Miracle-dz/UniFAR-FTUs huggingface dataset:
Respiratory chain Complex I of unparalleled divergence in diplonemids

Mitochondrial genes of Euglenozoa (Kinetoplastida, Diplonemea, and Euglenida) are notorious for being barely recognizable, raising the question of whether such divergent genes actually code for functional proteins. Here we demonstrate the translation and identify the function of five previously unassigned y genes encoded by mitochondrial DNA (mtDNA) of diplonemids. As is the rule in diplonemid mitochondria, y genes are fragmented, with gene pieces transcribed separately and then trans-spliced to form contiguous mRNAs. Further, y transcripts undergo massive RNA editing, including uridine insertions that generate up to 16-residue-long phenylalanine tracts, a feature otherwise absent from conserved mitochondrial proteins. By protein sequence analyses, MS, and enzymatic assays in Diplonema papillatum, we show that these y genes encode the subunits Nad2, -3, -4L, -6, and -9 of the respiratory chain Complex I (CI; NADH:ubiquinone oxidoreductase). The few conserved residues of these proteins are essentially those involved in proton pumping across the inner mitochondrial membrane and in coupling ubiquinone reduction to proton pumping (Nad2, -3, -4L, and -6) and in interactions with subunits containing electron-transporting Fe-S clusters (Nad9). Thus, in diplonemids, 10 CI subunits are mtDNA-encoded. Further, MS of D. papillatum CI allowed identification of 26 conventional and 15 putative diplonemid-specific nucleus-encoded components. Most conventional accessory subunits are well-conserved but unusually long, possibly compensating for the streamlined mtDNA-encoded components and for missing, otherwise widely distributed, conventional subunits. Finally, D. papillatum CI predominantly exists as a supercomplex I:III:IV that is exceptionally stable, making this protist an organism of choice for structural studies.
Antibiotic prophylaxis and clinical outcomes among older adults with recurrent urinary tract infection: cohort study

BACKGROUND clinical guidelines recommend antibiotic prophylaxis for preventing recurrent urinary tract infections (UTIs), but there is little evidence for their effectiveness in older adults. METHODS this was a retrospective cohort study of health records from 19,696 adults aged ≥65 with recurrent UTIs. We used prescription records to ascertain ≥3 months' prophylaxis with trimethoprim, cefalexin or nitrofurantoin. We used random effects Cox recurrent event models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of clinical recurrence (primary outcome), acute antibiotic prescribing and hospitalisation. RESULTS of 4,043 men and 15,653 women aged ≥65 with recurrent UTIs, 508 men (12.6%) and 2,229 women (14.2%) were prescribed antibiotic prophylaxis. In men, prophylaxis was associated with a reduced risk of clinical recurrence (HR, 0.49; 95% CI, 0.45-0.54), acute antibiotic prescribing (HR, 0.54; 95% CI, 0.51-0.57) and UTI-related hospitalisation (HR, 0.78; 95% CI, 0.64-0.94). In women, prophylaxis was also associated with a reduced risk of clinical recurrence (HR, 0.57; 95% CI, 0.55-0.59) and acute antibiotic prescribing (HR, 0.61; 95% CI, 0.59-0.62), but estimates of the risk of UTI-related hospitalisation were inconsistent between our main analysis (HR, 1.16; 95% CI, 1.05-1.28) and sensitivity analysis (HR, 0.82; 95% CI, 0.72-0.94). CONCLUSIONS antibiotic prophylaxis was associated with lower rates of UTI recurrence and acute antibiotic prescribing in older adults. To fully understand the benefits and harms of prophylaxis, further research should determine the frequency of antibiotic-related adverse events and the impact on antimicrobial resistance and quality of life.
Exploring major signaling cascades in melanomagenesis: a rationale route for targetted skin cancer therapy

Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.
Can Rates of Ocean Primary Production and Biological Carbon Export Be Related Through Their Probability Distributions?

We describe the basis of a theory for interpreting measurements of two key biogeochemical fluxes—primary production by phytoplankton (p, μg C · L−1 · day−1) and biological carbon export from the surface ocean by sinking particles (f, mg C · m−2 · day−1)—in terms of their probability distributions. Given that p and f are mechanistically linked but variable and effectively measured on different scales, we hypothesize that a quantitative relationship emerges between collections of the two measurements. Motivated by the many subprocesses driving production and export, we take as a null model that large‐scale distributions of p and f are lognormal. We then show that compilations of p and f measurements are consistent with this hypothesis. The compilation of p measurements is extensive enough to subregion by biome, basin, depth, or season; these subsets are also well described by lognormals, whose log‐moments sort predictably. Informed by the lognormality of both p and f we infer a statistical scaling relationship between the two quantities and derive a linear relationship between the log‐moments of their distributions. We find agreement between two independent estimates of the slope and intercept of this line and show that the distribution of f measurements is consistent with predictions made from the moments of the p distribution. These results illustrate the utility of a distributional approach to biogeochemical fluxes. We close by describing potential uses and challenges for the further development of such an approach.
Phylo‐PFP: improved automated protein function prediction using phylogenetic distance of distantly related sequences

Motivation: Function annotation of proteins is fundamental in contemporary biology across fields including genomics, molecular biology, biochemistry, systems biology and bioinformatics. Function prediction is indispensable in providing clues for interpreting omics‐scale data as well as in assisting biologists to build hypotheses for designing experiments. As sequencing genomes is now routine due to the rapid advancement of sequencing technologies, computational protein function prediction methods have become increasingly important. A conventional method of annotating a protein sequence is to transfer functions from top hits of a homology search; however, this approach has substantial short comings including a low coverage in genome annotation. Results: Here we have developed Phylo‐PFP, a new sequence‐based protein function prediction method, which mines functional information from a broad range of similar sequences, including those with a low sequence similarity identified by a PSI‐BLAST search. To evaluate functional similarity between identified sequences and the query protein more accurately, Phylo‐PFP reranks retrieved sequences by considering their phylogenetic distance. Compared to the Phylo‐PFP's predecessor, PFP, which was among the top ranked methods in the second round of the Critical Assessment of Functional Annotation (CAFA2), Phylo‐PFP demonstrated substantial improvement in prediction accuracy. Phylo‐PFP was further shown to outperform prediction programs to date that were ranked top in CAFA2. Availability and implementation: Phylo‐PFP web server is available for at http://kiharalab.org/phylo_pfp. php. Supplementary information: Supplementary data are available at Bioinformatics online.
Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features.

BACKGROUND & AIMS Genomic studies have revealed subtypes of pancreatic ductal adenocarcinoma (PDA) based on their molecular features, but different studies have reported different classification systems. It is a challenge to obtain high-quality, freshly frozen tissue for clinical analysis and determination of PDA subtypes. We aimed to redefine subtypes of PDA using a large number of formalin-fixed and paraffin-embedded PDA samples, which are more amenable to routine clinical evaluation. METHODS We collected PDA samples from 309 consecutive patients who underwent surgery from September 1996 through December 2010 at 4 academic hospitals in Europe; nontumor tissue samples were not included. Samples were formalin fixed and paraffin embedded. DNA and RNA were isolated; gene expression, targeted DNA sequencing, and immunohistochemical analyses were performed. We used independent component analysis to deconvolute normal, tumor, and microenvironment transcriptome patterns in samples. We devised classification systems from an unsupervised analysis using a consensus clustering approach of our data set after removing normal contamination components. We associated subtypes with overall survival and disease-free survival of patients using Cox proportional hazards regression with estimation of hazard ratios and 95% confidence interval. We used The Cancer Genome Consortium and International Cancer Genome Consortium PDA data sets as validation cohorts. RESULTS We validated the previously reported basal-like and classical tumor-specific subtypes of PDAs. We identified features of the PDA, including microenvironment gene expression patterns, that allowed tumors to be categorized into 5 subtypes, called pure basal like, stroma activated, desmoplastic, pure classical, and immune classical. These PDA subtypes have features of cancer cells and immune cells that could be targeted by pharmacologic agents. Tumor subtypes were associated with patient outcomes, based on analysis of our data set and the International Cancer Genome Consortium and The Cancer Genome Consortium PDA data sets. We also observed an exocrine signal associated with acinar cell contamination (from pancreatic tissue). CONCLUSIONS We identified a classification system based on gene expression analysis of formalin-fixed PDA samples. We identified 5 PDA subtypes, based on features of cancer cells and the tumor microenvironment. This system might be used to select therapies and predict patient outcomes. We found evidence that the previously reported exocrine-like (called ADEX) tumor subtype resulted from contamination with pancreatic acinar cells. ArrayExpress accession number: E-MTAB-6134.
The lack of environmental justice in Central and Eastern Europe.

scientists and grantees are performing basic studies of our susceptibility to environment-related disease: demonstrating that a carcinogen in cigarette smoke (benzo(a)pyrene) alters part of a gene to cause lung cancer . showing the effects of fetal exposure to PCBs . developing a strain of mouse that lacks functional estrogen receptors and that helps evaluate how some pesticides and other estrogen-like compounds might affect development and reproduction . discovering the genes for breast, ovarian, and prostate cancers . identifying women’s optimal days of fertility . seeking to reverse the damage from lead exposure . finding alternatives to traditional animal tests . pinpointing the functions of specific genes by eliminating them from specially bred mouse lines . discovering a way, using ordinary yeast cells, to isolate and clone genes and other fragments of genetic material more quickly . showing the effects of urban air on lung function .
A Coordinate-Free Construction of Scalable Natural Gradient

Most neural networks are trained using first-order optimization methods, which are sensitive to the parameterization of the model. Natural gradient descent is invariant to smooth reparameterizations because it is defined in a coordinate-free way, but tractable approximations are typically defined in terms of coordinate systems, and hence may lose the invariance properties. We analyze the invariance properties of the Kronecker-Factored Approximate Curvature (K-FAC) algorithm by constructing the algorithm in a coordinate-free way. We explicitly construct a Riemannian metric under which the natural gradient matches the K-FAC update; invariance to affine transformations of the activations follows immediately. We extend our framework to analyze the invariance properties of K-FAC applied to convolutional networks and recurrent neural networks, as well as metrics other than the usual Fisher metric.
The potential of wearable technology for monitoring social interactions based on interpersonal synchrony

Sensing data from wearables have been extensively evaluated for fitness tracking, health monitoring or rehabilitation of individuals. However, we believe that wearable sensing can go beyond the individual and offer insights into social dynamics and interactions with other users by considering multi-user data. In this work, we present a new approach to using wrist-worn wearables for social monitoring and the detection of social interaction features based on interpersonal synchrony - an approach transferable to smart-watches and fitness trackers. We build up on related work in the field of psychology and present a study where we collected wearable sensing data during a social event with 24 participants. Our preliminary results indicate differences in wearable sensing data during a social interaction between two people.
Characterizing Mobilized Virulence Factors and Multidrug Resistance Genes in Carbapenemase-Producing Klebsiella pneumoniae in a Sri Lankan Hospital

Limited data is available on the epidemiology and characteristics of carbapenem-resistant Enterobacteriaceae (CRE) and their associated plasmids or virulence determinants from Sri Lanka. Through whole genome sequencing of CREs from the intensive care units of a Sri Lankan teaching hospital, we identified a carbapenemase gene, blaOXA–181 in 10 carbapenemase-producing Klebsiella pneumoniae isolates (two strains of ST437 and eight strains of ST147) from 379 respiratory specimens. blaOXA–181 was carried in three variants of ColE-type plasmids. K. pneumoniae strains with ompK36 variants showed high minimum inhibitory concentrations to carbapenem. Furthermore, genes encoding for extended spectrum β-lactamases (ESBL), plasmid-mediated quinolone resistance (PMQR) determinants (qnr, aac(6′)-Ib-cr, and oqxAB) were present in all 10 strains. Amino acid substitution in chromosomal quinolone resistance-determining regions (QRDRs) gyrA (Ser83Ile) and parC (Ser80Ile) were also observed. All strains had yersiniabactin genes on mobile element ICEkp. Strict infection control practices and judicious use of antibiotics are warranted to prevent further spread of multidrug-resistant K. pneumoniae.
The NFκB subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells

The epithelial-mesenchymal transition (EMT) is a multistep dedifferentiation program important in tissue repair. Here, we examined the role of the transcriptional regulator NF-κB in EMT of primary human small airway epithelial cells (hSAECs). Surprisingly, transforming growth factor β (TGFβ) activated NF-κB/RELA proto-oncogene, NF-κB subunit (RELA) translocation within 1 day of stimulation, yet induction of its downstream gene regulatory network occurred only after 3 days. A time course of TGFβ-induced EMT transition was analyzed by RNA-Seq in the absence or presence of inducible shRNA-mediated silencing of RELA. In WT cells, TGFβ stimulation significantly affected the expression of 2,441 genes. Gene set enrichment analysis identified WNT, cadherin, and NF-κB signaling as the most prominent TGFβ-inducible pathways. By comparison, RELA controlled expression of 3,138 overlapping genes mapping to WNT, cadherin, and chemokine signaling pathways. Conducting upstream regulator analysis, we found that RELA controls six clusters of upstream transcription factors, many of which overlapped with a transcription factor topology map of EMT developed earlier. RELA triggered expression of three key EMT pathways: 1) the WNT/β-catenin morphogen pathway, 2) the JUN transcription factor, and 3) the Snail family transcriptional repressor 1 (SNAI1). RELA binding to target genes was confirmed by ChIP. Experiments independently validating WNT dependence on RELA were performed by silencing RELA via genome editing and indicated that TGFβ-induced WNT5B expression and downstream activation of the WNT target AXIN2 are RELA-dependent. We conclude that RELA is a master transcriptional regulator of EMT upstream of WNT morphogen, JUN, SNAI1–ZEB1, and interleukin-6 autocrine loops.
Will open access increase journal CiteScores? An empirical investigation over multiple disciplines

This paper empirically studies the effect of Open Access on journal CiteScores. We have found that the general effect is positive but not uniform across different types of journals. In particular, we investigate two types of heterogeneous treatment effect: (1) the differential treatment effect among journals grouped by academic field, publisher, and tier; and (2) differential treatment effects of Open Access as a function of propensity to be treated. The results are robust to a number of sensitivity checks and falsification tests. Our findings shed new light on Open Access effect on journals and can help stakeholders of journals in the decision of adopting the Open Access policy.
The Virology of Taterapox Virus In Vitro

Taterapox virus (TATV) is phylogenetically the closest related virus to variola—the etiological agent of smallpox. Despite the similarity, few studies have evaluated the virus. In vivo, TATV can infect several animals but produces an inapparent infection in wild-type mice; however, TATV does cause morbidity and mortality in some immunocompromised strains. We employed in vitro techniques to compare TATV to ectromelia (ECTV) and vaccinia (VACV) viruses. Both ECTV and TATV replicate efficiently in primate cell lines but TATV replicates poorly in murine cells lines. Furthermore, TATV induces cytopathic effects, but to a lesser extent than ECTV, and changes cytoskeletal networks differently than both ECTV and VACV. Bioinformatic studies revealed differences in several immunomodulator open reading frames that could contribute to the reduced virulence of TATV, which were supported by in vitro cytokine assays.
Learning End-to-end Autonomous Driving using Guided Auxiliary Supervision

Learning to drive faithfully in highly stochastic urban settings remains an open problem. To that end, we propose a Multi-task Learning from Demonstration (MT-LfD) framework which uses supervised auxiliary task prediction to guide the main task of predicting the driving commands. Our framework involves an end-to-end trainable network for imitating the expert demonstrator's driving commands. The network intermediately predicts visual affordances and action primitives through direct supervision which provide the aforementioned auxiliary supervised guidance. We demonstrate that such joint learning and supervised guidance facilitates hierarchical task decomposition, assisting the agent to learn faster, achieve better driving performance and increases transparency of the otherwise black-box end-to-end network. We run our experiments to validate the MT-LfD framework in CARLA, an open-source urban driving simulator. We introduce multiple non-player agents in CARLA and induce temporal noise in them for realistic stochasticity.
Investigation of the factors affecting the photothermal therapy potential of small iron oxide nanoparticles over the 730–840 nm spectral region

The use of superparamagnetic iron oxide nanoparticles (SPIONs) as a sensitizer in photothermal therapy (PTT) is relatively new and the origin of such a phenomenon is not known. Usually, large crystals and aggregated particles are preferred in the literature, suggesting that these increase the absorbance of particles at the irradiation wavelength, and hence, provide a larger temperature increase. This study has two major goals: identification of the key factors that affect the photo-induced temperature increase in well-controlled experiments and the influence of laser irradiation on nanoparticle properties. Small, biocompatible poly(acrylic acid) coated SPIONs (PAA/SPIONs) were used since they are more practical for future medical use than large aggregates. We studied the impact of three major laser-dependent variables, namely the wavelength (between 728 and 838 nm), intensity (1.85–9.76 W cm^−2) and power (105–800 mW) as well as attenuation at the irradiation wavelength, on photothermal heating achieved with PAA/SPIONs. Within the studied range of these variables, only the laser power plays a critical role on the magnitude of photothermal heating in solutions. There is no strong correlation between the attenuation at the excitation wavelength and the temperature increase. In addition, extensive characterization of SPIONs before and after irradiation revealed no significant difference, which supports the re-usability of SPIONs. Lastly, the PTT potential of these small PAA/SPIONs was demonstrated in vitro on HeLa cells. At these low laser powers no temperature increase in SPION-free water or cell death in SPION-free cells was detected. Hence, this study provides a new insight into the photothermal effect of SPIONs, provides a clear and repeatable experimental procedure and demonstrates great potential for small SPIONs to be exploited in PTT.
Robust optical polarization of nuclear spin baths using Hamiltonian engineering of nitrogen-vacancy center quantum dynamics

A robust and fast principle of optical hyperpolarization is proposed and demonstrated by using NV centers experimentally. Dynamic nuclear polarization (DNP) is an important technique that uses polarization transfer from electron to nuclear spins to achieve nuclear hyperpolarization. Combining efficient DNP with optically polarized nitrogen-vacancy (NV) centers offers promising opportunities for novel technological applications, including nanoscale nuclear magnetic resonance spectroscopy of liquids, hyperpolarized nanodiamonds as magnetic resonance imaging contrast agents, and the initialization of nuclear spin–based diamond quantum simulators. However, none of the current realizations of polarization transfer are simultaneously robust and sufficiently efficient, making the realization of the applications extremely challenging. We introduce the concept of systematically designing polarization sequences by Hamiltonian engineering, resulting in polarization sequences that are robust and fast. We theoretically derive sequences and experimentally demonstrate that they are capable of efficient polarization transfer from optically polarized NV centers in diamond to the surrounding 13C nuclear spin bath even in the presence of control errors, making the abovementioned novel applications possible.