julilili42/papers huggingface dataset:
openPrimeR for multiplex amplification of highly diverse templates
2020-01-25

To study the diversity of immune receptors and pathogens, multiplex PCR has become a central approach in research and diagnostics. However, insufficient primer design against highly diverse templates often prevents amplification and therefore limits the correct understanding of biological processes. Here, we present openPrimeR, an R-based tool for evaluating and designing multiplex PCR primers. openPrimeR provides a functional and intuitive interface and uses either a greedy algorithm or an integer linear program to compute the minimal set of primers that performs full target coverage. As proof of concept, we used openPrimeR to find optimal primer sets for the amplification of highly mutated immunoglobulins. Comprehensive analyses on specifically generated immunoglobulin variable gene segment libraries resulted in the composition of highly effective primer sets (oPR-IGHV, oPR-IGKV and oPR-IGLV) that demonstrated to be particularly suitable for the isolation of novel human antibodies.
Tissue Engineering in Liver Regenerative Medicine: Insights into Novel Translational Technologies
2020-01-27

Organ and tissue shortage are known as a crucially important public health problem as unfortunately a small percentage of patients receive transplants. In the context of emerging regenerative medicine, researchers are trying to regenerate and replace different organs and tissues such as the liver, heart, skin, and kidney. Liver tissue engineering (TE) enables us to reproduce and restore liver functions, fully or partially, which could be used in the treatment of acute or chronic liver disorders and/or generate an appropriate functional organ which can be transplanted or employed as an extracorporeal device. In this regard, a variety of techniques (e.g., fabrication technologies, cell-based technologies, microfluidic systems and, extracorporeal liver devices) could be applied in tissue engineering in liver regenerative medicine. Common TE techniques are based on allocating stem cell-derived hepatocyte-like cells or primary hepatocytes within a three-dimensional structure which leads to the improvement of their survival rate and functional phenotype. Taken together, new findings indicated that developing liver tissue engineering-based techniques could pave the way for better treatment of liver-related disorders. Herein, we summarized novel technologies used in liver regenerative medicine and their future applications in clinical settings.
The mechanisms and treatments for sarcopenia: could exosomes be a perspective research strategy in the future?
2020-01-27

Abstract The age‐related loss of muscle mass and muscle function known as sarcopenia is a primary contributor to the problems faced by the old people. Sarcopenia has been a major public health problem with high prevalence in many countries. The related underlying molecular mechanisms of sarcopenia are not completely understood. This review is focused on the potential mechanisms and current research strategies for sarcopenia with the aim of facilitating the recognition and treatment of age‐related sarcopenia. Previous studies suggested that protein synthesis and degradation, autophagy, impaired satellite cell activation, mitochondria dysfunction, and other factors associated with muscle weakness and muscle degeneration may be potential molecular pathophysiology of sarcopenia. Importantly, we also prospectively highlight that exosomes (small vesicles) as carriers can regulate muscle regeneration and protein synthesis according to recent researches. Dietary strategies and exercise represent the interventions that can also alleviate the progression of sarcopenia. At last, building on recent studies pointing to exosomes with the roles in increasing muscle regeneration, mediating the beneficial effects of exercise, and serving as messengers of intercellular communication and as carriers for research strategies of many diseases, we propose that exosomes could be a potential research direction or strategies of sarcopenia in the future.
Vascular Injuries following Knee Dislocation
2020-01-27

Abstract Knee dislocations (KDs) are frequently found in high-energy impact injuries, ranging from automobile accidents to contact sports. KDs require careful examination due to the limb-threatening nature of these injuries. A key examination in any KD comprises a proper assessment of the vascular status. The risk of popliteal artery injury with a KD has varied from 7 to 40%, with more contemporary studies reporting injury in the range of 7 to 15%. The notion of mandatory emergent arteriography was challenged in the trauma literature as several small retrospective studies suggested that selective arteriography was a safe and effective treatment protocol. New imaging modalities have evolved and have found their way into trauma surgery. Computed tomography angiography and magnetic resonance angiography are two contemporary imaging modalities that have different characteristics as well as availability. Arteriography has been the gold standard and is a reliable and proven method of evaluation. However, it has a number of negative aspects that must be considered when determining the ideal imaging for a patient following KD. Besides cost savings of about more than US$500,000, conventional arteriography, which comprises the use of X-ray, arterial puncture and cannulation, and the use of contrast agents containing iodine, has got a complication rate as high as 9% and more patient discomfort compared with the new imaging modalities. This clinical practice review documents that our algorithm of clinical examination first combined with advanced imaging in cases with abnormalities documented on examination is a safe and prudent policy in treating patients following KD.
Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids
2020-01-27

Abstract Mutations in pitrilysin metallopeptidase 1 ( PITRM1 ), a mitochondrial protease involved in mitochondrial precursor processing and degradation, result in a slow-progressive syndrome, characterized by cerebellar ataxia, psychotic episodes and obsessive behavior as well as cognitive decline. To investigate the pathogenetic mechanisms of mitochondrial presequence processing, we employed cortical neurons and cerebral organoids generated from PITRM1 knockout human induced pluripotent stem cells (iPSCs). PITRM1 deficiency strongly induced mitochondrial unfolded protein response (UPR mt ) and enhanced mitochondrial clearance in iPSC-derived neurons. Furthermore, we observed increased levels of amyloid precursor protein and amyloid β in PITRM1 knockout neurons. However, neither cell death nor protein aggregates were observed in 2D iPSC-derived cortical neuronal cultures. On the contrary, cerebral organoids generated from PITRM1 knockout iPSCs spontaneously developed over time pathological features of Alzheimer’s disease (AD), including accumulation of protein aggregates, tau pathology, and neuronal cell death. Importantly, we provide evidence for a protective role of UPR mt and mitochondrial clearance against impaired mitochondrial presequence processing and proteotoxic stress. In summary, we propose a novel concept of PITRM1-linked neurological syndrome whereby defects of mitochondrial presequence processing induce an early activation of UPR mt that, in turn, modulates cytosolic quality control pathways. Thus our work supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.
Ring Finger Protein 11 acts on ligand‐activated EGFR via the direct interaction with the UIM region of ANKRD13 protein family
2020-01-27

RING finger protein 11 (RNF11) is an evolutionary conserved Really Interesting New Gene E3 ligase that is overexpressed in several human tumours. Although several reports have highlighted its involvement in crucial cellular processes, the mechanistic details underlying its function are still poorly understood. Utilizing stable isotope labelling by amino acids in culture (SILAC)‐based proteomics analysis, we identified 51 proteins that co‐immunoprecipitate with wild‐type RNF11 and/or with its catalytically inactive mutant. We focused our attention on the interaction of RNF11 with Ankyrin repeat domain‐containing protein 13 (ANKRD13)s family. Members of the ANKRD13 family contain ubiquitin‐interacting motifs (UIM) that recognize the Lys‐63‐linked ubiquitin (Ub) chains appended to Epidermal growth factor receptor (EGFR) soon after ligand binding. We show that ANKRD13A, ANKRD13B and ANKRD13D form a complex with RNF11 in vivo and that the UIMs are required for complex formation. However, at odds with the conventional UIM binding mode, Ub modification of RNF11 is not required for the interaction with ANKRD13 proteins. We also show that the interaction between ANKRD13A and RNF11 is modulated by the EGF stimulus and that a complex formed by ANKRD13A, RNF11 and activated EGFR is transiently assembled in the early phases of receptor endocytosis. Moreover, loss of function of the E3 ligases Itchy E3 ubiquitin‐protein ligase (ITCH) or RNF11, respectively, abrogates or increases the ubiquitination of endogenous ANKRD13A, affecting its ability to bind activated EGFR. We propose a model whereby the ANKRD13 proteins act as molecular scaffolds that promote the transient formation of a complex between the activated EGFR and the E3 ligases ITCH and RNF11. By regulating the ubiquitination status of ANKRD13A and consequently its endocytic adaptor function, RNF11 promotes sorting of the activated EGFR for lysosomal degradation.
Modulating the Electronic and Solid‐State Structure of Organic Semiconductors by Site‐Specific Substitution: The Case of Tetrafluoropentacenes
2020-01-27

Abstract The properties as well as solid‐state structures, singlet fission, and organic field‐effect transistor (OFET) performance of three tetrafluoropentacenes (1,4,8,11: 10 , 1,4,9,10: 11 , 2,3,9,10: 12 ) are compared herein. The novel compounds 10 and 11 were synthesized in high purity from the corresponding 6,13‐etheno‐bridged precursors by reaction with dimethyl 1,2,4,5‐tetrazine‐3,6‐dicarboxylate at elevated temperatures. Although most of the molecular properties of the compounds are similar, their chemical reactivity and crystal structures differ considerably. Isomer 10 undergoes the orbital symmetry forbidden thermal [4+4] dimerization, whereas 11 and 12 are much less reactive. The isomers 11 and 12 crystallize in a herringbone motif, but 10 prefers π–π stacking. Although the energy of the first electric dipole‐allowed optical transition varies only within 370 cm −1 (0.05 eV) for the neutral compounds, this amounts to roughly 1600 cm −1 (0.20 eV) for radical cations and 1300 cm −1 (0.16 eV) for dications. Transient spectroscopy of films of 11 and 12 reveals singlet‐fission time constants (91±11, 73±3 fs, respectively) that are shorter than for pentacene (112±9 fs). OFET devices constructed from 11 and 12 show close to ideal thin‐film transistor (TFT) characteristics with electron mobilities of 2×10 −3 and 6×10 −2 cm 2 V −1 s −1 , respectively.
Genetic loss of NFAT2 (NFATc1) impairs B cell development of B1 and B2 B cells
2020-01-27

NFAT2 activity was shown to be of critical importance in B cell receptor signaling, development and proliferation; however its role in B cell development in the periphery is still not completely understood. We confirmed that NFAT2 deletion leads to impaired B1 B cell development, supported by our finding of limited B1 progenitors in the bone marrow and spleen of NFAT2 deficient mice. Moreover, we show for the first time that loss of NFAT2 increases immature B cells in particular transitional T2 and T3 as well as mature follicular B cells while marginal zone B cells are decreased. We further demonstrate that NFAT2 regulates the expression of B220, CD23, CD38, IgM/IgD and ZAP70 in murine B cells. In vivo analyses revealed decreased proliferation and increased apoptosis of NFAT2 deficient B cells. In summary, this study provides an extensive analysis of the role of NFAT2 in peripheral B lymphocyte development.
A mosaic renal myeloid subtype with T-cell inhibitory and protumoral features is linked to immune escape and survival in clear cell renal cell cancer
2020-01-27

Summary Mononuclear phagocytes moderate tissue repair, immune activation and tolerance. In the renal tubulo-interstitium specialized dendritic cells help maintain homeostasis and protect tubuli from immune injury. Human renal cell carcinoma (RCC) is immunogenic; yet immunotherapies that target T-cell dysfunction show limited clinical efficacy suggesting additional mechanisms of immunoinhibiton. We previously described “enriched-in-renal cell carcinoma” (erc)DCs that are often found in tight contact with T cells which are dysfunctional. Here we describe that ercDCs exhibit a distinct polarization state imparted by tissue-specific signals characteristic for RCC and renal tissue homeostasis. The resulting mosaic transcript signature includes features associated with host defense activity, angiogenesis/invasion and T-cell inhibition. An ercDC-specific profile was predictive for patient survival and suggests potential therapeutic targets for improved immunotherapy. Significance Immunotherapies, which re-invigorate T-cell activity, achieve clinical responses in subsets of patients only revealing additional layers of T-cell inhibition. Mononuclear phagocytes can be immunoinhibitory. But, they are highly plastic and repolarization may be possible if key programming molecules can be identified, potentially enabling antitumor responses in tumors refractory to checkpoint blockade. We describe a myeloid cell type with mosaic feature including tumor-promotion and immunoinhibition in human clear cell renal cell carcinoma. Observed tight contacts with T cells may translate into T-cell dysfunction. A high ercDC score in tumor tissue correlates with poor patient survival suggesting ercDCs as targets for therapeutic intervention. Targeting molecules that are identified in the ercDC profile may expand the range of patients effectively treated by immunotherapy. Highlights Bullet points: Renal cell carcinoma (ccRCC) harbors polarized mosaic myeloid cells (ercDCs) ercDCs are found in contact with dysfunctional T cells in ccRCC ercDCs express novel immunoinhibitory proteins High ercDC z-score in ccRCC tissue correlates with poor patient survival
Let’s (Not) (Dis)Agree to Disagree!? Some Thoughts on the ‘Dispute’ Requirement in International Adjudication
2020-01-27

International courts and tribunals only enjoy jurisdiction to settle a ‘dispute’. ‘Dispute’ requires disagreement. However, what if the parties disagree over whether there actually exists such disagreement? What if, before the International Court of Justice, the respondent argues that there is no ‘dispute’ because it declined to react to the applicant’s contentions? In other words, can a disputing party avoid a dispute by playing dead? On the other hand, where to draw the line in order to prevent the applicant from seizing an international court or tribunal where there is in fact no real disagreement among the parties? This article critically assesses the Court’s case law on the ‘dispute’ requirement and argues for a fragmented approach to ‘dispute’ in international adjudication that carefully defines this jurisdictional requirement along the lines of the judicial function of the respective international judicial dispute settlement forum.
Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert opinion
2020-01-28

Abstract Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma ( BCC ). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (la BCC ) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with la BCC are unclear, as no head‐to‐head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence‐based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of la BCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single‐arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors ( RECIST ), while the more recent double‐blind randomized BOLT trial used the stringent modified RECIST . A preplanned analysis adjusted the outcomes from BOLT with RECIST ‐like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate ( ORR ) for vismodegib was 47.6% (95% CI: 35.5–60.6) at 21‐month follow‐up using RECIST . After adjusting with RECIST ‐like criteria, the ORR for sonidegib according to central review at 18‐month follow‐up was 60.6% (95% CI: 47.8–72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half‐life. Further studies are needed to understand how these differences may impact clinical practice.
In vivo anatomical mapping of human locus coeruleus functional connectivity at 3 T MRI
2020-01-28

Abstract The locus coeruleus (LC) is involved in numerous crucial brain functions and several disorders like depression and Alzheimer's disease. Recently, the LC resting‐state functional connectivity (rs‐fc) has been investigated in functional MRI by calculating the blood oxygen level–dependent (BOLD) response extracted using Montreal Neurological Institute (MNI) space masks. To corroborate these results, we aimed to investigate the LC rs‐fc at native space by improving the identification of the LC location using a neuromelanin sensitive sequence. Twenty‐five healthy male participants (mean age 24.8 ± 4.2) were examined in a Siemens MAGNETOM Prisma 3 T MRT applying a neuromelanin sensitive T1TSE sequence and functional MRI. We compared the rs‐fc of LC calculated by a MNI‐based approach with extraction of the BOLD signal at the exact individual location of the LC after applying CompCor and field map correction. As a measure of advance, a marked increase of regional homogeneity (ReHo) of time series within LC could be achieved with the subject‐specific approach. Furthermore, the methods differed in the rs‐fc to the right temporoparietal junction, which showed stronger connectivity to the LC in the MNI‐based method. Nevertheless, both methods comparably revealed LC rs‐fc to multiple brain regions including ACC, bilateral thalamus, and cerebellum. Our results are relevant for further research assessing and interpreting LC function, especially in patient populations examined at 3 T MRI.
TGF-β2 silencing to target biliary-derived liver diseases
2020-01-28

Objective TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases. Design As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels. Results TgfB2 -induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2 -directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3 , Ccl4 , Ccl5 , Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue. Conclusions Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.
Sex differences in muscle activity and motor variability in response to a non-fatiguing repetitive screwing task
2020-01-28

Abstract Background Musculoskeletal disorders are more prevalent among women than among men, which may be explained by aspects of motor control, including neuromuscular requirements and motor variability. Using an exploratory approach, this study aimed to evaluate sex differences in neuromuscular responses and motor variability during a repetitive task performed on 3 days. Methods Thirty women and 27 men performed the non-fatiguing, repetitive, 1-h screwing task. For neuromuscular responses, the mean and difference values of static, median, and peak percentile muscle activity levels (normalized to a reference voluntary contraction force) and, for motor variability, the mean and difference values of relative and absolute cycle-to-cycle variability across days were compared between both sexes for each muscle. A mixed-design analysis of variance was used to assess differences between both sexes. Results The non-fatiguing character of the screwing task was confirmed by the absence of decreased force levels in maximal voluntary contractions performed before and after the task and by absence of electromyographic signs of muscle fatigue. The static and median muscle activity levels tended to be higher among women (on average 7.86 and 27.23 %RVE) than men (on average 6.04 and 26.66 %RVE). Relative motor variability of the flexor and biceps muscles and absolute motor variability of both upper arm muscles were lower in women (on average 0.79 and 29.70 %RVE) than in men (on average 0.89 and 37.55 %RVE). The median activity level of both upper arms muscles tended to decrease within days among women (on average - 2.63 %RVE) but increase among men (on average + 1.19 %RVE). Absolute motor variability decreased within days among women (on average - 5.32 to - 0.34%RVE), whereas it tended to decrease less or increase within days among men (on average - 1.21 to + 0.25 %RVE). Conclusion Women showed higher levels of muscle activity and lower initial relative and absolute motor variability than males when performing the same occupational task, implying women may have a higher risk for developing disorders and point to both sexes using different intrinsic motor control strategies in task performance. Clearly, biological aspects alone cannot explain why women would be at higher risk for developing disorders than men. Therefore, a wider range of individual and environmental factors should be taken into account for optimizing work station designs and organizations by taking into account sex differences.