Miracle-dz/UniFAR-FTUs huggingface dataset:
StartLink+: Prediction of Gene Starts in Prokaryotic Genomes by an Algorithm Integrating Independent Sources of Evidence

Algorithms of ab initio gene finding were shown to make sufficiently accurate predictions in prokaryotic genomes. Nonetheless, for up to 15-25% of genes per genome the gene start predictions might differ even when made by the supposedly most accurate tools. To address this discrepancy, we have introduced StartLink+, an approach combining ab initio and multiple sequence alignment based methods. StartLink+ makes predictions for a majority of genes per genome (73% on average); in tests on sets of genes with experimentally verified starts the StartLink+ accuracy was shown to be 98-99%. When StartLink+ predictions made for a large set of prokaryotic genomes were compared with the database annotations we observed that on average the gene start annotations deviated from the predictions for ~5% of genes in AT-rich genomes and for 10-15% of genes in GC-rich genomes.
An Algorithmic framework for genome-wide identification of Sugarcane (Saccharum officinarum L.)-encoded microRNA targets against SCBV

Sugarcane Bacilliform Virus (SCBV) is considered an economically the most damaging pathogen for sugarcane production worldwide. Three ORFs are characterized in a single molecule of circular, ds-DNA genome of the SCBV, encoding for hypothetical protein (ORF1), DNA binding protein (ORF2) and Polyprotein (ORF3). The study was aimed to predict and comprehensively evaluate sugarcane miRNAs for the silencing of SCBV genome using in-silico algorithms. Computational methods were used for prediction of candidate miRNAs from sugarcane (S. officinarum L.) to silence the expression of SCBV genes through translational inhibition by mRNA cleavage. Mature sugarcane miRNAs were retrieved and were assessed to hybridization with the SCBV genome. A total of fourteen potential candidate miRNAs from sugarcane were computed by all the algorithms used for the silencing of SCBV. A consensus of three algorithms predicts hybridization sites of sof-miR159e at common locus 5534. The miRNA-mRNA interaction was estimated by computing free-energy of miRNA-mRNA duplex using RNAcofold algorithm. Regulatory network of predicted candidate miRNAs of sugarcane with SCBV ORFs, generated using Circos, identify novel targets. Consequently, detecting and discarding inefficient amiRNAs prior to cloning would help suppressed mutants faster. The efficacy of predicted candidate miRNAs was evaluated to test the survival rate of the in vitro amiRNA-mediated effective badnaviral silencing and resistance in sugarcane cultivars.
Rag GTPases and phosphatidylinositol 3-phosphate mediate recruitment of the AP-5/SPG11/SPG15 complex

Adaptor protein complex 5 (AP-5) and its partners, SPG11 and SPG15, are recruited onto late endosomes and lysosomes. Here we show that recruitment of AP-5/SPG11/SPG15 is enhanced in starved cells, and occurs by coincidence detection, requiring both phosphatidylinositol 3-phosphate (PI3P) and Rag GTPases. PI3P binding is via the SPG15 FYVE domain, which on its own localises to early endosomes. GDP-locked RagC promotes recruitment of AP-5/SPG11/SPG15 while GTP-locked RagA prevents its recruitment. Our results uncover an interplay between AP-5/SPG11/SPG15 and the mTORC1 pathway, and help to explain the phenotype of AP-5/SPG11/SPG15 deficiency in patients, including the defect in autophagic lysosome reformation. Summary The AP-5/SPG11/SPG15 complex is recruited onto late endosomes/lysosomes, and contributes to lysosomal homeostasis and autophagic lysosome reformation. Hirst et al. show that recruitment is by coincidence detection, requiring both phosphatidylinositol 3-phosphate and Rag GTPases, thus uncovering a link between AP-5/SPG11/SPG15 and the mTORC1 pathway.
Membrane-Dependent Amyloid Aggregation of Human BAX α9 (173-192)

Mitochondrial outer membrane permeabilization, which is a critical step in apoptosis, is initiated upon transmembrane insertion of the C-terminal α-helix (α9) of the pro-apoptotic Bcl-2 family protein BAX. The isolated α9 fragment (residues 173-192) is also competent to disrupt model membranes, and the structures of its membrane-associated oligomers are of interest in understanding the potential roles of this sequence in apoptosis. Here, we used ultrafast two-dimensional infrared (2D IR) spectroscopy, thioflavin T binding, and transmission electron microscopy to show that the synthetic BAX α9 peptide (α9p) forms amyloid aggregates in solution and on the surfaces of anionic small unilamellar vesicles (SUVs). Its inherent amyloidogenicity was predicted by sequence analysis, and 2D IR spectra reveal that SUVs modulate the β-sheet structures of the resulting amyloid species. These results contradict prior models of transmembrane α9p pores and motivate further examination of the formation or suppression of BAX amyloids in apoptosis.
Functional genomic analyses highlights a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells (OPC) and underlying myelin dysregulation in the aged forebrain

Brain aging is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to aging as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain aging hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrates that oligodendroglial and myelin genes are amongst the most altered in the aging mouse cortex. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that define oligodendroglial disruption in aging. The results highlighted that the G-protein coupled receptor GPR17 is central to the disruption of OPC in aging and this was confirmed by genetic fate mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPC and restore myelination in age-related neuropathological contexts.
Spatial modulation of dark versus bright stimulus responses in mouse visual cortex

A fundamental task of the visual system is to respond to luminance increments and decrements. In primary visual cortex (V1) of cats and primates, luminance decrements elicit stronger, faster, and more salient neural activity (OFF responses) than luminance increments (ON responses). However, studies of V1 in ferrets and mice show that ON responses may be stronger. These discrepancies may arise from differences in species, experimental conditions, or from measuring responses in single neurons versus populations. Here, we examined OFF versus ON responses across different regions of visual space in both single neurons and populations of mouse V1. We used high-density silicon probes and whole-cell patch-clamp recordings to assess OFF versus ON dominance in local field potential (LFP), single neuron, and membrane potential responses. Across these levels, we found that OFF responses clearly dominated in the central visual field, whereas ON responses were more evident in the periphery. These observations were clearest in LFP and subthreshold membrane potential. Our findings consolidate and resolve prior conflicting results and reveal that retinotopy may provide a common organizing principle for spatially biasing OFF versus ON processing in mammalian visual systems.
IFN-λ4 may contribute to HCV persistence by increasing ER stress and enhancing IRF1 signaling

Chronic hepatitis C virus (HCV) infection and cirrhosis are major risk factors for developing hepatocellular carcinoma (HCC). Genetic polymorphisms in the IFNL3/IFNL4 locus have been associated both with impaired clearance of HCV and protection from liver fibrosis, an early stage of cirrhosis. Here, we aimed to address the genetic and functional relationships between IFNL3/IFNL4 polymorphisms, HCV-related cirrhosis, and HCC risk. We evaluated associations between IFNL4 genotype, defined as the presence of rs368234815-dG or rs12979860-T alleles, with cirrhosis and HCC risk in patients with chronic HCV - 2,931 from Taiwan and 3,566 from Japan. We detected associations between IFNL4 genotype and decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwan), but increased risk of HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058, in Japan). In-vitro, IFN-λ4 expression increased ER stress, and enhanced positive regulation of IFN responses via IRF1 induction, which mediated antiproliferative effects in hepatic cells. Our data present novel IFN-λ4-associated pathways that may be contributing to HCV persistence and development of HCC.
Inter-species variation in number of bristles on forewings of tiny insects does not impact clap-and-fling aerodynamics

Flight-capable miniature insects of body length (BL) < 2 mm typically possess wings with long bristles on the fringes. Though their flight is challenged by needing to overcome significant viscous resistance at chord-based Reynolds number (Rec) on the order of 10, these insects use clap-and-fling mechanism coupled with bristled wings for lift augmentation and drag reduction. However, inter-species variation in the number of bristles (n) and inter-bristle gap (G) to bristle diameter (D) ratio (G/D) and their effects on clap-and-fling aerodynamics remain unknown. Forewing image analyses of 16 species of thrips and 21 species of fairyflies showed that n and maximum wing span were both positively correlated with BL. We conducted aerodynamic force measurements and flow visualization on simplified physical models of bristled wing pairs that were prescribed to execute clap-and-fling kinematics at Rec=10 using a dynamically scaled robotic platform. 23 bristled wing pairs were tested to examine the isolated effects of changing dimensional (G, D, span) and non-dimensional (n, G/D) geometric variables on dimensionless lift and drag. Within biologically observed ranges of n and G/D, we found that: (a) increasing G provided more drag reduction than decreasing D; (b) changing n had minimal impact on lift generation; and (c) varying G/D produced minimal changes in aerodynamic forces. Taken together with the broad variation in n (32-161) across the species considered here, the lack of impact of changing n on lift generation suggests that tiny insects may experience reduced biological pressure to functionally optimize n for a given wing span. SUMMARY STATEMENT Integrating morphological analysis of bristled wings seen in miniature insects with physical model experiments, we find that aerodynamic forces are unaffected across the broad biological variation in number of bristles.
Harnessing multivariate, penalized regression methods for genomic prediction and QTL detection to cope with climate change affecting grapevine

Viticulture has to cope with climate change and decrease pesticide inputs, while maintaining yield and wine quality. Breeding is a potential key to meet this challenge, and genomic prediction is a promising tool to accelerate breeding programs, multivariate methods being potentially more accurate than univariate ones. Moreover, some prediction methods also provide marker selection, thus allowing quantitative trait loci (QTLs) detection and allowing the identification of positional candidate genes. We applied several methods, interval mapping as well as univariate and multivariate penalized regression, in a bi-parental grapevine progeny, in order to compare their ability to predict genotypic values and detect QTLs. We used a new denser genetic map, simulated two traits under four QTL configurations, and re-analyzed 14 traits measured in semi-controlled conditions under different watering conditions. Using simulations, we recommend the penalized regression method Elastic Net (EN) as a default for genomic prediction, and controlling the marginal False Discovery Rate on EN selected markers to prioritize the QTLs. Indeed, penalized methods were more powerful than interval mapping for QTL detection across various genetic architectures. Multivariate prediction did not perform better than its univariate counterpart, despite strong genetic correlation between traits. Using experimental data, penalized regression methods proved as very efficient for intra-population prediction whatever the genetic architecture of the trait, with accuracies reaching 0.68. These methods applied on the denser map found new QTLs controlling traits linked to drought tolerance and provided relevant candidate genes. These methods can be applied to other traits and species.
ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

Aims Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Neuroinflammation mediated by microglial activation is evident in post-mortem brain tissues, and in brain imaging of patients with ALS. However, the exact role of microglia in ALS remains to be elucidated partly due to the lack of an accurate microglial model system that is able to recapitulate the clinical pathology of ALS. Moreover, direct sampling of microglia from patients with ALS is not feasible, further limiting the study of microglial function in ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia (MDMi) that are capable of expressing molecular markers, and functional characteristics similar to resident human brain microglia. Importantly, MDMi can be routinely and reproducibly generated from ALS patient blood, and reveal patient heterogeneity associated with age, sex and disease subgroup. Methods MDMi were successfully established from all 30 ALS patients, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected heathy controls (HC). Results Our ALS MDMi model recapitulated canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive pathological inclusions. We further observed significantly impaired phagocytosis, altered cytokine expression and microglial morphology, as well as elevated DNA damage in ALS compared to HC MDMi. Abnormal phagocytosis was observed in all ALS cases, and was correlated to the progression of disease. Moreover, in-depth analysis of individual microglia revealed cell-specific variation in phagocytic function that was significantly altered, and exacerbated in rapid disease progression. Conclusions Our approach enabled us to generate ALS patient microglia from peripheral blood samples using a rapid, robust, cost-effective, and reproducible protocol. We have shown that ALS monocyte-derived microglia have significantly altered functional behaviour compared to age-matched HCs, with a major deficit in phagocytic activity. This is also the first demonstration of abnormal TDP-43 localisation in microglia grown from ALS patients. Overall, this approach is highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents. Additionally, this model system can be used as a basis for personalised therapeutic treatment for ALS, as well as other neurodegenerative diseases.
Glycinergic axonal inhibition subserves acute spatial sensitivity to sudden increases in sound intensity

Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically-evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients.
The Influence of Pre-Supplementary Motor Area Targeted High-Definition Transcranial Direct Current Stimulation on Inhibitory Control

The neural underpinnings of inhibitory control, an executive cognitive control function, has been a topic of interest for several decades due to both its clinical significance and the maturation of cognitive science disciplines. Behavioral, imaging, and electrophysiological studies suggest that the pre-supplementary motor area (preSMA) serves as a primary hub in a network of regions engaged in inhibition. High-definition transcranial direct current stimulation (HD-tDCS) allows us to modulate neural function to assess cortical contribution to cognitive functioning. The present study targeted HD-tDCS modulation of preSMA to affect inhibition. Participants were randomly assigned to receive 20 min of Sham, Anodal, or Cathodal stimulation prior to completing a semantically cued go/nogo task while electroencephalography (EEG) data were recorded. Both anodal and cathodal stimulation improved inhibitory performance as measured by faster reaction times and increased (greater negative) N2 event-related potentials (ERPs). In contrast, the Sham group did not show such changes. We did not find support for the anodal/cathodal dichotomy for HD neural stimulation. These findings constitute an early investigation into role of the preSMA in inhibitory control and in exploring application of HD-tDCS to the preSMA in order to improve inhibitory control.
Integrating indigenous knowledge, ontology, and molecular barcoding to characterize spider monkey (Ateles paniscus) filariasis

Zoonotic disease risk is greatly influenced by cultural practices and belief systems. Yet, few studies have integrated traditional ecological knowledge and ontology with western ways of knowing to better understand potential zoonoses. Here, we integrate molecular phylogenetics, histopathology, and ethnography to characterize a filarial nematode found within the abdominal cavity of spider monkeys (Ateles paniscus). The filarid is recognized as ‘spider monkey cotton’ by indigenous Waiwai in the Konashen Community Owned Conservation Area, Guyana. Ethnographic data revealed that the Waiwai perceive of ‘spider monkey cotton’ as a normal characteristic within the ‘spider monkey person. ’ Further, the Waiwai indicated that ‘cotton’ was ubiquitous with spider monkeys and is not understood to be infectious nor zoonotic. This distinction is in contrast to other internal parasites found within spider monkeys that the Waiwai know to cause disease in both monkeys and humans. Our morphological and molecular characterization support the classification of the filarid as Dipetalonema caudispina, a minimally studied and seemingly non-zoonotic parasite, consistent with Waiwai beliefs. Thus, our findings allow us to establish commensurability between scientific knowledge and indigenous ontology. More broadly, this work highlights the importance of integrating multiple knowledge systems and leveraging advanced genomics to better understand and prevent emerging zoonotic diseases.
Transcriptome analysis reveals the main metabolic pathway of c-GMP induced by salt stress in tomato seedlings

Tomato is a model crop, as well as important food worldwide. In the arid areas, aggravation of soil salinity has become the primary problem that threatens the high yield in tomato production. As a second messenger substance, cyclic guanosine monophosphate (c-GMP) plays an indispensable role in plant response to salt stress through regulating cell processes to promote plant growth and development. However, this mechanism has not been fully explored in tomato seedlings. In this experiment, the tomato seeds were cultured in distilled water (CK), 20 μM c-GMP (T1), 50 mM NaCl (T2), 20 μM c-GMP + 50 mM NaCl (T3). The results show that 20 μM c-GMP effectively alleviated the inhibition of 50 mM NaCl on tomato growth and development, inducing the expression of 1580 DEGs. 95 DEGs were up-regulated and 442 DEGs were down-regulated (CK vs T1), whereas in the T2 vs T3 comparison 271 DEGs were up-regulated and 772 DEGs were down-regulated. Based on KEGG analysis, the majority of DEGs were involved in metabolism; exogenous c-GMP induced significant enrichment of pathways associated with carbohydrates, phenylpropanoids and fatty acid metabolism. Most PMEs, acCoA, PAL, PODs, FADs, and AD were up-regulated, and GAPDHs, PL, PG, BXL4, and β-G were down-regulated, which reduced susceptibility of tomato seedlings to salt and promoted their salt adaptation. The application of c-GMP promoted soluble sugar, flavonoids and lignin content, reduced accumulation of MDA, and enhanced the activity of POD. Thus, our results provide insights into the molecular mechanisms associated with salt tolerance of tomato seedlings.