of board gender diversity on environmental and social performance. Yet, the moderation effect is positive and highly significant, which suggest that particularly smaller firms are able to improve environmental and social performance though board gender diversity.
Which Way to Grow? Startup Internationalization and Innovation in Latin America and Europe
2022-07-06

Internationalization and innovation are both critical strategies for growth-oriented startups. Whereas high uncertainty and unique learning challenges in emerging markets such as Latin America make the respective startups set their preference on internationalization, and only thereafter on innovation, in developed markets like Europe internationalization and innovation are more and more regarded as “vicious circle”, reinforcing each other. This suggests that the institutional context of firms shapes the priorities set on innovation and internationalization, and the relationship of the two strategies. In this paper, we investigate potential tradeoffs between internationalization and innovation in Latin America and Europe by having a closer look at the legal business context in a startups home country. Our paper contributes to the literature on international and strategic entrepreneurship and the institutional context startups face in their home countries. Relying on proprietary data of a globally operating European ICT corporation that is listed at the EUROSTOXX 50 index, we analyze the strategic choices between internationalization and innovation in an unbalanced panel of 359 (336) ICT startups and 1,613 (1,422) observations from seven Latin American countries and five European countries during the years 2014-2016. Our findings suggest that the legal business context in a startup’s home country influences the likelihood of startup internationalization.
Shared Fairness Perceptions of Chinese Subordinates and German Supervisors
2022-07-06

Enriching organizational justice literature with insights from cultural identity negotiation theory, our explorative, qualitative study develops an evidence-based model illuminating how culturally diverse subordinates and supervisors can achieve through their cross-cultural interactions shared fairness perceptions. Our analysis is based on a complex research design comprising in total 133 interviews in China and in Germany from Chinese subordinates of German supervisors, German subordinates of Chinese supervisors, Chinese supervisors of German subordinates and from German supervisors of Chinese subordinates. As a result of our empirically induced theorizing, we came to understand the centrality of inter-linked cultural identity negotiation processes. Only those subordinates and supervisors who were willing and able to engage in such processes, once they came into contact with the other respective party, succeeded in arriving at the approximation of previously more distinct fairness perceptions and ultimately to a partially shared understanding of fairness. In addition, we found various moderating factors influencing the cultural identity negotiation processes. From these factors cultural preservation, i.e., the degree to which the subordinates and supervisors cling to their original cultural identity, was by far the most important one.
Insights to HIV-1 coreceptor usage by estimating HLA adaptation with Bayesian generalized linear mixed models
2022-07-06

Abstract The mechanisms triggering the human immunodeficiency virus type I (HIV-1) to switch the coreceptor usage from CCR5 to CXCR4 during the course of infection are not entirely understood. While low CD4 + T cell counts are associated with CXCR4 usage, a predominance of CXCR4 usage with still high CD4 + T cell counts remains puzzling. Here, we explore the hypothesis that viral adaptation to the human leukocyte antigen (HLA) complex, especially to the HLA class II alleles, contributes to the coreceptor switch. To this end, we sequence the viral gag and env protein with corresponding HLA class I and II alleles of a new cohort of 312 treatment-naive, subtype C, chronically-infected HIV-1 patients from South Africa. To estimate HLA adaptation, we develop a novel computational approach using Bayesian generalized linear mixed models (GLMMs). Our model allows to consider the entire HLA repertoire without restricting the model to pre-learned HLA-polymorphisms as well as to correct for phylogenetic relatedness of the viruses within the model itself to account for founder effects. Using our model, we observe that CXCR4-using variants are more adapted than CCR5-using variants (p-value =1.34e-2). Additionally, adapted CCR5-using variants have a significantly lower predicted false positive rate (FPR) by the geno2pheno[coreceptor] tool compared to the non-adapted CCR5-using variants (p-value =2.21e-2), where a low FPR is associated with CXCR4 usage. Consequently, estimating HLA adaptation can be an asset in predicting not only coreceptor usage, but also an approaching coreceptor switch in CCR5-using variants. We propose the usage of Bayesian GLMMs for modeling virus-host adaptation in general. Author summary Viral control is currently our only counter mechanism against HIV-1 with no practicable cure nor a vaccine at hand. In treatment-naive patients, HLA adaptation and coreceptor usage of HIV-1 play a major role in their capability to control the virus. The interplay between both factors, however, has remained unexplored so far. Assessing the degree of viral HLA adaptation is challenging due to the exceptional genetic diversity of both the HLA complex and HIV-1. Therefore, current approaches constrain the adaptation prediction to a set of p-value selected HLA-polymorphism candidates. The selection of these candidates, however, requires extensive external large-scale population-based experiments that are not always available for the population of interest, especially not for newly emerging viruses. In this work, we present a novel computational approach using Bayesian generalized linear mixed models (GLMMs) that enables not only to predict the adaptation to the complete HLA profile of a patient, but also to handle phylogenetic-dependencies of the variants within the model directly. Using this light-weight approach for modeling (any) virus-host adaptation, we show that HLA adaptation is associated with coreceptor usage.
Japanese Women Pursuing a Career at Foreign Subsidiaries: A Question of Identity
2022-07-06

This study investigates what attracts career-oriented women to foreign subsidiaries and how they experience this work context. Based on 125 interviews with career-oriented women in Japan, we find that their frequent choice of foreign employers is not only motivated by professional aspirations but also by identity-related aspirations. Japanese women who embraced an internationalist orientation experience a confirmation of their progressive identity by working for foreign subsidiaries; by contrast, those who still felt bound by traditional role expectations, undergo a liberating identity transformation. Based on the perceptions of these particular employees, we develop recommendations for gender diversity management in foreign subsidiaries. We further argue that women, who are disadvantaged in the local employment context, often desire that foreign subsidiaries implement standardized home country HRM practices, instead of adopting local practices. By focusing on the recruitment of highly qualified women, foreign subsidiaries may turn their liability of foreignness into a competitive advantage.
De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial
2022-07-07

Abstract Purpose: Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial. Experimental Design: ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL). Results: After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68–1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41–4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis. Conclusions: Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs. See related commentary by Sharma, p. 4840
Au20(tBu3P)8: A Highly Symmetric Metalloid Gold Cluster in Oxidation State 0
2022-07-07

Abstract Metalloid gold clusters have unique properties with respect to size and structure and are key intermediates in studying transitions between molecular compounds and the bulk phase of the respective metal. In the following, the synthesis of the all‐phosphine protected metalloid cluster Au 20 ( t Bu 3 P) 8 , solely built from gold atoms in the oxidation state of 0 is reported. Single‐crystal X‐ray analysis revealed a highly symmetric hollow cube‐octahedral arrangement of the gold atoms, resembling gold bulk structure. Quantum‐chemical calculations illustrated the cluster can be described as a 20‐electron superatom. Optical properties of the compound have shown molecular‐like behavior.
In vitro Model Systems for Studies Into Retinal Neuroprotection
2022-07-07

Therapy development for neurodegenerative diseases of the retina constitutes a major unmet medical need, and this may be particularly relevant for inherited diseases of the retina, which are largely untreatable to this day. Therapy development necessitates appropriate models to improve the understanding of the underlying degenerative mechanisms, as well as for the testing and evaluation of novel treatment approaches. This review provides an overview of various in vitro model systems used to study retinal neuroprotection. The in vitro methods and technologies discussed range from primary retinal cell cultures and cell lines, to retinal organoids and organotypic retinal explants, to the cultivation of whole eyeballs. The advantages and disadvantages of these methods are compared and evaluated, also in view of the 3R principles (i.e., the refinement, reduction, and replacement of live animal testing), to identify suitable in vitro alternatives for in vivo experimentation. The article further expands on the use of in vitro models to test and evaluate neuroprotective treatments and to aid the development of retinal drug delivery systems. Among the pharmacological agents tested and characterized in vitro are such that interfere with aberrant cyclic guanosine monophosphate (cGMP) -signaling or such that inhibit the activities of poly (ADP-ribose) polymerase (PARP), histone deacetylases (HDAC), calpain-type proteases, as well as unfolded protein response-related stress. We then introduce nanoparticle-based drug delivery systems and discuss how different in vitro systems may be used to assess their efficacy in the treatment of retinal diseases. The summary provides a brief comparison of available in vitro models and relates their advantages and limitations to the various experimental requirements, for instance, for studies into disease mechanisms, novel treatments, or retinal toxicity. In many cases, combinations of different in vitro models may be required to obtain a comprehensive view of the efficacy of a given retinal neuroprotection approach.
Exploring the within-person contemporaneous network of motivational engagement
2022-07-07

Existing theoretical frameworks on motivation have identified a number of critical components in our motivational engagement process in learning. However, little empirical research has examined how these different components interact with each other to support our overall motivational engagement. This study explores such dynamics in a bottom-up manner by examining the within-person contemporaneous network structure of key components in the motivational engagement process (i.e., reasons/values, expectancy belief, goals, social relations, affective experiences, and perceived autonomy). We tracked four participants working on psychological research projects over the course of a year on a daily basis, and found that their motivational engagement mainly consisted of a large network of nodes that support autonomous forms of self-regulation. Scrutiny of the network also suggests the critical roles of curiosity and intrinsic reason in bridging affective and core motivational aspects of engagement.
A Novel Patient-Tailored, Cumulative Neurotechnology-Based Therapy for Upper-Limb Rehabilitation in Severely Impaired Chronic Stroke Patients: The AVANCER Study Protocol
2022-07-07

Effective, patient-tailored rehabilitation to restore upper-limb motor function in severely impaired stroke patients is still missing. If suitably combined and administered in a personalized fashion, neurotechnologies offer a large potential to assist rehabilitative therapies to enhance individual treatment effects. AVANCER ( clinicaltrials.gov NCT04448483) is a two-center proof-of-concept trial with an individual based cumulative longitudinal intervention design aiming at reducing upper-limb motor impairment in severely affected stroke patients with the help of multiple neurotechnologies. AVANCER will determine feasibility, safety, and effectivity of this innovative intervention. Thirty chronic stroke patients with a Fugl-Meyer assessment of the upper limb (FM-UE) &amp;lt;20 will be recruited at two centers. All patients will undergo the cumulative personalized intervention within two phases: the first uses an EEG-based brain-computer interface to trigger a variety of patient-tailored movements supported by multi-channel functional electrical stimulation in combination with a hand exoskeleton. This phase will be continued until patients do not improve anymore according to a quantitative threshold based on the FM-UE. The second interventional phase will add non-invasive brain stimulation by means of anodal transcranial direct current stimulation to the motor cortex to the initial approach. Each phase will last for a minimum of 11 sessions. Clinical and multimodal assessments are longitudinally acquired, before the first interventional phase, at the switch to the second interventional phase and at the end of the second interventional phase. The primary outcome measure is the 66-point FM-UE, a significant improvement of at least four points is hypothesized and considered clinically relevant. Several clinical and system neuroscience secondary outcome measures are additionally evaluated. AVANCER aims to provide evidence for a safe, effective, personalized, adjuvant treatment for patients with severe upper-extremity impairment for whom to date there is no efficient treatment available.
Measurement of light-absorbing particles in surface snow of central and western Himalayan glaciers: spatial variability, radiative impacts, and potential source regions
2022-07-07

Abstract. We collected surface snow samples from three different glaciers – Yala, Thana, and Sachin – in the central and western Himalayas to understand the spatial variability and radiative impacts of light-absorbing particles. The Yala and Thana glaciers in Nepal and Bhutan, respectively, were selected to represent the central Himalayas. The Sachin glacier in Pakistan was selected to represent the western Himalayas. The samples were collected during the pre- and post-monsoon seasons of the year 2016. The samples were analyzed for black carbon (BC) and water-insoluble organic carbon (OC) through the thermal optical method. The average mass concentrations (BC 2381 ng g−1; OC 3896 ng g−1; dust 101 μg g−1) in the western Himalayas (Sachin glacier) were quite high compared to the mass concentrations (BC 358 ng g−1, OC 904 ng g−1, dust 22 μg g−1) in the central Himalayas (Yala glacier). The difference in mass concentration may be due to the difference in elevation, snow age, local pollution sources, and meteorological conditions. BC in surface snow was also estimated through Weather Research and Forecasting (WRF) model coupled with Chemistry (WRF-Chem) simulations at the three glacier sites during the sampling periods. Simulations reasonably capture the spatial and seasonal patterns of the observed BC in snow but with a relatively smaller magnitude. Absolute snow albedo was estimated through the Snow, Ice, and Aerosol Radiative (SNICAR) model. The absolute snow albedo reduction ranged from 0.48 % (Thana glacier during September) to 24 % (Sachin glacier during May) due to BC and 0.13 % (Yala glacier during September) to 5 % (Sachin glacier during May) due to dust. The instantaneous radiative forcing due to BC and dust was estimated in the range of 0 to 96.48 and 0 to 25 W m−2, respectively. The lowest and highest albedo reduction and radiative forcing were observed in central and western Himalayan glaciers, respectively. The potential source regions of the deposited pollutants were inferred using WRF-Chem tagged-tracer simulations. Selected glaciers in the western Himalayas were mostly affected by long-range transport from the Middle East and central Asia; however, the central Himalayan glaciers were mainly affected by local and south Asia emissions (from Nepal, India, and China) especially during the pre-monsoon season. Overall, south Asia and west Asia were the main contributing source regions of pollutants.