Miracle-dz/UniFAR-FTUs huggingface dataset:
On the prediction of protein abundance from RNA

In eukaryotes, mRNA abundance is often a poor proxy for protein abundance1–5. Despite this, the majority of methods used to dissect function in mammalian biology6 and for biomarker discovery in complex diseases7 involve manipulation or measurement of mRNA. The discrepancy between mRNA and protein abundance is likely due to several factors, including differences in the rates of translation and degradation between proteins and cell-types8, unequal contribution of individual splice variants to the production of a given protein9 and cell-type specific differences in splice variant use10. Here we performed experimental and computational time-series analysis of RNA-seq and mass-spectrometry of three key immune cell-types in human and mice and constructed mathematical mixed time-delayed splice variant models to predict protein abundances. These models had median correlations to protein abundance measurements of 0.79-0.94, which is a significant increase from the previously reported 0.21 on human protein atlas data1, and out-performed less complicated models without the usage of multiple splice variants and time-delay in cross-validation tests. We showed the importance of our models for biomarker discovery by re-analysing RNA-seq data from five different complex diseases, which led to the prediction of new disease proteins that were validated in multiple sclerosis. Our findings suggest that similar protein abundance models may be created for the most critical cell-types in the human body.
Comprehensive in virio structure probing analysis of the influenza A virus identifies a functional RNA structure involved in replication and segment interactions

The influenza A virus genome is segmented into eight viral RNAs (vRNA). Secondary structures on vRNA are thought to be involved in the viral proliferation process, such as intersegment interactions that are necessary for segment bundling. However, the functional RNA structure on vRNA is not well known because the secondary structure of vRNA in virion was partially unwound by binding viral non-specific RNA binding proteins in a sequence-independent manner. Here, we establish the global map of the vRNA secondary structure in virion using the combination of dimethyl sulfate (DMS)-seq and selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE)-seq. By integrating DMS-seq and SHAPE-seq analyses with robust statistical analysis, we inferred quite a few bases paired regions including a pseudoknot structure on segment 5. Notably, when cells were infected with the recombinant virus which had mutations in the pseudoknot structure, the impairment of replication and packaging was observed on the other specific segment. Moreover, we analyzed the comprehensive intersegment RNA interactions in virion by ligation of interacting RNA followed by high-throughput sequencing (LIGR-seq). Our LIGR-seq analysis revealed that the intersegment interactions of the specific segment became less frequent and rearranged in the recombinant virus in concordance with the strength of genome packaging impairment. Our data provide evidence that the functional RNA structure motif on the influenza A virus genome can affect the efficiency of replication and segment bundling through the segment interactions.
Memory reconsolidation impairments in sign-tracking to an audiovisual compound stimulus

Studies of memory reconsolidation of pavlovian memories have typically employed unimodal conditioned stimuli, despite the use of multimodal compound stimuli in other settings. Here we studied sign-tracking behaviour to a compound audiovisual stimulus. First, we observed not unexpectedly that sign-tracking was poorer to the audiovisual compound than to unimodal visual stimuli. Then, we showed that, depending on the parameters of compound stimulus re-exposure at memory reactivation, systemic MK-801 treatment either impaired extinction to improve signtracking at test, or disrupted reconsolidation to impair test behaviour. When memory reactivation consisted of re-exposure to only the auditory component of the compound stimulus, we observed sign-tracking impairments following MK-801 treatment, but only under certain test conditions. This was in contrast to the consistent impairment following reactivation with the full audiovisual compound. Moreover, the parameters of auditory stimulus presentation to enable MK-801-induced impairment at test varied depending on whether the stimulus was presented within or outside the training context. These findings suggest that behaviour under the control of appetitive pavlovian compound stimuli can be modulated by targeting both extinction and reconsolidation, and that it is not necessary to re-expose to the full compound stimulus in order to achieve a degree of modulation of behaviour.
Dynamin-related Irgm proteins modulate LPS-induced caspase-4 activation and septic shock

Inflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-4. Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-4 are largely unknown. This study identifies dynamin-related membrane remodeling proteins belonging to the family of Immunity related GTPases M clade (IRGM) as negative regulators of caspase-4 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2 aberrantly activate caspase-4-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles or gram-negative bacteria. Consequently, Irgm2-deficient mice display increased susceptibility to caspase-4-mediated septic shock in vivo. This Irgm2 phenotype is partly reversed by the simultaneous genetic deletion of the two additional Irgm paralogs Irgm1 and Irgm3, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-4 activation.
Evaluation of the Seroprevalence of Hepatit A and Vaccination Status in Children Aged Two and Sixteen Years

Ad dress for Cor res pon den ce: Nurcan Kolancalı MD, University of Health Sciences, Haydarpaşa Numune Training and Research Hospital, Clinic of Pediatrics, Istanbul, Turkey Phone: +90 543 823 57 25 E-mail: drnurcan86@gmail.com ORCID ID: orcid.org/0000-0002-1137-0440 Re cei ved: 15.02. 2017 Ac cep ted: 06.11. 2017 ©Copyright 2017 by Viral Hepatitis Society / Viral Hepatitis Journal published by Galenos Publishing House. ABSTRACT ÖZ
Comparison between proton magnetic resonance spectroscopy and high- performance liquid chromatography to quantify muscle carnosine in humans

Proton magnetic resonance spectroscopy (1H-MRS) has been used as a non-invasive alternative to quantify carnosine in human muscle. It is unclear whether 1H-MRS is a valid and reliable method. 1H-MRS validity and reliability was examined in a series of in vitro and in vivo studies. In the in vitro study, phantoms containing different concentrations of carnosine, imidazole, histidine and bovine serum albumin (BSA) were submitted to 1H-MRS to verify: 1) signal linearity; 2) whether other sources of imidazole could contribute to carnosine signal. In the in vivo study, carnosine was determined in the m. gastrocnemius by 1H-MRS and by high-performance liquid chromatography (HPLC, a reference method) in muscle biopsy samples from 16 young men. Test-retest reliability was determined with (n=10) and without (n=5) voxel repositioning and re-shimming. Convergent validity (n=16) was determined by comparing carnosine values obtained with 1H-MRS vs. HPLC. Discriminant validity (n=14) was determined by measuring carnosine before and after 4 weeks of β-alanine supplementation. In vitro carnosine signal showed excellent linearity (Pearson correlation: r=0.999). Histidine and imidazole, but not BSA, emitted quantifiable signals in the same chemical shift of carnosine. A clear loss in signal quality was shown in the signal obtained in vivo. 1H-MRS coefficient of variation without repositioning voxel was 6.6% and increased to 16.9% with voxel repositioning. 1H-MRS was able to detect a significant increase in muscle carnosine after β-alanine supplementation, both a substantial disagreement with HPLC was shown. 1HMRS showed adequate discriminant validity, but limited reliability and poor agreement with the reference method.
Identification of Conserved Evolutionary Trajectories in Tumors

Motivation As multi-region, time-series, and single cell sequencing data become more widely available, it is becoming clear that certain tumors share evolutionary characteristics with others. In the last few years, several computational methods have been developed with the goal of inferring the subclonal composition and evolutionary history of tumors from tumor biopsy sequencing data. However, the phylogenetic trees that they report differ significantly between tumors (even those with similar characteristics). Results In this paper, we present a novel combinatorial optimization method, CONETT, for detection of recurrent tumor evolution trajectories. Our method constructs a consensus tree of conserved evolutionary trajectories based on the information about temporal order of alteration events in a set of tumors. We apply our method to previously published datasets of 100 clear-cell renal cell carcinoma and 99 non-small-cell lung cancer patients and identify both conserved trajectories that were reported in the original studies, as well as new trajectories. Availability CONETT is implemented in C++ and available at https://github.com/ehodzic/CONETT.
A new form of actin assembly around the Shigella-containing vacuole regulates its intracellular niche

The enteroinvasive bacterium Shigella flexneri forces its uptake into non-phagocytic host cells through the translocation of T3SS effectors that subvert the actin cytoskeleton. Here, we report de novo actin polymerization after cellular entry around the bacterial containing vacuole (BCV) leading to the formation of a dynamic actin cocoon. This cocoon is thicker than any described cellular actin structure and functions as a gatekeeper for the cytosolic access of the pathogen. Host Cdc42, Toca-1, N-WASP, WIP, the Arp2/3 complex, cortactin, coronin, and cofilin are recruited to the actin cocoon. They are subverted by T3SS effectors, such as IpgD, IpgB1, and IcsB. IcsB immobilizes components of the actin polymerization machinery at the BCV. This represents a novel microbial subversion strategy through localized entrapment of host actin regulators causing massive actin assembly. We propose that the cocoon protects Shigella’s niche from canonical maturation or host recognition.
A Humanized Monoclonal Antibody against the Enzymatic Subunit of Ricin Toxin Rescues Rhesus macaques from the Lethality of Aerosolized Ricin

Ricin toxin (RT) ranks at the top of the list of potential bioweapons of concern to civilian and military personnel alike due to its high potential for morbidity and mortality after inhalation. In non-human primates, aerosolized ricin triggers a severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and severe necrotizing bronchiolitis and alveolitis. There are currently no approved countermeasures for ricin intoxication. In this report, we demonstrate the therapeutic potential of huPB10, a toxin-neutralizing humanized monoclonal antibody (MAb) against an immunodominant epitope on ricin’s enzymatic A chain (RTA). Five rhesus macaques that received intravenous huPB10 (10 mg/kg) four hours after lethal dose ricin aerosol exposure all survived the toxin challenge, as compared to control animals, which succumbed to ricin intoxication within 30 h. Antibody treatment at 12 h after ricin exposure resulted in the survival of only one of five monkeys, indicating that, in the majority of animals, ricin intoxication and local tissue damage had progressed beyond the point where huPB10 intervention was beneficial. Change in pro-inflammatory cytokine/chemokines levels in bronchial alveolar lavage fluids before and after toxin challenge successfully clustered monkeys based on survival, as well as treatment group. IL-6 was the most apparent marker of ricin intoxication. This study represents the first demonstration in nonhuman primates that the lethal effects of inhalational ricin exposure can be negated by a drug candidate and opens up a path forward for product development.
Interactions between DksA and Stress-Responsive Alternative Sigma Factors Control Inorganic Polyphosphate Accumulation in Escherichia coli

Inorganic polyphosphate (polyP) is an evolutionarily ancient, widely conserved biopolymer required for stress resistance and pathogenesis in diverse bacteria, but we do not understand how its synthesis is regulated. In this work, I gained new insights into this process by characterizing the role of the transcriptional regulator DksA in polyP regulation in Escherichia coli and identifying previously unknown links between polyP synthesis and the stress-responsive alternative sigma factors FliA, RpoN, and RpoE. ABSTRACT Bacteria synthesize inorganic polyphosphate (polyP) in response to a variety of different stress conditions. polyP protects bacteria by acting as a protein-stabilizing chaperone, metal chelator, or regulator of protein function, among other mechanisms. However, little is known about how stress signals are transmitted in the cell to lead to increased polyP accumulation. Previous work in the model enterobacterium Escherichia coli has indicated that the RNA polymerase-binding regulatory protein DksA is required for polyP synthesis in response to nutrient limitation stress. In this work, I set out to characterize the role of DksA in polyP regulation in more detail. I found that overexpression of DksA increases cellular polyP content (explaining the long-mysterious phenotype of dksA overexpression rescuing growth of a dnaK mutant at high temperatures) and characterized the roles of known functional residues of DksA in this process, finding that binding to RNA polymerase is required but that none of the other functions of DksA appear to be necessary. Transcriptomics revealed genome-wide transcriptional changes upon nutrient limitation, many of which were affected by DksA, and follow-up experiments identified complex interactions between DksA and the stress-sensing alternative sigma factors FliA, RpoN, and RpoE that impact polyP production, indicating that regulation of polyP synthesis is deeply entwined in the multifactorial stress response network of E. coli. IMPORTANCE Inorganic polyphosphate (polyP) is an evolutionarily ancient, widely conserved biopolymer required for stress resistance and pathogenesis in diverse bacteria, but we do not understand how its synthesis is regulated. In this work, I gained new insights into this process by characterizing the role of the transcriptional regulator DksA in polyP regulation in Escherichia coli and identifying previously unknown links between polyP synthesis and the stress-responsive alternative sigma factors FliA, RpoN, and RpoE.
Choosing what we like vs liking what we choose: How choice-induced preference change might actually be instrumental to decision-making

For more than 60 years, it has been known that people report higher (lower) subjective values for items after having selected (rejected) them during a choice task. This phenomenon is coined “choice-induced preference change” or CIPC, and its established interpretation is that of “cognitive dissonance” theory. In brief, if people feel uneasy about their choice, they later convince themselves, albeit not always consciously, that the chosen (rejected) item was actually better (worse) than they had originally estimated. While this might make sense from a pragmatic psychological standpoint, it is challenging from a theoretical evolutionary perspective. This is because such a cognitive mechanism might yield irrational biases, whose adaptive fitness would be unclear. In this work, we assume that CIPC is mostly driven by the refinement of option value representations that occurs during (and not after) difficult choices. This makes CIPC the epiphenomenal outcome of a cognitive process that is instrumental to the decision. Critically, our hypothesis implies novel predictions about how observed CIPC should relate to two specific meta-cognitive processes, namely: choice confidence and subjective certainty regarding pre-choice value judgments. We test these predictions in a behavioral experiment where participants rate the subjective value of food items both before and after choosing between equally valued items; we augment this traditional design with reports of choice confidence and subjective certainty about value judgments. The results confirm our predictions and provide evidence against the standard post-choice cognitive dissonance reduction explanation. We then discuss the relevance of our work in the context of the existing debate regarding the putative cognitive mechanisms underlying cognitive dissonance reduction.
Cells collectively reshape habitability of temperature by helping each other replicate

How the rising global temperatures affect organisms is a timely question. The conventional view is that high temperatures cause microbes to replicate slowly or die, both autonomously. Yet, microbes co-exist as a population, raising the underexplored question of whether they can cooperatively combat rising temperatures. Here we show that, at high temperatures, budding yeasts help each other and future generations of cells replicate by secreting and extracellularly accumulating glutathione - a ubiquitous heat-damage-reducing antioxidant. Yeasts thereby collectively delay and can halt population extinctions at high temperatures. As a surprising consequence, even for the same temperature, a yeast population can either exponentially grow, never grow, or grow after unpredictable durations (hours-to-days) of stasis, depending on its population density. Despite the conventional theory stating that heat-shocked cells autonomously die and cannot stop population extinctions, we found that non-growing yeast-populations at high temperatures - due to cells cooperatively accumulating extracellular glutathione - continuously decelerate and can eventually stop their approach to extinction, with higher population-densities stopping faster. We show that exporting glutathione, but not importing, is required for yeasts to survive high temperatures. Thus, cooperatively eliminating harmful extracellular agents – not glutathione’s actions inside individual cells – is both necessary and sufficient for surviving high temperatures. We developed a mathematical model - which is generally applicable to any cells that cooperatively replicate by secreting molecules - that recapitulates all these features. These results show how cells can cooperatively extend boundaries of life-permitting temperatures.
Short term effects of instrument assisted soft tissue mobilization on pain and activities of daily living in subjects with patellofemoral joint osteoarthritis – A randomized controlled trial.

Aim: To study the effectiveness of Instrument assisted soft tissue mobilization using M2T blade in Osteoarthritis of Patello-Femoral joint to reduce pain and improve Activities of daily living. Objectives: To compare the effectiveness of M2T blade and conventional physiotherapy with Conventional physiotherapy alone on pain and activities of daily living in subjects with patellofemoral joint osteoarthritis. Method: A Randomized controlled trial, 34 Patellofemoral osteoarthritis subjects were, divided in 2 groups. All the subjects were evaluated for Pain, Physical functioning of joints and the range of motion and outcome measures such as VAS, WOMAC and ROM which were noted on Day 1 of intervention and Day 7, both Pre and Post treatment. Results: Analysis was done using T-test, Subjects of Group A received M2T blade and Conventional physiotherapy showed significant improvement as compared to the subjects of group B which received Conventional physiotherapy only. Conclusion: Present study concluded that M2T blade along Conventional Physiotherapy was effective in improving VAS, WOMAC and ROM as compared to conventional Physiotherapy group with patellofemoral osteoarthritis subject.
Testing the efficacy of lionfish traps in the northern Gulf of Mexico

Spearfishing is currently the primary approach for removing invasive Indo-Pacific lionfish (Pterois volitans/miles complex) to mitigate their impacts to western Atlantic marine ecosystems. However, a substantial portion of lionfish spawning biomass is beyond the depth limits of SCUBA. Innovative technologies may offer an alternative means to target lionfish and allow for the development of a deepwater lionfish trap fishery, but the removal efficiency and potential environmental impacts of traps have not been evaluated. We tested a collapsible non-containment trap (the ‘Gittings trap’) near artificial reefs in the northern Gulf of Mexico. A total of 327 lionfish and 28 native fishes (4 of which regulated species) recruited to traps (i.e., number of fish observed within the trap footprint) during 82 trap sets, catching 144 lionfish and 29 native species. Lionfish recruitment was highest for single (versus paired) traps deployed <15 m from reefs with a 1-day soak time, for which mean lionfish and native species recruitment per trap were approximately 5 and 0.1, respectively. Gittings traps selected for larger lionfish (mean size 277 mm total length) compared to spearfishing (mean size 258 mm). Community impacts from Gittings traps appeared minimal given recruitment patterns and catch rates were >10X higher for lionfish versus native fishes. Gittings traps did not move on the bottom during two major storm events; however, further testing will be necessary to test trap movement with surface buoys. Additional research should also focus on design and operational modifications to improve Gittings trap deployment success (68% successfully opened on the seabed) and reduce lionfish escapement (56% escaped from traps upon retrieval). While removal efficiency for lionfish (12–24%) was far below that of spearfishing, study results demonstrate Gittings traps are suitable for future testing on deepwater natural reefs, which constitute >90% of the region’s reef habitat.
Isolation and characterization of SARS-CoV-2 from the first US COVID-19 patient

The etiologic agent of the outbreak of pneumonia in Wuhan China was identified as severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) in January, 2020. The first US patient was diagnosed by the State of Washington and the US Centers for Disease Control and Prevention on January 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens, and characterized the viral sequence, replication properties, and cell culture tropism. We found that the virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into two virus repositories, making it broadly available to the public health and research communities. We hope that open access to this important reagent will expedite development of medical countermeasures. Article Summary Scientists have isolated virus from the first US COVID-19 patient. The isolation and reagents described here will serve as the US reference strain used in research, drug discovery and vaccine testing.