Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic divergence and differential gene expression between crustacean ecotypes across a marine thermal gradient

Environmental gradients between marine biogeographical provinces separate distinct faunal communities; in the absence of absolute dispersal barriers numerous species nonetheless occur on either side of such boundaries. While the regional populations of such widespread species tend to be morphologically indistinguishable from each other, genetic evidence suggests that they represent unique ecotypes, and likely even cryptic species, that may be uniquely adapted to their local environment. Here, we explored genomic divergence in four sympatric southern African decapod crustaceans whose ranges span the boundary between the cool-temperate west coast (south-eastern Atlantic) and the warm-temperate south coast (south-western Indian Ocean) near the southern tip of the African continent. Using genome-wide data, we found that all four species comprise distinct west- and south coast ecotypes, with molecular dating suggesting divergence during the Pleistocene. Using transcriptomic data from one of the decapod crustaceans, we further found a clear difference in gene expression profiles between the west- and south coast ecotypes. This was particularly clear in the individual from the south coast, which experienced a ‘transcriptomic shock’ at low temperatures that are more typical of the west coast and may explain their absence from that coastline. Our results shed new light on the processes involved in driving genomic divergence and incipient speciation.
Cytomegalovirus Generates Assembly Compartment in the Early Phase of Infection by Perturbation of Host-Cell Factors Recruitment at the Early Endosome/Endosomal Recycling Compartment/Trans-Golgi Interface

Beta-herpesviruses develop a unique structure within the infected cell known as an assembly compartment (AC). This structure, as large as the nucleus, is composed of host-cell-derived membranous elements. The biogenesis of the AC and its contribution to the final stages of beta-herpesvirus assembly are still unclear. In this study, we performed a spatial and temporal analysis of the AC in cells infected with murine CMV (MCMV), a member of the beta-herpesvirus family, using a panel of markers that characterize membranous organelle system. Out of 64 markers that were analyzed, 52 were cytosolic proteins that are recruited to membranes as components of membrane-shaping regulatory cascades. The analysis demonstrates that MCMV infection extensively reorganizes interface between early endosomes (EE), endosomal recycling compartment (ERC), and the trans-Golgi network (TGN), resulting in expansion of various EE-ERC-TGN intermediates that fill the broad area of the inner AC. These intermediates are displayed as over-recruitment of host-cell factors that control membrane flow at the EE-ERC-TGN interface. Most of the reorganization is accomplished in the early (E) phase of infection, indicating that the AC biogenesis is controlled by MCMV early genes. Although it is known that CMV infection affects the expression of a large number of host-cell factors that control membranous system, analysis of the host-cell transcriptome and protein expression in the E phase of infection demonstrated no sufficiently significant alteration in expression levels of analyzed markers. Thus, our study demonstrates that MCMV-encoded early phase function targets recruitment cascades of host cell-factors that control membranous flow at the EE-ERC-TGN interface in order to initiate the development of the AC.
Development of Resistance to 4’-Ethynyl-2-Fluoro-2’-Deoxyadenosine (EFdA) by WT and Nucleoside Reverse Transcriptase Inhibitor Resistant Human Immunodeficiency Virus Type 1

4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA, MK-8591, islatravir) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) with exceptional potency against WT and drug-resistant HIV strains. However, HIV resistance to EFdA is not well characterized. We therefore developed resistance to EFdA by serial passages using progressively increasing concentrations of EFdA. The starting virus was either WT or clinically relevant NRTI-resistant viruses K65R, M184V, and D67N/K70R/T215F/K219Q). In all cases, the selected mutations included M184V. Additional mutations in the RT connection domain (R358K and E399K) and one mutation in the RNase H domain (A502V) were noted. Site-specific mutagenesis validated the role for M184V as the primary determinant for resistance to EFdA; none of the connection domain mutations contributed significantly to phenotypic resistance to EFdA. A novel EFdA resistance mutation was also observed in the background of M184V. The A114S/M184V combination of mutations imparted higher resistance to EFdA (~24-fold) than M184V (−8-fold) or A114S (~2-fold) alone. Virus fitness data suggested that A114S affects HIV fitness by itself and in the presence of M184V. This is consistent with biochemical experiments that showed decreases in the enzymatic efficiency (kcat/Km) of WT RT vs. A114S (2.1-fold) and A114S/M184V/502V (6.5-fold), whereas there was no significant effect of A502V on RT or virus fitness. The observed EFdA resistance of M184V by itself and in combination with A114S combined with the strong published in vitro and in vivo data, confirm that EFdA is an excellent candidate as a potential HIV therapeutic.
Mental chronometry of speaking in dialogue: Semantic interference turns into facilitation

Numerous studies demonstrate that the production of words is delayed when speakers process in temporal proximity semantically related words. Yet the experimental settings underlying this effect are different from those under which we typically speak. This study demonstrates that semantic interference disappears, and can even turn into facilitation, when semantically related words are embedded in a meaningful communicative exchange. Experiment 1 and 3 (each N=32 university students) implemented a picture-word interference task in a game played between two participants: one named the distractor word and, after a stimulus-onset-asynchrony of −150ms or −650ms, the other named a semantically related or unrelated target picture. Semantic interference reappeared with identical experimental parameters in a single-person picture-word interference setting (Experiment 2, N=32). We conclude that the inhibitory context effects leading to semantic interference in single-subject settings are attenuated whereas facilitatory effects are enhanced in communicative settings. Highlights In isolated speakers processing semantically related words interferes with speaking Yet we typically speak to communicate with others This study transfers picture-word interference to a communicative setting Semantically related words produced by a partner do not interfere with speaking
Catecholamines in Alzheimer's Disease: A Systematic Review and Meta-Analysis

Background and Purpose: Previous studies found inconsistent results regarding the relationship between Alzheimer's disease (AD) and catecholamines, such as dopamine (DA), norepinephrine (NE), and epinephrine (EPI). Therefore, the purpose of this study was to perform a systematic review and meta-analysis to evaluate the results of previous studies on this relationship. Method: Literature retrieval of eligible studies was performed in four databases (Web of Science, PubMed, Embase, and PsycARTICLES). Standardized mean differences (SMDs) were calculated to assess differences in catecholamine concentrations between the AD groups and controls. Results: Thirteen studies met the eligibility criteria. Compared with the controls, significant lower concentrations of NE (SMD = −1.10, 95% CI: −2.01 to −0.18, p = 0.019) and DA (SMD = −1.12, 95% CI: −1.88 to −0.37, p = 0.003) were observed in patients with AD. No difference was found in the concentrations of EPI between the two groups (SMD = −0.74, 95% CI: −1.85 to 0.37, p = 0.189). Conclusion: Overall, these findings are in line with the hypothesis that reduced NE and DA may be an important indicator for AD (Registration number CRD42018112816).
Study on Improvement of RNA Isolating Reagent Kit—TRIZOL

To isolate total RNA fromS accharomyces cerevisiae by the method of TRIZOL reagent kit, the RNA purified was rather not complete, since it showed band 5s rRNA only. After changing several steps of the method, the results showed that there appeared three clear bands—28s rRNA, 18s rRNA and 5s rRNA respectively with little RNA decomposed. The ratio of A260/A280 was 1.961, and A260/A230 2.070, so the purity was high.
Cholinergic neuromodulation of inhibitory interneurons facilitates functional integration in whole-brain models

Segregation and integration are two fundamental principles of brain structural and functional organization. Neuroimaging studies have shown that the brain transits between different functionally segregated and integrated states, and neuromodulatory systems have been proposed as key to facilitate these transitions. Although computational models have reproduced the effect of neuromodulation at the whole-brain level, the role of local inhibitory circuits and their cholinergic modulation has not been studied. In this article, we consider a Jansen & Rit whole-brain model in a network interconnected using a human connectome, and study the influence of the cholinergic and noradrenergic neuromodulatory systems on the segregation/integration balance. In our model, a newly introduced local inhibitory feedback enables the integration of whole-brain activity, and its modulation interacts with the other neuromodulatory influences to facilitate the transit between different functional states. Our work proposes a new possible mechanism behind segregation and integration in the brain.
A Novel and Potent Thrombolytic Fusion Protein Consisting of Anti-Insoluble Fibrin Antibody and Mutated Urokinase

Abstract Tissue plasminogen activator (tPA) is used clinically because it has a higher binding specificity for insoluble fibrin (IF) than urokinase (UK), but even pro-tPA has catalytic activity against substrates other than IF. UK has the advantage that it is specifically activated on IF; however, it binds IF weakly. Previously, we established a monoclonal antibody (mAb) that recognizes a pit structure formed only in IF. Here, we developed a new mAb against the pit, 1101, that does not affect coagulation or fibrinolysis, and prepared a fusion protein of UK with humanized 1101 Fab to transport UK selectively to IF. In IF-containing lesions, UK is cleaved by plasmin at two sites, Lys158/Ile159 and Lys135/Lys136. Cleavage of the former leads to activation of UK; however, because activated UK is linked by S-S bonds before and after cleavage, it is not released from the fusion. Cleavage at the latter site causes UK to leave the fusion protein; hence, we mutated Lys135/Lys136 to Gly135/Gly136 to prevent release of UK. This engineered UK-antibody fusion, AMU1114, significantly decreased the reduction of plasma plasminogen levels in vivo relative to UK. In a photochemically induced mouse model of thrombus, the vascular patency rate was 0% (0/10) in the control, 50% (5/10) in the tPA treatment group, and 90% (9/10) in the AMU1114 treatment group. Although no death was observed 1 hour after administration of each thrombolytic agent, some mice died within 24 hours in all treatment groups, including control. These data indicate the need for further basic studies of AMU1114.
Limitation of phosphate assimilation maintains cytoplasmic magnesium homeostasis

Significance Phosphorus (P) is essential for life. As the fifth-most-abundant element in living cells, P is required for the synthesis of an array of biological molecules including (d)NTPs, nucleic acids, and membranes. Organisms typically acquire environmental P as inorganic phosphate (Pi). While essential for growth and viability, excess intracellular Pi is toxic for both bacteria and eukaryotes. Using the bacterium Salmonella enterica serovar Typhimurium as a model, we establish that Pi cytotoxicity is manifested following its assimilation into adenosine triphosphate (ATP), which acts as a chelating agent for Mg2+ and other cations. Our findings identify physiological processes disrupted by excessive Pi and how bacteria tune P assimilation to cytoplasmic Mg2+ levels. Phosphorus (P) is an essential component of core biological molecules. In bacteria, P is acquired mainly as inorganic orthophosphate (Pi) and assimilated into adenosine triphosphate (ATP) in the cytoplasm. Although P is essential, excess cytosolic Pi hinders growth. We now report that bacteria limit Pi uptake to avoid disruption of Mg2+-dependent processes that result, in part, from Mg2+ chelation by ATP. We establish that the MgtC protein inhibits uptake of the ATP precursor Pi when Salmonella enterica serovar Typhimurium experiences cytoplasmic Mg2+ starvation. This response prevents ATP accumulation and overproduction of ribosomal RNA that together ultimately hinder bacterial growth and result in loss of viability. Even when cytoplasmic Mg2+ is not limiting, excessive Pi uptake increases ATP synthesis, depletes free cytoplasmic Mg2+, inhibits protein synthesis, and hinders growth. Our results provide a framework to understand the molecular basis for Pi toxicity. Furthermore, they suggest a regulatory logic that governs P assimilation based on its intimate connection to cytoplasmic Mg2+ homeostasis.
Chronic Pain Patients Exhibit Individually Unique Cortical Signatures of Pain

We investigated how the trajectory of pain patients’ ongoing and fluctuating pain is encoded in the brain. In repeated fMRI sessions, 20 chronic back pain patients and 20 chronic migraineurs were asked to continuously rate the intensity of their endogenous pain. Linear mixed effects models were used to disentangle cortical processes related to pain intensity and to pain intensity changes. We found that the intensity of pain in chronic back pain patients is encoded in the anterior insula, the frontal operculum, and the pons; the change of pain of chronic back pain and chronic migraine patients is mainly encoded in the anterior insula. At the individual level, we identified a more complex picture where each patient exhibited their own signature of endogenous pain encoding. The diversity of the individual cortical signatures of chronic pain encoding results adds to the understanding of chronic pain as a complex and multifaceted disease.
Seasonal and long-term consequences of esca on grapevine stem xylem integrity

Hydraulic failure has been extensively studied during drought-induced plant dieback, but its role in plant-pathogen interactions is under debate. During esca, a grapevine (Vitis vinifera) disease, symptomatic leaves are prone to irreversible hydraulic dysfunctions but little is known about the hydraulic integrity of perennial organs over the short- and long-term. We investigated the effects of esca on stem hydraulic integrity in naturally infected plants within a single season and across season(s). We coupled in vivo X-ray microtomography visualizations with direct (ks) and indirect (kth) hydraulic conductivity measurements, and tylose and vascular pathogen detection. Although no loss of hydraulic conductivity (PLC) was observed in asymptomatic and 40% of symptomatic stems, 60% of symptomatic stems presented xylem occlusions with subsequent PLC, which could reach critical levels (over 50% PLC). A loss of stem ks was observed simultaneously, or after, the occurrence of leaf symptoms in the presence of tyloses. The impact of esca on xylem integrity was only seasonal and no long-term impact of disease history was recorded. Our study demonstrated how and to what extent a vascular disease such as esca, affecting xylem integrity, could amplify plant mortality by hydraulic failure.
ClinePlotR: Visualizing genomic clines and detecting outliers in R

Patterns of multi-locus differentiation (i.e., genomic clines) often extend broadly across hybrid zones and their quantification can help diagnose how species boundaries are shaped by adaptive processes, both intrinsic and extrinsic. In this sense, the transitioning of loci across admixed individuals can be contrasted as a function of the genome-wide trend, in turn allowing an expansion of clinal theory across a much wider array of biodiversity. However, computational tools that serve to interpret and consequently visualize ‘genomic clines’ are limited. Here, we introduce the ClinePlotR R-package for visualizing genomic clines and detecting outlier loci using output generated by two popular software packages, bgc and Introgress. ClinePlotR bundles both input generation (i.e, filtering datasets and creating specialized file formats) and output processing (e.g., MCMC thinning and burn-in) with functions that directly facilitate interpretation and hypothesis testing. Tools are also provided for post-hoc analyses that interface with external packages such as ENMeval and RIdeogram. Our package increases the reproducibility and accessibility of genomic cline methods, thus allowing an expanded user base and promoting these methods as mechanisms to address diverse evolutionary questions in both model and non-model organisms.
Discoidin Domain Receptors in Melanoma: Potential Therapeutic Targets to Overcome MAPK Inhibitor Resistance

Melanoma is a highly malignant skin cancer with high propensity to metastasize and develop drug resistance, making it a difficult cancer to treat. Current therapies targeting BRAF (V600) mutations are initially effective, but eventually tumors overcome drug sensitivity and reoccur. This process is accomplished in part by reactivating alternate signaling networks that reinstate melanoma proliferative and survival capacity, mostly through reprogramming of receptor tyrosine kinase (RTK) signaling. Evidence indicates that the discoidin domain receptors (DDRs), a set of RTKs that signal in response to collagen, are part of the kinome network that confer drug resistance. We previously reported that DDR1 is expressed in melanomas, where it can promote tumor malignancy in mouse models of melanoma, and thus, DDR1 could be a promising target to overcome drug resistance. In this review, we summarize the current knowledge on DDRs in melanoma and their implication for therapy, with emphasis in resistance to MAPK inhibitors.
Temporal and Reciprocal Relations Between Worry and Rumination Among Subgroups of Metacognitive Beliefs

Metacognitive theory provides strong foundation for hypothesizing relations between worry and rumination among subgroups of metacognitive beliefs. However, empirical exploration of prospective and reciprocal relations between worry and rumination are lacking. This study investigated the stability and relations between worry and rumination to better understand how they influence each other over time, and how different levels of metacognitive beliefs affect relations between (i) initial and future worry, and initial and future rumination, and (ii) the cross-lag relations between worry and rumination. Overall, 482 (Females = 63%) participants (Mean age = 26 years) participated in a two-wave data collection and completed the Metacognition Questionnaire (MCQ-30), the Ruminative Response Scale and the Penn State Worry Questionnaire (PSWQ). A multigroup two-wave autoregressive cross-lagged model was estimated. Multigroup autoregression analyses revealed that independent of participants being in the high or low metacognition group, initial levels of worry predicted future levels of worry, as was the case for rumination. Multigroup cross-lagged analyses revealed that initial levels of worry did not predict future levels of rumination in both high and low levels of metacognitions. However, initial rumination predicted future levels of worry in the high metacognitions group, which was not the case for the low metacognitions group. Thus, high levels of metacognitions do not only strengthen the relation between both present and future worry, present and future rumination, but also present rumination with future worry. This finding may imply that those with rumination related conditions at present are more likely in the future to show both rumination and worry related conditions. Conversely, those with worry related conditions show future worry related conditions. These findings may have implications for a clinical sample regarding the high complexity of rumination conditions that may proceed with multifinality causal pathways especially for individuals with high levels of metacognitions. This complexity may be a possible explanation for the limited success in other traditional treatment of rumination related conditions and the relatively high relapse rates for such conditions in clinical samples.
NWB Query Engines: Tools to Search Data Stored in Neurodata Without Borders Format

The Neurodata Without Borders (abbreviation NWB) format is a current technology for storing neurophysiology data along with the associated metadata. Data stored in the format is organized into separate HDF5 files, each file usually storing the data associated with a single recording session. While the NWB format provides a structured method for storing data, so far there have not been tools which enable searching a collection of NWB files in order to find data of interest for a particular purpose. We describe here three tools to enable searching NWB files. The tools have different features making each of them most useful for a particular task. The first tool, called the NWB Query Engine, is written in Java. It allows searching the complete content of NWB files. It was designed for the first version of NWB (NWB 1) and supports most (but not all) features of the most recent version (NWB 2). For some searches, it is the fastest tool. The second tool, called “search_nwb” is written in Python and also allow searching the complete contents of NWB files. It works with both NWB 1 and NWB 2, as does the third tool. The third tool, called “nwbindexer” enables searching a collection of NWB files using a two-step process. In the first step, a utility is run which creates an SQLite database containing the metadata in a collection of NWB files. This database is then searched in the second step, using another utility. Once the index is built, this two-step processes allows faster searches than are done by the other tools, but does not enable as complete of searches. All three tools use a simple query language which was developed for this project. Software integrating the three tools into a web-interface is provided which enables searching NWB files by submitting a web form.