julilili42/papers huggingface dataset:
Organ-on-a-disc: A platform technology for the centrifugal generation and culture of microphysiological 3D cell constructs amenable for automation and parallelization
2020-10-01

Organ-on-a-chip (OoC) systems have evolved to a promising alternative to animal testing and traditional cell assays in drug development and enable personalization for precision medicine. So far, most OoCs do not fully exploit the potential of microfluidic systems regarding parallelization and automation. To date, many OoCs still consist of individual units, integrating only one single tissue per chip, and rely on manual, error-prone handling. However, with limited parallelization and automation, OoCs remain a low-throughput technology, preventing their widespread application in industry. To advance the concept of microphysiological systems and to overcome the limitations of current OoCs, we developed the Organ-on-a-disc (Organ-Disc) technology. Driven only by rotation, Organ-Discs enable the parallelized generation and culture of multiple 3D cell constructs per disc. We fabricated polydimethylsiloxane-free Organ-Discs using thermoplastic materials and scalable fabrication techniques. Utilizing precisely controllable centrifugal forces, cells were loaded simultaneously into 20 tissue chambers, where they formed uniform cell pellets. Subsequently, the cells compacted into dense 3D cell constructs and were cultured under vasculature-like perfusion through pump- and tubing-free, centrifugal pumping, solely requiring a low-speed rotation (&amp;lt;1 g) of the Organ-Disc. Here, we provide a proof-of-concept of the Organ-Disc technology, showing the parallelized generation of tissue-like cell constructs and demonstrating the controlled centrifugal perfusion. Furthermore, Organ-Discs enable versatile tissue engineering, generating cell constructs with a customizable shape and a layered multi-cell type structure. Overall, the Organ-Disc provides a user-friendly platform technology for the parallelization and automation of microphysiological systems, bringing this technology one-step closer to high-throughput applications in industry.
Protocol of a prospective, multicentre phase I study to evaluate the safety, tolerability and preliminary efficacy of the bispecific PSMAxCD3 antibody CC-1 in patients with castration-resistant prostate carcinoma
2020-10-01

Introduction Prostate cancer is the second most common cancer in men worldwide. When the disease becomes resistant to androgen-deprivation therapy, treatment options are sparse. To address the high medical need in castration-resistant prostate cancer (CRPC), we generated a novel PSMAxCD3 bispecific antibody termed CC-1. CC-1 binds to prostate-specific membrane antigen that is expressed on prostate cancer cells and tumour vessels, thereby allowing a dual anticancer effect. Methods and analysis This first in human clinical study is a prospective and multicentre trial which enrols patients with metastatic CRPC after failure of established third-line therapy. CC-1 is applied after prophylactic interleukin-6 receptor blockade with tocilizumab (once 8 mg/kg body weight). Each patient receives at least one cycle of CC-1 over a time course of 7 days in an inpatient setting. If clinical benefit is observed, up to five additional cycles of CC-1 can be applied. The study is divided in two parts: (1) a dose escalation phase with intraindividual dose increase from 28 μg to the target dose of 1156 μg based on a modified fast titration design by Simon et al to determine safety, tolerability and the maximum tolerated dose (MTD) as primary endpoints and (2) a dose expansion phase with additional 14 patients on the MTD level of part (1) to identify first signs of efficacy. Secondary endpoints compromise overall safety, tumour response, survival and a translational research programme with, among others, the analysis of CC-1 half-life, the induced immune response, as well as the molecular profiling in liquid biopsies. Ethics and dissemination The PSMAxCD3 study was approved by the Ethics Committee of The University Hospital Tübingen (100/2019AMG1) and the Paul-Ehrlich-Institut (3684/02). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers ClinicalTrials.gov Registry ( NCT04104607 ) and ClinicalTrials.eu Registry (EudraCT2019-000238-20).
An Inclination Shallowing‐Corrected Early Triassic Paleomagnetic Pole for the North China Craton: Implication for the Mesozoic Geography of Proto‐Asia
2020-10-01

Abstract The Early Mesozoic is a key period for the formation of the Asia continent. In this study, in order to reconstruct the Early Mesozoic paleogeography of Proto‐Asia, we carried out a paleomagnetic study on the Early Triassic strata from the Chengde Basin in the northeastern North China Craton (NCC). Rock magnetic investigations reveal magnetite and hematite as the main magnetic carriers. Characteristic remanent magnetization directions from 21 sites show normal and reversed polarities and site‐mean directions pass fold tests. After inclination shallowing (IS) correction with the elongation/inclination method, a mean direction is calculated at D s / I s = 322.5°/39.5° ( k s = 32.6, α 95s = 5.7°) in stratigraphic coordinates. The corresponding Early Triassic paleomagnetic pole (λ/φ = 53.5°N/9.5°E, A 95 = 5.3°) overlaps with coeval poles that have also been corrected for IS reported from the western part of the NCC. This result indicates that there is no relative movement between the eastern and western parts of the NCC. With all IS‐corrected paleomagnetic poles, a mean Early Triassic pole is recalculated for the NCC at λ/φ = 59.4°N/13.4°E ( A 95 = 4.7°). We use this pole to reconstruct the paleogeography of Proto‐Asia and confirm previous studies that did not use IS corrections, in which two “triangle bay‐shaped” oceans, the Paleo‐Tethys Ocean and the Mongol‐Okhotsk Ocean, existed along the southern and northern margins of the unified NCC‐Mongolian Block (MOB). Clockwise rotations of the South China Craton and Siberia Craton relative to the NCC‐MOB during the Early Mesozoic led to the final closure of both oceans.
CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons
2020-10-01

ABSTRACT C-terminus of HSC70-interacting protein (CHIP) encoded by the gene STUB1 is a co-chaperone and E3 ligase that acts as a key regulator of cellular protein homeostasis. Mutations in STUB1 cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16) with widespread neurodegeneration manifesting as spastic-ataxic gait disorder, dementia and epilepsy. CHIP−/− mice display severe cerebellar atrophy, show high perinatal lethality and impaired heat stress tolerance. To decipher the pathomechanism underlying SCAR16, we investigated the heat shock response (HSR) in primary fibroblasts of three SCAR16 patients. We found impaired HSR induction and recovery compared to healthy controls. HSPA1A/B transcript levels (coding for HSP70) were reduced upon heat shock but HSP70 remained higher upon recovery in patient- compared to control-fibroblasts. As SCAR16 primarily affects the central nervous system we next investigated the HSR in cortical neurons (CNs) derived from induced pluripotent stem cells of SCAR16 patients. We found CNs of patients and controls to be surprisingly resistant to heat stress with high basal levels of HSP70 compared to fibroblasts. Although heat stress resulted in strong transcript level increases of many HSPs, this did not translate into higher HSP70 protein levels upon heat shock, independent of STUB1 mutations. Furthermore, STUB1(−/−) neurons generated by CRISPR/Cas9-mediated genome editing from an isogenic healthy control line showed a similar HSR to patients. Proteomic analysis of CNs showed dysfunctional protein (re)folding and higher basal oxidative stress levels in patients. Our results question the role of impaired HSR in SCAR16 neuropathology and highlight the need for careful selection of proper cell types for modeling human diseases.
Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense RASGRP2 Mutation
2020-10-01

Abstract Next-generation sequencing is increasingly applied during the diagnostic work-up of patients with bleeding diathesis and has facilitated the diagnosis of rare bleeding disorders such as inherited platelet function disorders. Mutations in RAS guanyl releasing protein 2 (RasGRP2), also known as calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), underlie a recently described platelet signal transduction abnormality. Here we present the case of a consanguineous family originating from Afghanistan with two siblings affected by recurrent severe mucocutaneous bleedings. Platelet function testing demonstrated a marked reduction of aggregation induced by collagen and adenosine diphosphate. Whole exome sequencing revealed a novel homozygous nonsense RASGRP2 mutation segregating with the bleeding disorder in the family.
Correlates of intellectual development before and after hemispherotomy: an analysis of 75 children and adolescents
2020-10-01

This study describes the intellectual development of 75 children and adolescents who underwent hemispherotomy. Furthermore, we aimed to reveal predicting factors on pre- and postsurgical development with a focus on the role of aetiology. We analysed presurgical and six-month postsurgical developmental and intellectual data of 75 patients (age range: 0.87-19.78 years) and divided them into two groups: a not severely impaired group in which outcome of intellectual functioning was reported based on FSIQ score, and a severely impaired group (not testable by IQ tests) in which intellectual developmental outcome was described based on developmental quotients instead. In the not severely impaired group (n = 31), the preoperative level of intellectual functioning was a strong predictor of postoperative intellectual outcome; for 22/31 (71%) patients, postoperative FSIQ and its subscales were similar to preoperative levels. Improvements were observed for FSIQ in five patients, only for Verbal IQ in one patient and only for Performance IQ in one further patient; significant losses occurred in two patients, only for Performance IQ in both. In the severely impaired group, 30/40 (75%) patients showed further development after surgery, nine (23%) patients had the same results as before surgery, and one (2%) patient showed regression. Longer duration of presurgical epilepsy was related to a marginally lower presurgical developmental level, and good seizure outcome was a predictor of better postoperative development. For all patients, early age at seizure onset and early lesion origin correlated with poorer presurgical intellectual development. Although an entire hemisphere was disconnected, most patients exhibited ongoing development after hemispherotomy or had at least the same preoperative intellectual status; deterioration was rare.
Combining epiGBS markers with long read transcriptome sequencing to assess differentiation associated with habitat inReynoutria(akaFallopia)
2020-10-01

Summary Despite the limitations of genetic bottlenecks, several invasive species appear to thrive in non-native ranges with extremely low levels of sequence-based genetic variation. We previously demonstrated differentiation of DNA methylation to habitat types of the highly clonal, genetically depauperate Japanese knotweeds using anonymous markers, but the functional relevance of this DNA methylation variation is unknown. Here, we sequenced the full transcriptome combined with a reduced representation bisulfite sequencing approach, epigenotyping by sequencing (epiGBS), to characterize the association among DNA methylation, functional transcripts and the diverse habitat types occupied by the invasive Reynoutria species. We identified 50,435 putative transcripts overall, of which 48,866 were annotated with the NCBI NR database. Of these 17,872 (35%) and 16,122 (32%) transcripts shared sequence identity with Arabidopsis thaliana and Beta vulgaris , respectively. We found genetic differentiation by habitat type suggesting the action of selection and a marginal pattern of differentiation of DNA methylation among habitats, which appears to be associated with sequence differences. However, we found no individual methylation loci associated with habitat, limiting our ability to make functional interpretations. Regardless of the source of variation in DNA methylation, these changes may represent an important component of the response to environmental conditions, particularly in highly clonal plants, but more fine scale genomics analysis is required to test if DNA methylation variation in this system is responsible for functional divergence.
“What Type of Activity Suits Me?”
2020-10-01

Abstract. Counseling is seen as a promising method for promoting exercise behavior. The aims of this study were (1) to describe the design of a novel counseling approach based on motives and goals in exercise and sport (COMET). The COMET approach considers individual preferences, while focusing on identifying suitable types of activities. Furthermore, (2) implementation of the counseling was evaluated. A survey was carried out where 37 and 56 participants, were asked about their satisfaction with the counseling. In-depth interviews were conducted with a subsample of seven participants. Sixteen counsellors were questioned about implementation fidelity. The results showed that the COMET approach was implemented successfully in a nonclinical setting. Overall, participants were satisfied with the counseling. They found the trial exercise sessions helpful, as they offered diverse experiences and the opportunity to reflect on them. One-to-one conversations with the counselor were also beneficial, allowing participants to identify their preferences. Implementation fidelity was good. Further research could examine the implementation of the COMET approach in different settings.
Indeterminate pronouns in Old English: a compositional semantic analysis
2020-10-01

Abstract Indeterminate pronouns in Old English (expressions like hwa ‘who/what’ and hwelc ‘which’) permit several interpretations in addition to their use as interrogative pronouns, for example readings as universal or existential quantifiers. They combine with morphological prefixes ( ge - ‘and, also’ and a - ‘always, ever’), which change the range of possible interpretations. Old English indeterminate pronouns are shown to contribute a crosslinguistically hitherto unattested pattern of available interpretations. In particular, bare indeterminate pronouns have a universal interpretation and ge -indeterminate pronouns can be both universal and existential. This paper offers an alternative semantic analysis in the spirit of Hamblin (Found Lang 10:41–53, 1973) and Shimoyama (Nat Lang Semant 14:139–173, 2006). A compositional semantics is given for the pronouns and the prefixes, which derives the available readings. The paper ends with a proposal for compositional semantic change relating Old English indeterminate pronouns to their modern descendants.
Towards the targeted assessment of relevant problems: Optimization of the distress Thermometer for adult neuro‐oncological patients
2020-10-01

Abstract Objective Generic psychosocial screening tools may not reflect the unique symptom profile of brain tumour patients (BTPs). The aim was to adapt the problem list of the distress thermometer (DT) for BTPs. Methods First, items of low relevance for BTPs were identified on basis of retrospective analyses. Second, relevant yet missing problems were identified via an extensive literature search, qualitative interviews with BTPs and experts, as well as an online expert survey. The resulting raw version of the adapted problem list in BTPs was subsequently pretested. Results In the first part, data of n = 657 BTPs were analysed. Twelve items (20%) were excluded in this step as they proved to be less relevant for BTPs (i.e., items were endorsed by less than 10% and without significant correlations to patients' DT score). In the second part, qualitative interviews and the online survey with 102 professionals led to the addition of 21 new and the modification and condensation of 17 relevant problems specific for BTPs. This adapted list was than successfully pretested in n = 19 patients, leading to the ‘distress thermometer brain tumour problem list’ (DT‐BT), consisting of 42 relevant problems. Conclusion The adapted problem list for the DT particularly reflects the neurological and psychosocial burden of an intracranial tumour and allows for the targeted assessment of the specific burdens and needs of BTPs. Our revised version of the DTs problem list (DT‐BT) should in the next step be widely validated in multinational samples.
Bringing context back into international business studies: own research experiences, reflections and suggestions for future research
2020-10-01

This paper argues for the inclusion of (cultural and institutional) context into International Business studies. It is based on own research experiences, findings, reflections and conclusions. Particular emphasis is put, among others, on (1) universalities, particularities and singularities in cross-national management research; (2) the superior explanatory power of detailed description of cultural differences compared to the mere provision of cultural distance scores; (3) the relevance of language differences as a topic for International Business studies; and (4) the importance of qualitative research for in-depth, contextualized International Business studies. This paper also calls for more phenomena driven, emic and interdisciplinary International Business research that focuses on real business problems as well as their societal implications.
Influence of beam quality on reference dosimetry correction factors in magnetic resonance guided radiation therapy
2020-10-01

Correction factors for reference dosimetry in magnetic resonance (MR) imaging-guided radiation therapy ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow><mml:msub><mml:mi>k</mml:mi> <mml:mrow><mml:mover><mml:mi>B</mml:mi> <mml:mo>→</mml:mo></mml:mover> <mml:mo>,</mml:mo> <mml:mi>M</mml:mi> <mml:mo>,</mml:mo> <mml:mi>Q</mml:mi></mml:mrow> </mml:msub> </mml:mrow> </mml:math> ) are often determined in setups that combine a conventional 6 MV linac with an electromagnet. This study investigated whether results based on these measurements were applicable for a 7 MV MR-linac using Monte Carlo simulations. For a Farmer-type ionization chamber, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow><mml:msub><mml:mi>k</mml:mi> <mml:mrow><mml:mover><mml:mi>B</mml:mi> <mml:mo>→</mml:mo></mml:mover> <mml:mo>,</mml:mo> <mml:mi>M</mml:mi> <mml:mo>,</mml:mo> <mml:mi>Q</mml:mi></mml:mrow> </mml:msub> </mml:mrow> </mml:math> was assessed for different tissue-phantom ratios ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:msub><mml:mrow><mml:mi>TPR</mml:mi></mml:mrow> <mml:mrow><mml:mn>20</mml:mn> <mml:mo>,</mml:mo> <mml:mn>10</mml:mn></mml:mrow> </mml:msub> </mml:mrow> </mml:math> ). <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow><mml:msub><mml:mi>k</mml:mi> <mml:mrow><mml:mover><mml:mi>B</mml:mi> <mml:mo>→</mml:mo></mml:mover> <mml:mo>,</mml:mo> <mml:mi>M</mml:mi> <mml:mo>,</mml:mo> <mml:mi>Q</mml:mi></mml:mrow> </mml:msub> </mml:mrow> </mml:math> differed by <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>0.0029</mml:mn> <mml:mo>(</mml:mo> <mml:mn>43</mml:mn> <mml:mo>)</mml:mo></mml:mrow> </mml:math> between <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:msub><mml:mrow><mml:mi>TPR</mml:mi></mml:mrow> <mml:mrow><mml:mn>20</mml:mn> <mml:mo>,</mml:mo> <mml:mn>10</mml:mn></mml:mrow> </mml:msub> <mml:mo>=</mml:mo> <mml:mn>0.6790</mml:mn> <mml:mrow><mml:mo>(</mml:mo> <mml:mn>23</mml:mn> <mml:mo>)</mml:mo></mml:mrow> </mml:mrow> </mml:math> (6 MV linac) and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:msub><mml:mrow><mml:mi>TPR</mml:mi></mml:mrow> <mml:mrow><mml:mn>20</mml:mn> <mml:mo>,</mml:mo> <mml:mn>10</mml:mn></mml:mrow> </mml:msub> <mml:mo>=</mml:mo> <mml:mn>0.7028</mml:mn> <mml:mrow><mml:mo>(</mml:mo> <mml:mn>14</mml:mn> <mml:mo>)</mml:mo></mml:mrow> </mml:mrow> </mml:math> (7 MV MR-linac) at <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mn>1.5</mml:mn> <mml:mi>T</mml:mi></mml:mrow> </mml:math> . The agreement was best in an orientation in which the secondary electrons were deflected to the stem of the ionization chamber.
New taxa of the water mite family Limnocharidae (Actinotrichida: Eylaoidea) parasitising tropical water bugs of the genusRhagoveliaMayr, 1865 (Hemiptera: Veliidae) reveal unsuspected diversity of larval morphologies
2020-10-01

The larval stage of Neolimnochares johnstoni Smith and Cook, 2005 is first described in detail, and the larva of a similar undescribed species, Neolimnochares sp. B, see Table 1, is recorded from Peru. Larvae attributed to Limnochares (Cyclothrix) australica Lundblad, 1941a Lundblad, O. (1941a), 'Neue Wassermilben. Vorläufige Mitteilung', Entomologisk Tidskrift, 62 (1‒2), 97‒121. [Google Scholar] by Martin and Smit (2002 Martin, P., and Smit, H. (2002), 'The Larval Morphology and Host of the Australian Water Mite Limnochares australica (Acari: Hydrachnidia: Limnocharidae)', Records of the Western Australian Museum, 20, 409‒414. [Google Scholar]) are considered to belong to Neolimnochares Lundblad, 1941c Lundblad, O. (1941c), 'Die Hydracarinenfauna Südbrasiliens und Paraguays. Erster Teil', Kungliga Svenska Vetenskapsakademiens Handlingar, (3) 19 (7): 1‒183, pls I‒V. [Google Scholar]. Neolimnocharinae subfam. n. is proposed and discussed. For larvae assigned to this subfamily, parasitic on veliid water bugs (Rhagovelia Mayr, 1865 Mayr, G.L. (1865), 'Diagnosen neuer Hemipteren II', Verhandlungen der kaiserlich-königlichen Zoologisch-Botanischen Gesellschaft in Wien, 15: 429–446. [Google Scholar]) and with extraordinary morphological modifications, new taxa are proposed: Veliacola gen. n., (V. mirificus sp. n., Madagascar); Archaeveliacola gen. n. (A. papuanus sp. n., Indonesia, A. smiti sp. n., Australia); Armaveliacola gen. n. (A. rhagoveliae sp. n., Madagascar, A. major sp. n., Madagascar, A. minor sp. n., Cameroon, Kenya); Isoveliacola gen. n. (I. costaricensis sp. n., Costa Rica, I. borneoensis sp. n., Indonesia). Additional records are: Veliacola sp. (Dominican Republic), Archaeveliacola sp. (Bolivia), and Isoveliacola sp. (Belize). Neolimnochares (Paracyclothrix) Lundblad, 1967 Lundblad, O. (1967), 'Wassermilben von Hinterindien', Arkiv för Zoologi, (2) 19 (21), 391‒419. [Google Scholar] is synonymised with Limnochares (Cyclothrix) Wolcott, 1905 Wolcott, R.H. (1905), 'A Review of the Genera of the Water Mites, Transactions of the American Microscopical Society, 26, 161–243.[Crossref] , [Google Scholar], resulting in Limnochares (Cyclothrix) hyaliniseta (Lundblad, 1969 Lundblad, O. (1969), 'Indische Wassermilben, Hauptsächlich von Hinterindien', Arkiv för Zoologi, 22 (10), 289‒443. [Google Scholar]) comb. n., and L. (C.) longimaxillaris (Lundblad, 1969 Lundblad, O. (1969), 'Indische Wassermilben, Hauptsächlich von Hinterindien', Arkiv för Zoologi, 22 (10), 289‒443. [Google Scholar]) comb. n. (both Myanmar). LSID: http://www.zoobank.org/urn:lsid:zoobank.org:pub:275E6D4B-98E7-4A26-B7C7-DABCCF73A9EA
My Friend Johann Baptist Metz
2020-10-01

Johann Baptist Metz died on December 2, 2019. He and Jürgen Moltmann shared a theological and personal friendship marked by affection and respect. It was an honest friendship and it lasted for over fifty years. It started when two texts met: Metz’s essay “God before Us” and Moltmann’s essay “The Category of Novum in Christian Theology.” Both were published in the volume To Honor Ernst Bloch (1965). This article is a personal reminiscence.