Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic scores for predicting longevity in the Croatian oldest-old population

Longevity is a hallmark of successful ageing and a complex trait with a significant genetic component. In this study, 43 single nucleotide polymorphisms (SNPs) were chosen from the literature and genotyped in a Croatian oldest-old sample (85+ years, sample size (N) = 314), in order to determine whether any of these SNPs have a significant effect on reaching the age thresholds for longevity (90+ years, N = 212) and extreme longevity (95+ years, N = 84). The best models were selected for both survival ages using multivariate logistic regression. In the model for reaching age 90, nine SNPs explained 20% of variance for survival to that age, while the 95-year model included five SNPs accounting for 9.3% of variance. The two SNPs that showed the most significant association (p ≤ 0.01) with longevity were TERC rs16847897 and GHRHR rs2267723. Unweighted and weighted Genetic Longevity Scores (uGLS and wGLS) were calculated and their predictive power was tested. All four scores showed significant correlation with age at death (p ≤ 0.01). They also passed the ROC curve test with at least 50% predictive ability, but wGLS90 stood out as the most accurate score, with a 69% chance of accurately predicting survival to the age of 90.
AdpAlin regulates lincomycin and melanin biosynthesis by modulating precursors flux in Streptomyces lincolnensis

Lincomycin is one of the most important antibiotics. However, transcriptional regulation network of secondary metabolism in Streptomyces lincolnensis, the lincomycin producer, remained obscure. AdpA from S. lincolnensis (namely AdpAlin) has been proved to activate lincomycin biosynthesis. Here we found that both lincomycin and melanin took l‐tyrosine as precursor, and AdpAlin activated melanin biosynthesis as well. Three tyrosinases, MelC2, MelD2, and MelE, and one tyrosine peroxygenase, LmbB2, participated in lincomycin and melanin biosynthesis in different ways. For melanin biosynthesis, MelC2 was the only key enzyme required. For lincomycin biosynthesis, MelD2 and LmbB2 were positive factors and were suggested to convert l‐tyrosine to l‐dihydroxyphenylalanine (l‐DOPA). Otherwise, MelC2 and MelE were negative factors for lincomycin biosynthesis and they were supposed to oxidize l‐DOPA to generate melanin and certain unknown metabolite, respectively. Based on in silico analysis combined with electrophoretic mobility shift assays (EMSAs), we proved that AdpAlin directly interacted with promoters of melC, melD, and melE by binding to putative AdpA‐binding sites in vitro. Moreover, in vivo experiments revealed that AdpAlin positively regulated the transcription of melC and melE, but negatively regulated melD. In conclusion, AdpAlin was the switch of secondary metabolism in S. lincolnensis, and it modulated precursor flux of lincomycin and melanin biosynthesis by directly activating melC, melE, and lmbB1/lmbB2 or repressing melD.
Establishment of Cell-Based Assay System for Evaluating Cytotoxic Activity Modulated by the Blockade of PD-1 and PD-L1 Interactions with a Therapeutic Antibody

ABSTRACT Background Therapeutic antibodies targeting the PD-1/PD-L1 immune checkpoint are widely used in cancer therapy and are under active further development. Historically, the antitumor activity of PD-1/PD-L1 immune checkpoint inhibitors has been evaluated using in vivo and ex vivo test methods; however, a simple in vitro assay method to evaluate antitumor activity accurately is needed for the efficient development of new therapeutic agents. In the present study, we attempted to establish a simple cell-based assay system to evaluate the modulating effect of PD-1/PD-L1 immune checkpoint inhibitors on cytotoxic activity. Methods We established a new natural killer (NK) cell line stably transfected with the PD-1 and IL-2 genes and a new NK-sensitive target cell line stably transfected with the PD-L1 gene. Then, the assay system was established by co-cultivation of the established cell lines and measurement of the cytotoxic activities using the europium release assay. To confirm the performance of the established assay system, model therapeutic antibodies to block the PD-1/PD-L1 signal, nivolumab and atezolizumab were added to the co-culture system and the modulating effect on the cytotoxic activities were evaluated. Results Nivolumab and atezolizumab clearly showed a modulating effect on cytotoxic activity in a dose-dependent manner in our assay system, whereas a human IgG isotype control antibody did not show any modulating effect on the assay system. Conclusion The newly established cell-based assay system can quantitatively evaluate the modulating effect of PD-1/PD-L1 immune checkpoint inhibitors by measuring cytotoxic activity, playing an important role in antitumor effects as innate immunity.
Numerical analysis for relief gratings working in the soft x ray and XUV region by the integral equation method

Differential formalism gives a rapid convergence of accurate results even under conditions of propagation of several hundred spectral orders and grazing angles of incidence for the gratings with low groove-depth-to-groove-spacing ratio (h/d << 1) which are typical for this wavelength region. In the same way it was found that the rigorous results on the region of low (delta) /d ratios under the short time of computation may also be done through the modified integral method. By way of the programs created on the base of integral equations, the results done through the differential method were repeated and a good coincidence with them was found. These data allow us to speak about the equivalence of both methods -- integral and differential -- and about the convergence of algorithms.
Accuracy and reliability of self-administered visual acuity tests: Systematic review of pragmatic trials

Background: Remote self-administered visual acuity (VA) tests have the potential to allow patients and non-specialists to assess vision without eye health professional input. Validation in pragmatic trials is necessary to demonstrate the accuracy and reliability of tests in relevant settings to justify deployment. Methods: A systematic review was undertaken in accordance with a preregistered protocol (CRD42022385045). The Cochrane Library, Embase, MEDLINE, and Scopus were searched. Screening was conducted according to the following criteria: (1) English languge; (2) primary research article; (3) visual acuity test conducted remotely; (4) no clinical administration of remote test; (5) accuracy or reliability of remote test analysed. There were no restrictions on trial participants. Quality assessment was conducted with QUADAS-2. Results: Of 1227 identified reports, 10 studies were ultimately included. One study was at high risk of bias and two studies exhibited concerning features of bias; all studies were applicable. Three trials--of DigiVis, iSight Professional, and Peek Acuity--from two studies suggested that accuracy of the remote tests was comparable to clinical assessment. All other trials exhibited inferior accuracy, including conflicting results from a pooled study of iSight Professional and Peek Acuity. Two studies evaluated test-retest agreement--one trial provided evidence that DigiVis is as reliable as clinical assessment. The three most accurate tests required access to digital devices. Reporting was inconsistent and often incomplete, particularly with regards to describing methods and conducting statistical analysis. Conclusions: Remote self-administered VA tests appear promising, but further pragmatic trials are indicated to justify deployment at scale to facilitate patient or non-specialist led assessment which could augment teleophthalmology, non-specialist eye assessment, pre-consultation triage, and autonomous long-term monitoring of vision.
Variance WIE based infrared images processing

As a robust criterion to evaluate the complex degree of infrared (IR) backgrounds, the variance weighted information entropy (WIE) is applied to preprocess the IR small target images and detect the sea-sky line in sea-sky IR images. Experimental results show that the local variance WIE filter can evidently increase the signal-to-noise ratio of preprocessed images. In addition, the validity of the variance WIE based sea-sky line detection method is verified by experiments.
Seasonal variation in the Canastra cheese mycobiota

Canastra cheese is the most well-known artisanal cheese produced in Brazil. Although its production includes a step to remove fungi from the cheese surface, in recent years some cheesemakers have preserved the autochthonous fungi grown during ripening due to an interest in the sensory characteristics attributed to these microorganisms. In this work, the mycobiota of artisanal cheeses produced in the Canastra region was characterized based on ITS marker gene analysis. A total of 96 artisanal cheeses from 16 different farms across 9 cities were collected during two different periods (dry and wet seasons). The Canastra cheese mycobiota was significantly impacted by the season, the city of production and the farm but altitude did not affect the fungal community of the cheeses analyzed. Debaryomyces prosopidis was most abundant in the majority of samples across both seasons. During the wet season, Trichosporon asahii, Kluyveromyces lactis and Fusarium solani were the next most abundant species, followed by Torulaspora delbrueckii and Acremonium citrinum. These results highlight the importance of manufacturing practices and seasonality on the fungal composition of Canastra cheeses. These insights are particularly important in light of recent new regulation in Brazil, removing previous obstacles for surface fungi to persist on cheese. These new regulations will allow new approaches to cheese production, and ultimately, novel products.
Production of antigenically stable enterovirus A71 virus-like particles in Pichia pastoris as a vaccine candidate

Enterovirus A71 (EVA71) causes widespread disease in young children with occasional fatal consequences. In common with other picornaviruses, both empty capsids (ECs) and infectious virions are produced during the viral lifecycle. While initially antigenically indistinguishable from virions, ECs readily convert to an expanded conformation at moderate temperatures. In the closely related poliovirus, these conformational changes result in loss of antigenic sites required to elicit protective immune responses. Whether this is true for EVA71 remains to be determined and is the subject of this investigation. We previously reported the selection of a thermally resistant EVA71 genogroup B2 population using successive rounds of heating and passage. The mutations found in the structural protein-coding region of the selected population conferred increased thermal stability to both virions and naturally produced ECs. Here, we introduced these mutations into a recombinant expression system to produce stabilised virus-like particles (VLPs) in Pichia pastoris. The stabilised VLPs retain the native virion-like antigenic conformation as determined by reactivity with a specific antibody. Structural studies suggest multiple potential mechanisms of antigenic stabilisation, however, unlike poliovirus, both native and expanded EVA71 particles elicited antibodies able to directly neutralise virus in vitro. Therefore, the anti-EVA71 neutralising antibodies are elicited by sites which are not canonically associated with the native conformation, but whether antigenic sites specific to the native conformation provide additional protective responses in vivo remains unclear. VLPs are likely to provide cheaper and safer alternatives for vaccine production and these data show that VLP vaccines are comparable with inactivated virus vaccines at inducing neutralising antibodies.
SPI-1 virulence gene expression modulates motility of Salmonella Typhimurium in a proton motive force- and adhesins-dependent manner

Both the bacterial flagellum and the evolutionary related injectisome encoded on the Salmonella pathogenicity island 1 (SPI-1) play crucial roles during the infection cycle of Salmonella species. The interplay of both is highlighted by the complex cross-regulation that includes transcriptional control of the flagellar master regulatory operon flhDC by HilD, the master regulator of SPI-1 gene expression. Contrary to the HilD-dependent activation of flagellar gene expression, we report here that activation of HilD resulted in a dramatic loss of motility, which was dependent on the presence of SPI-1. Single cell analyses revealed that HilD-activation results in a SPI-1-dependent induction of the stringent response and a pronounced decrease of proton motive force (PMF), while flagellation was not affected. We further found that activation of HilD enhanced the adhesion of Salmonella to epithelial cells. A transcriptome analysis revealed a concomitant upregulation of several adhesin systems, which when overproduced, phenocopied the HilD-induced motility defect. We propose that a combination of SPI-1-dependent depletion of the PMF and upregulation of adhesins upon HilD-activation allows flagellated Salmonella to rapidly modulate their motility during infection, thereby enabling efficient adhesion to host cells and delivery of effector proteins.
Wolbachia-infected pharaoh ant colonies have higher egg production, metabolic rate, and worker survival

Wolbachia is a widespread endosymbiotic bacteria with diverse phenotypic effects on its insect hosts. Wolbachia also commonly infects social insects, where it faces unique challenges associated with its hosts’ caste-based reproductive division of labor and colony living. Here we dissect the benefits and costs of Wolbachia infection on life-history traits of pharaoh ants, Monomorium pharaonis. Pharaoh ants are relatively short-lived and show natural variation in Wolbachia infection between colonies, thereby making them an ideal model system for this study. We quantified effects on the lifespan of queen and worker castes, the egg-laying rate of queens across queen lifespan, and the metabolic rates of whole colonies and colony members. Newly-infected queens laid more eggs than uninfected queens but had similar metabolic rates and lifespans. Surprisingly, infected workers outlived uninfected workers. Infected colonies were more productive due to increased queen egg-laying rates and worker longevity, and infected colonies had higher metabolic rates during peak colony productivity. While some effects of infection, such as elevated colony-level metabolic rates may be detrimental in more stressful conditions, we did not find any costs of infection under laboratory conditions. Overall, our study emphasizes the beneficial effects of Wolbachia on colony-level growth and metabolism in this species.
Two teosintes made modern maize

Despite its global importance as a crop with broad economic, dietary, and cultural importance, the origins of maize and its closest wild relatives remained the topic of vigorous debate for nearly a century. Molecular analyses ultimately concluded that maize was domesticated once from a common ancestor with its closest extant relative, the lowland wild grass Zea mays ssp. parviglumis. But neither the current genetic model nor earlier models based on archaeological data account for the totality of available data, and recent work has highlighted the potential contribution of a second wild relative, the highland Zea mays ssp. mexicana. Here we present a detailed population genetic analysis of the contributions of both wild taxa to modern maize diversity using the largest sample of traditional maize varieties sequenced to date. We show that all modern maize can trace its origin to an ancient admixture event between domesticated ancient maize and Zea mays ssp. mexicana in the highlands of Mexico ca 5300 cal BP, some 4,000 years after domestication began. We show that variation in admixture is a key component of modern maize genetic and phenotypic diversity, both at the level of individual loci and as a factor driving a substantial component of additive genetic variation across a number of agronomic traits. Our results clarify the long-debated origin of modern maize, highlight the potential contributions of crop wild relatives to agronomic improvement, and raise new questions about the anthropogenic mechanisms underlying multiple waves of dispersal throughout the Americas. One-Sentence Summary Our results clarify the long-debated origin of modern maize and highlight the contributions of crop wild relatives to the agronomic improvement of modern varieties.
Identification of two β-cell subtypes by 7 independent criteria

Despite the recent explosion in surveys of cell-type heterogeneity, the mechanisms that specify and stabilize highly related cell subtypes remain poorly understood. Here, focusing initially on exploring quantitative histone mark heterogeneity, we identify two major sub-types of pancreatic β-cells (βHI and βLO). βHI and βLO cells differ in their size, morphology, cytosolic and nuclear ultrastructure, transcriptional output, epigenomes, cell surface marker, and function. Importantly, βHI and βLO cells can be FACS separated live into CD24+ (βHI) and CD24- (βLO) fractions. From an epigenetic viewpoint, βHI-cells exhibit ∼4-fold higher levels of H3K27me3, more compacted chromatin, and distinct chromatin organization that associates with a specific pattern of transcriptional output. Functionally, βHI cells have increased mitochondrial mass, activity, and insulin secretion both in vivo and ex vivo. Critically, Eed and Jmjd3 loss-of-function studies demonstrate that H3K27me3 dosage is a significant regulator of βHI / βLO cell ratio in vivo, yielding some of the first-ever specific models of β-cell sub-type distortion. βHI and βLO sub-types are conserved in humans with βHI-cells enriched in human Type-2 diabetes. These data identify two novel and fundamentally distinct β-cell subtypes and identify epigenetic dosage as a novel regulator of β-cell subtype specification and heterogeneity. Highlights Quantitative H3K27me3 heterogeneity reveals 2 common β-cell subtypes βHI and βLO cells are stably distinct by 7 independent sets of parameters H3K27me3 dosage controls βHI / βLO ratio in vivo βHI and βLO cells are conserved in humans and enriched in Type-2 diabetes
CALCIUM-DEPENDENT PROTEIN KINASE32 regulates cellulose biosynthesis through post-translational modification of cellulose synthase

Cellulose is an economically important source of food, paper, textiles, and biofuel. As an essential component of plant cell walls, cellulose is critical for plant cell growth. Despite its economic and biological significance, the regulation of cellulose biosynthesis is poorly understood. Phosphorylation and dephosphorylation of cellulose synthases (CESAs) were shown to impact the direction and velocity of cellulose synthase complexes (CSCs). Despite a high prevalence of phosphorylation sites in CESAs, the protein kinases that phosphorylate CESAs are largely unknown. Here, we demonstrate that CALCIUM-DEPENDENT PROTEIN KINASE32 (CPK32) regulates cellulose biosynthesis via phosphorylation of CESA3. Phosphorylation of CESA3 is important for the motility and stability of CSCs. Hence, we uncovered a new function of CPKs that regulates cellulose biosynthesis and a novel mechanism by which phosphorylation regulates the stability of CSCs.
When do longer reads matter? A benchmark of long read de novo assembly tools for eukaryotic genomes

Background Assembly algorithm choice should be a deliberate, well-justified decision when researchers create genome assemblies for eukaryotic organisms from third-generation sequencing technologies. While third-generation sequencing by Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) have overcome the disadvantages of short read lengths specific to next-generation sequencing (NGS), third-generation sequencers are known to produce more error-prone reads, thereby generating a new set of challenges for assembly algorithms and pipelines. Since the introduction of third-generation sequencing technologies, many tools have been developed that aim to take advantage of the longer reads, and researchers need to choose the correct assembler for their projects. Results We benchmarked state-of-the-art long-read de novo assemblers, to help readers make a balanced choice for the assembly of eukaryotes. To this end, we used 13 real and 72 simulated datasets from different eukaryotic genomes, with different read length distributions, imitating PacBio CLR, PacBio HiFi, and ONT sequencing to evaluate the assemblers. We include five commonly used long read assemblers in our benchmark: Canu, Flye, Miniasm, Raven and Redbean. Evaluation categories address the following metrics: reference-based metrics, assembly statistics, misassembly count, BUSCO completeness, runtime, and RAM usage. Additionally, we investigated the effect of increased read length on the quality of the assemblies, and report that read length can, but does not always, positively impact assembly quality. Conclusions Our benchmark concludes that there is no assembler that performs the best in all the evaluation categories. However, our results shows that overall Flye is the best-performing assembler, both on real and simulated data. Next, the benchmarking using longer reads shows that the increased read length improves assembly quality, but the extent to which that can be achieved depends on the size and complexity of the reference genome.
Representations and classifications of stochastic processes

We show that to every stochastic process X one can associate a unique collection 4>+, T(t), E{U), p*) consisting of a linear space on which is defined a linear functional p*, together with a convex subset *+ which is invariant under the semigroup of operators T\t) and the resolution of the identity E(U). The joint distributions of X, there being one version for each <t> € 4>+, are then given by P0(A-(tj) eUv. , XUj + . + tn) e UJ . p*E(UJT(t) • • • E(U ̂TU^. To each 4> contained in the extreme points *++ of 4>+ and each time t we find a probability measure P*(<t>, •) on *++ suchthat T(t)<t> = fc+^P*(<t>,d$. P* is the transition probability function of a temporally homogeneous Markov process X* on «>++ for which there exists a function / such that X = f{X*). We show that in a certain sense X* is the smallest of all Markov processes Y for which there exists a function g with X=g(Y). We then apply these results to a class of stochastic process in which future and past are independent given the present and the conditional distribution, on the past, of a collection of random variables in the future. Introduction. It is the purpose of this paper to find minimal algebraic and Markov process representations of general stochastic processes and then to apply these representations to what we hope will turn out to be an interesting class of stochastic processes. The reader should note that our definition of a stochastic process will not be the standard one. Indeed we will define a stochastic process to be simply a convex set of probability measures on the sample path space which is closed under conditioning on the past. There are several reasons for our doing this. In the first place, a Markov process consists of a convex set of measures on the sample path space, one measure for each initial distribution, and these measures are closed under conditioning on the past. In the second place, suppose that an observer is looking at some random phenomenon which at some initial time is described by a particular measure on the sample path space. If a different Received by the editors March 7, 1972 and, in revised form, March 3, 1973. AMS (MOS) subject classifications (1970). Primary 60G05; Secondary 60J05, 60J25, 60K99.