julilili42/papers huggingface dataset:
Parental environmental effects are common and strong, but unpredictable, in Arabidopsis thaliana
2021-11-04

Abstract The phenotypes of plants can be influenced by the environmental conditions experienced by their parents. In some cases, such parental effects have been found to be adaptive, which has led to much speculation about their ecological and evolutionary significance. However, there is still much uncertainty about how common and how predictable parental environmental effects really are. We carried out a comprehensive test for parental effects of different environmental stresses in the model plant Arabidopsis thaliana . We subjected plants of three Arabidopsis genotypes to a broad range of biotic or abiotic stresses, or combinations thereof, and compared their offspring phenotypes in a common environment. The majority of environmental stresses (16 out of 24 stress treatments) caused significant parental effects, in particular on plant biomass and reproduction, with positive or negative effects ranging from −35% to +38% changes in offspring fitness. The expression of parental effects was strongly genotype-dependent, with some effects only present in some genotypes but absent, or even in the opposite direction, in others. Parental effects of multiple environmental stresses were often non-additive, and their effects can thus not be predicted from what we know about the effects of individual stresses. Intriguingly, the direction and magnitude of parental effects were unrelated to the direct effects on the parents: some stresses did not affect the parents but caused substantial effects on offspring, while for others the situation was reversed. In summary, parental environmental effects are common and often strong in A. thaliana , but they are genotype-dependent and difficult to predict. Significance Stress experienced by plants can alter the phenotypes of their offspring. To understand the ecological and evolutionary significance of such parental effects, we must know how common and how predictable they are. In a large experiment with Arabidopsis thaliana , we show that the majority of 24 environmental stresses cause significant, and often strong, positive or negative parental effects. However, we also find that parental effects are genotype-specific and unrelated to the direct effect of individual stresses, and that multiple stresses often act in non-additive ways across generations. Thus, parental effects appear to be common and strong, but difficult to predict. Our findings have important implications for the study of plant responses to environmental change, and the design of stress experiments.
Ancient genomes from the last three millennia support multiple human dispersals into Wallacea
2021-11-05

Abstract Previous research indicates that the human genetic diversity found in Wallacea - islands in present-day Eastern Indonesia and Timor-Leste that were never part of the Sunda or Sahul continental shelves - has been shaped by complex interactions between migrating Austronesian farmers and indigenous hunter-gatherer communities. Here, we provide new insights into this region’s demographic history based on genome-wide data from 16 ancient individuals (2600-250 yrs BP) from islands of the North Moluccas, Sulawesi, and East Nusa Tenggara. While the ancestry of individuals from the northern islands fit earlier views of contact between groups related to the Austronesian expansion and the first colonization of Sahul, the ancestry of individuals from the southern islands revealed additional contributions from Mainland Southeast Asia, which seems to predate the Austronesian admixture in the region. Admixture time estimates for the oldest individuals of Wallacea are closer to archaeological estimates for the Austronesian arrival into the region than are admixture time estimates for present-day groups. The decreasing trend in admixture times exhibited by younger individuals supports a scenario of multiple or continuous admixture involving Papuan- and Asian-related groups. Our results clarify previously debated times of admixture and suggest that the Neolithic dispersals into Island Southeast Asia are associated with the spread of multiple genetic ancestries.
Targeting Cancer Chemotherapy Resistance by Precision Medicine-Driven Nanoparticle-Formulated Cisplatin
2021-11-05

Therapy resistance is the major cause of cancer death. As patients respond heterogeneously, precision/personalized medicine needs to be considered, including the application of nanoparticles (NPs). The success of therapeutic NPs requires to first identify clinically relevant resistance mechanisms and to define key players, followed by a rational design of biocompatible NPs capable to target resistance. Consequently, we employed a tiered experimental pipeline from <i>in silico</i> to analytical and <i>in vitro</i> to overcome cisplatin resistance. First, we generated cisplatin-resistant cancer cells and used next-generation sequencing together with CRISPR/Cas9 knockout technology to identify the ion channel LRRC8A as a critical component for cisplatin resistance. LRRC8A's cisplatin-specificity was verified by testing free as well as nanoformulated paclitaxel or doxorubicin. The clinical relevance of LRRC8A was demonstrated by its differential expression in a cohort of 500 head and neck cancer patients, correlating with patient survival under cisplatin therapy. To overcome LRRC8A-mediated cisplatin resistance, we constructed cisplatin-loaded, polysarcosine-based core cross-linked polymeric NPs (NP<sub>Cis</sub>, Ø ∼ 28 nm) with good colloidal stability, biocompatibility (low immunogenicity, low toxicity, prolonged <i>in vivo</i> circulation, no complement activation, no plasma protein aggregation), and low corona formation properties. 2D/3D-spheroid cell models were employed to demonstrate that, in contrast to standard of care cisplatin, NP<sub>Cis</sub> significantly (<i>p</i> < 0.001) eradicated all cisplatin-resistant cells by circumventing the LRRC8A-transport pathway <i>via</i> the endocytic delivery route. We here identified LRRC8A as critical for cisplatin resistance and suggest LRRC8A-guided patient stratification for ongoing or prospective clinical studies assessing therapy resistance to nanoscale platinum drug nanoformulations versus current standard of care formulations.
Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex
2021-11-05

Background Fetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved. Methods We performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature. Results We identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene ( KIF21A ) was found. Conclusion Our study underlines the broad locus heterogeneity of FA with well-established and atypical genotype–phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.
NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia
2021-11-05

Abstract With more than 40 causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3:c.1165G&amp;gt;A: p.G389R, segregating with the phenotype. Further investigations with whole-exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3:c.980A&amp;gt;G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p.E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p.E327G substitution, located at the interface between monomers. On the contrary, the p.G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants.
Development of an agar-plug cultivation system for bioactivity assays of actinomycete strain collections
2021-11-05

Natural products are an important source of lead compounds for the development of drug substances. Actinomycetes have been valuable especially for the discovery of antibiotics. Increasing occurrence of antibiotic resistance among bacterial pathogens has revived the interest in actinomycete natural product research. Actinobacteria produce a different set of natural products when cultivated on solid growth media compared with submersed culture. Bioactivity assays involving solid media (e.g. agar-plug assays) require manual manipulation of the strains and agar plugs. This is less convenient for the screening of larger strain collections of several hundred or thousand strains. Thus, the aim of this study was to develop a 96-well microplate-based system suitable for the screening of actinomycete strain collections in agar-plug assays. We developed a medium-throughput cultivation and agar-plug assay workflow that allows the convenient inoculation of solid agar plugs with actinomycete spore suspensions from a strain collection, and the transfer of the agar plugs to petri dishes to conduct agar-plug bioactivity assays. The development steps as well as the challenges that were overcome during the development (e.g. system sterility, handling of the agar plugs) are described. We present the results from one exemplary screening campaign targeted to identify compounds inhibiting Agr-based quorum sensing where the workflow was used successfully. We present a novel and convenient workflow to combine agar diffusion assays with microtiter-plate-based cultivation systems in which strains can grow on a solid surface. This workflow facilitates and speeds up the initial medium throughput screening of natural product-producing actinomycete strain collections against monitor strains in agar-plug assays.
Direct Current Electrical Fields Improve Experimental Wound Healing by Activation of Cytokine Secretion and Erk1/2 Pathway Stimulation
2021-11-05

There is growing evidence that cell behaviors can be influenced by the direct current electric fields (EFs). Some behaviors may influence wound healing directly. This study aimed to investigate the effects of EF (200 mV/mm) on immortalized nontumorigenic human epidermal (HaCaT) cells. We established a setup that can transmit an EF and maintain a stable cell culture environment. An EF was applied to HaCaT cells, and scratch-assays were performed as a model of wound healing to observe cell migration. Proliferation was evaluated by mitochondrial activity, total protein, and DNA content. Secretion of healing-associated cytokines was evaluated via cytokine arrays, and Western blot was applied to investigate signaling pathway alterations. Compared with the control group, the migration of cells exposed to EFs significantly increased (p &lt; 0.01). After 7 days, the changes in proliferation also increased significantly (p &lt; 0.05). The cytokine arrays revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) was the most abundant factor secreted by HaCaT following EF exposure. The signals for phospho-Erk1/2 showed a significant (p &lt; 0.0001) increase following EF exposure. The results demonstrate that exposure of HaCaT cells to EFs has positive effects on migration, proliferation, and cytokine secretion—three important steps in wound healing—and these effects may be partially mediated by activation of the Erk1/2 signaling pathway.
Potters in Transition
2021-11-05

Abstract For many years, the Late Bronze/Iron Age transition in the southern Levant has been the subject of intense debates concerning chronological matters and cultural developments. Ceramic studies were often the focal point of the discussion, but they usually concentrated on the appearance of Aegean-style pottery in the southern Coastal Plain and the nearby Shephelah, while largely disregarding the indigenous pottery tradition. In this paper, I study the processes of continuity and change in ceramic shape morphology and decoration techniques of three important tell-sites in the Shephelah: Lachish, ʿAzẹqȧ (Tel Azekah) and Ekron. It will be shown that marked innovations took place during the transition to the Iron I. These were most likely triggered by the appearance of foreign potters who produced local Aegean-style wares and seem to have influenced the traditions of the indigenous ceramic workshops. Such insights not only allow a fine-tuning of the relative chronology of the region at the end of the second millennium BCE, but also illuminate the transmission of professional knowledge and cultural traits through the ages.
The Evolutionary Pattern of Language in English Fiction over the Last Two Centuries: Insights from Linguistic Concreteness and Imageability
2021-11-05

Fiction has come to play an essential part in human culture and life in recent centuries. Because of its importance, the language or discourse of fiction has been widely studied. Discerning the evolutionary pattern of language in fiction is greatly helpful in understanding the changes in human culture and society. However, most previous studies on literary language that made use of quantitative or computational methods restricted themselves to a few authors or groups and only took into account a relative short span of time. Furthermore, most of the quantitative analysis therein was based on a primary and rather primitive algorithm that summarizes the frequencies of linguistic units in corpora. To overcome these limitations, this study uses semantic similarity as computed by semi-supervised methods to examine diachronic changes. In this study, the three large-scale corpora representing the English language and English fiction were used to investigate the evolutionary patterns concerning diachronic concreteness/imageability. The data from the two measures are well mapped and shown to support the argument that English fiction, as a special genre, exhibits an evolutionary tendency towards increasing concreteness/imageability. This indicates that modern fiction may have become increasingly important in human society, but easier to read and process in words than 19th century English fiction. This study proposed that learnability, genre difference, the changes of population size, and the other factors might have caused the systemic change. The current study is thus an important contribution to understanding the evolutionary trend of language in fiction as well as understanding the development of the English language as a whole. This study creates a novel quantitative methodology and applies this to the examination of diachronic changes of language in literary works.
Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia
2021-11-06

3',5'-cyclic guanosine monophosphate (cGMP) is a druggable second messenger regulating cell growth and survival in a plethora of cells and disease states, many of which are associated with hypoxia. For example, in myocardial infarction and heart failure (HF), clinical use of cGMP-elevating drugs improves disease outcomes. Although they protect mice from ischemia/reperfusion (I/R) injury, the exact mechanism how cardiac cGMP signaling is regulated in response to hypoxia is still largely unknown. By monitoring real-time cGMP dynamics in murine and human cardiomyocytes using in vitro and in vivo models of hypoxia/reoxygenation (H/R) and I/R injury combined with biochemical methods, we show that hypoxia causes rapid but partial degradation of cGMP-hydrolyzing phosphodiesterase-3A (PDE3A) protein via the autophagosomal-lysosomal pathway. While increasing cGMP in hypoxia prevents cell death, partially reduced PDE3A does not change the pro-apoptotic second messenger 3',5'-cyclic adenosine monophosphate (cAMP). However, it leads to significantly enhanced protective effects of clinically relevant activators of nitric oxide-sensitive guanylyl cyclase (NO-GC). Collectively, our mouse and human data unravel a new mechanism by which cardiac cGMP improves hypoxia-associated disease conditions.
Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study
2021-11-07

Objective Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker‐based stratification and biomarker cascade of the likely most treatment‐relevant stage within the presymptomatic phase: the conversion stage. Methods We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single‐molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72 , GRN , or MAPT , and 174 mutation‐negative within‐family controls. Results In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra‐individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage‐dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity‐to‐onset. We estimate stage‐dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. Interpretation Blood NfL and pNfH provide dynamic stage‐dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker‐based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33–47
Metabolomics and Molecular Networking to Characterize the Chemical Space of Four Momordica Plant Species
2021-11-08

Momordica plant species (Cucurbitaceae), have been used for centuries in traditional medicine and for nutritional purposes. Plants from this family are thus claimed to be phytochemically rich, representing an inexhaustible source of natural products. However, the chemical space of these Momordica species has not yet been fully decoded, and due to the inherent complexity of plant metabolomes, the characterization of the Momordica phytochemistry remains challenging. Thus, in this study we propose the use of molecular networking to unravel the molecular families within the metabolomes of four Momordica species (M. cardiospermoides, M. balsamina, M. charantia and M. foetida) and highlight the relevance of molecular networking in exploring the chemotaxonomy of these plants. In silico annotation tools (Network Annotation Propagation and DEREPLICATOR) and an unsupervised substructure identification tool (MS2LDA) were also explored to complement the classical molecular networking output and integration using MolNetEnhancer within GNPS. This allowed for the visualisation of chemical classes and the variety of substructures within the molecular families. The use of computational tools in this study highlighted various classes of metabolites, such as a wide range of flavonoids, terpenoids and lipids. Herein, these species are revealed to be phytochemically rich plants consisting of many biologically active metabolites differentially distributed within the different species, with the metabolome of M. cardiospermoides dereplicated in this paper for the first time.