Miracle-dz/UniFAR-FTUs huggingface dataset:
Genome Wide Association Studies on 7 Yield-related Traits of 183 Rice Varieties in Bangladesh

Rice genetic diversity is regulated by multiple genes and is largely dependent on various environmental factors. Uncovering the genetic variations associated with the diversity in rice populations is the key to breed stable and high yielding rice varieties. We performed Genome Wide Association Studies (GWAS) on 7 rice yielding traits (grain length, grain width, grain weight, panicle length, leaf length, leaf width and leaf angle) based on 39,40,165 single nucleotide polymorphisms (SNPs) in a population of 183 rice landraces of Bangladesh. Our studies reveal various chromosomal regions that are significantly associated with different traits in Bangladeshi rice varieties. We also identified various candidate genes, which are associated with these traits. This study reveals multiple candidate genes within short intervals. We also identified SNP loci, which are significantly associated with multiple yield-related traits. The results of these association studies support previous findings as well as provide additional insights into the genetic diversity of rice. This is the first known GWAS study on various yield-related traits in the varieties of Oryza sativa available in Bangladesh – the fourth largest rice producing country. We believe this study will accelerate rice genetics research and breeding stable high-yielding rice in Bangladesh.
ATP Drives Efficient Terpene Biosynthesis in Marine Thraustochytrids

Terpenoids are a large class of lipid molecules with important biological functions and diverse industrial and medicinal applications. Metabolic engineering for terpene production has been hindered by the low-flux distribution to its biosynthesis pathway. ABSTRACT Understanding carbon flux controlling mechanisms in a tangled metabolic network is an essential question of cell metabolism. Secondary metabolism, such as terpene biosynthesis, has evolved with low carbon flux due to inherent pathway constraints. Thraustochytrids are a group of heterotrophic marine unicellular protists and can accumulate terpenoids under the high-salt conditions in their natural environment. However, the mechanism behind terpene accumulation is not well understood. Here, we show that terpene biosynthesis in Thraustochytrium sp. ATCC 26185 is constrained by local thermodynamics in the mevalonate pathway. Thermodynamic analysis reveals metabolite limitation in the nondecarboxylative Claisen condensation of acetyl-coenzyme A (CoA) to the acetoacetyl-CoA step, catalyzed by the acetyl-CoA acetyltransferase (ACAT). Through a sodium-elicited mechanism, higher respiration leads to increased ATP investment into the mevalonate pathway, providing a strong thermodynamic driving force for enhanced terpene biosynthesis. Proteomic and metabolomic analyses further show that the increased ATP demands are fulfilled by shifting energy generation from carbohydrate to lipid oxidation. This study demonstrates a unique strategy in nature that uses ATP to drive a low-flux metabolic pathway, providing an alternative solution for efficient terpene metabolic engineering. IMPORTANCE Terpenoids are a large class of lipid molecules with important biological functions and diverse industrial and medicinal applications. Metabolic engineering for terpene production has been hindered by the low-flux distribution to its biosynthesis pathway. In practice, a high substrate load is generally required to reach high product titers. Here, we show that mevalonate-derived terpene biosynthesis is constrained by local pathway thermodynamics, which can only be partially relieved by increasing substrate levels. Through comparative omics and biochemical analyses, we discovered a unique mechanism for high terpene accumulation in marine protist thraustochytrids. Through a sodium-induced mechanism, thraustochytrids shift their energy metabolism from carbohydrate to lipid oxidation for enhanced ATP production, providing a strong thermodynamic driving force for efficient terpene biosynthesis. This study reveals an important mechanism in eukaryotes to overcome the thermodynamic constraint in low-flux pathways by increased ATP consumption. Engineering energy metabolism thus provides an important alternative to relieve flux constraints in low-flux and energy-consuming pathways.
A unique adhesive motif of protein disulfide isomerase P5 supports its function via dimerization

P5, also known as PDIA6, is a PDI-family member that plays an important role in the ER quality control. Herein, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. This motif is apparently similar to, but radically different from conventional leucine-zipper motifs, in that the former includes a periodic repeat of leucine or valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel α-helices, unlike the latter of which the leucine residues appear every two helical turns on ∼30-residue parallel α-helices at dimer interfaces. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as an aberrant protein that induces the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1α via reduction of intermolecular disulfide bonds and its Ca2+-dependent regulation of chaperone function in vitro. Thus, the leucine-valine adhesive motif supports structure and physiological function of P5.
LncRNA H19X is required for placenta development and angiogenesis through regulating a noncoding RNA regulatory network

H19X is a lncRNA specifically expressed in the placenta, whose expression is induced by hypoxia. H19X overexpression promoted trophoblast proliferation and invasion, while its knockdown or knockout inhibited trophoblast proliferation and invasion. Mechanistically, we demonstrated that reciprocal regulation exists with miR-424/miR-503 in the control of genes related to placental development and angiogenesis, including VEGF and VEGFR2. H19X inhibited ubiquitination of PIWIL1, thereby maintaining its stability and homeostatic expression of piRNAs. PIWIL1 overexpression rescued the defects of cell behavior caused by H19X KO. H19X deletion led to compromised HIF-1A/HIF-2A expression, which was correlated with the dysregulation of downstream genes under hypoxic conditions. CRISPR/Cas-9 knockout of H19X in animals led to defective placenta differentiation and compromised embryo development under hypoxic conditions. Western blotting showed reduced expression levels of PIWIL1 as well as angiogenesis marker genes, including VEGF and VEGFR2, in H19X KO mice. Thus, this study provides evidence of an unexpected link among lncRNA, miRNA, PIWIL1-related piRNA, and angiogenesis in placentation, the dysregulation of which leads to poor placental development and embryo loss under hypoxic conditions.
Naturalistic spatiotemporal stimulus modulation during epiretinal stimulation increases the persistence of retinal ganglion cell responsivity

Objective Retinal stimulation in blind patients evokes the sensation of discrete points of light called phosphenes, which allows them performing visual guided tasks, such as orientation, navigation, object recognition, object manipulation and reading. However, the clinical benefit of artificial vision in profoundly blind patients is still tenuous, as several engineering and biophysical obstacles keep it away from natural perception. The relative preservation of the inner retinal neurons in hereditary degenerative retinal diseases, such as retinitis pigmentosa, supports artificial vision through the network-mediated stimulation of retinal ganglion cells. However, the response of retinal ganglion cells to repeated electrical stimulation rapidly declines, primarily because of the intrinsic desensitisation of their excitatory network. In patients, upon repetitive stimulation, phosphenes fade out in less than half of a second, which drastically limits the understanding of the percept. Approach A more naturalistic stimulation strategy, based on spatiotemporal modulation of electric pulses, could overcome the desensitisation of retinal ganglion cells. To investigate this hypothesis, we performed network-mediated epiretinal stimulations paired to electrophysiological recordings in retinas explanted from both male and female retinal degeneration 10 mice. Main results The results showed that the spatial and temporal modulation of the network-mediated epiretinal stimulation prolonged the responsivity of retinal ganglion cells from 400 ms up to 4.2 s. Significance A time-varied, non-stationary and interrupted stimulation of the retinal network, mimicking involuntary microsaccades, might reduce the fading of the visual percept and improve the clinical efficacy of retinal implants.
Effects of Endogenous Angiotensin II on Abdominal Aortic Aneurysms and Atherosclerosis in Angiotensin II–Infused Mice

Angiotensin II (Angll), a major effector of the renin-angiotensin system, exerts critical roles in regulating vascular function. AngII infusion induces abdominal aortic aneurysms (AAAs) and exacerbates atherosclerosis in hypercholesterolemic mice. We determined the effects of AngII infusion on endogenous AngII regulation and AngII-mediated AAAs and atherosclerosis. AngII infusion increased renal, but not plasma, AngII concentrations in male mice. AngI concentrations were decreased modestly in kidney, but more profoundly in plasma, during AngII infusion. Bovine AngII (DRVYVHPF) has one amino acid difference from mouse AngII (DRVYIHPF) that can be distinguished by LC-MS/MS to determine exogenous versus endogenous peptides. AngII infusion reduced endogenous renal AngII concentrations. To determine whether the residual endogenous AngII exerted an effect on exogenous AngII-mediated AAAs and atherosclerosis, aliskiren (a direct renin inhibitor) was administered to AngII-infused male LDL receptor deficient mice. Although aliskiren did not attenuate AAAs in AngII-infused mice, atherosclerotic lesion size was reduced. In conclusion, endogenous AngII concentrations are reduced during AngII infusion but still contribute to atherosclerosis, but not AAA, in AngII-infused hypercholesterolemic mice.
Milo: differential abundance testing on single-cell data using k-NN graphs

Single-cell omic protocols applied to disease, development or mechanistic studies can reveal the emergence of aberrant cell states or changes in differentiation. These perturbations can manifest as a shift in the abundance of cells associated with a biological condition. Current computational workflows for comparative analyses typically use discrete clusters as input when testing for differential abundance between experimental conditions. However, clusters are not always an optimal representation of the biological manifold on which cells lie, especially in the context of continuous differentiation trajectories. To overcome these barriers to discovery, we present Milo, a flexible and scalable statistical framework that performs differential abundance testing by assigning cells to partially overlapping neighbourhoods on a k-nearest neighbour graph. Our method samples and refines neighbourhoods across the graph and leverages the flexibility of generalized linear models, making it applicable to a wide range of experimental settings. Using simulations, we show that Milo is both robust and sensitive, and can reveal subtle but important cell state perturbations that are obscured by discretizing cells into clusters. We illustrate the power of Milo by identifying the perturbed differentiation during ageing of a lineage-biased thymic epithelial precursor state and by uncovering extensive perturbation to multiple lineages in human cirrhotic liver. Milo is provided as an open-source R software package with documentation and tutorials at https://github.com/MarioniLab/miloR.
Immunoproteasome impairment via β5i/LMP7-deletion leads to sustained pancreatic injury and delayed recovery from experimental pancreatitis

Uncovering potential new targets involved in pancreas recovery may permit the development of new therapies and lead to improved outcome of pancreatitis. One of the reported disease mechanisms of pancreatitis comprises the endoplasmic reticulum (ER) stress response, since pancreatic acini exhibit high levels of protein synthesis and subsequently, ER stress. A key regulator to prevent proteotoxic stress in an inflammatory context is the immunoproteasome, an induced form of the constitutive proteasome. Our aim was therefore to investigate the role of the immunoproteasome in acute pancreatitis. In this study, we demonstrate that immunoproteasome-deficiency by deletion of the β5i/LMP7-subunit correlates with persistent pancreatic damage. Interestingly, immunoproteasome-deficient mice unveil increased activity of pancreatic enzymes in the acute disease phase as well as higher secretion of Interleukin-6 and transcript expression of the Interleukin IL-1β, IFN-β cytokines and the CXCL-10 chemokine. Cell death was increased in immunoproteasome-deficient mice, which appears to be due to the greater accumulation of ubiquitin-protein conjugates and prolonged unfolded protein response. Accordingly, our findings suggest that the immunoproteasome plays a protective role in acute pancreatitis via its role in the clearance of damaged proteins and the balance of ER-stress responses in pancreatic acini as well as in macrophages cytokine production.
CHD7 interacts with the nucleosome acidic patch for its efficient activity via its N-terminal region

Chromodomain-Helicase DNA binding protein 7 (CHD7) is an ATP dependent chromatin remodeler involved in maintaining open chromatin structure. Mutations of CHD7 gene causes multiple developmental disorders, notably CHARGE syndrome. However, there is not much known about the molecular mechanism by which CHD7 remodels nucleosomes. Here, we performed integrative biophysical analysis on CHD7 chromatin remodeler using crosslinking-mass spectrometry (XL-MS), cryo-Electron Microscopy (cryo-EM) and single-molecule Förster Resonance Energy Transfer (smFRET). We uncover that N-terminal to the Chromodomain (N-CRD) interacts with nucleosome. Importantly, this region is required for efficient ATPase stimulation and nucleosome remodeling activity of CHD7. The cryo-EM analysis on the N-CRD_Chromodomain bound to nucleosome reveals that the N-CRD interacts with the acidic patch of nucleosome. Furthermore, smFRET analysis shows the mutations in the N-CRD result in slow or highly-fluctuating remodeling activity. Collectively, our results uncover the functional importance of a previously unidentified N-terminal region in CHD7 and implicate that the multiple domains in chromatin remodelers are involved in regulating their activities.
Control of mitochondrial superoxide production includes programmed mtDNA deletion and restoration

Age-related diseases are intimately linked to mitochondrial impairment. Whether oxidative stress is a major driver of this impairment is still a contentious issue. Here we show that yeast cells adapt to intramitochondrial superoxide anion production beyond antioxidant defenses by swiftly reducing the copy numbers of mitochondrial electron transport chain (ETC) genes, while maintaining the copy numbers of undeleted mtDNA. The copy numbers of the ETC genes are rapidly restored after cessation of a short-term stress, whereas long-term stress causes irreversible loss of this capacity through maladaptive persistence of the mtDNA deletion process. As chronic oxidative stress is a hallmark of ageing, maladaptive mtDNA deletion may be a marked contributor to age-related mtDNA impairment.
Cis regulation within a cluster of viral microRNAs

MicroRNAs (miRNAs) are small regulatory RNAs involved in virtually all biological processes. Although a large number of them are co-expressed from clusters, little is known regarding the impact of this organization on the regulation of their accumulation. In this study, we set to decipher the regulatory mechanism controlling the expression of the ten clustered pre-miRNAs from Kaposi’s sarcoma associated herpesvirus (KSHV). We measured in vitro the efficiency of cleavage of each individual pre-miRNA by the Microprocessor. Strikingly, pre-miR-K1 and -K3 were the most efficiently cleaved pre-miRNAs but their mature forms accumulated at low levels, indicating that they might perform an additional function. A mutational analysis showed that they are indeed important for the optimal expression of the whole set of miRNAs. We showed that this solely relies on the presence of a canonical pre-miRNA at this localization since we could functionally replace pre-miR-K1 by a heterologous pre-miRNA. Further in vitro processing analysis suggests that the two stem-loops act in cis and that the cluster is cleaved in a sequential manner. Finally, we showed that we can exploit this feature of the cluster to inhibit the expression of the whole set of miRNAs by targeting the pre-miR-K1 with LNA-based antisense oligonucleotides.
Age-related Changes in Memory for Object and Position-In-Context

There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared to younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and non-spatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and non-spatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The current findings show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared to younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and non-spatial information may be differentially processed relative to independent and isolated representations of object and spatial information.
A large panel of chicken cells are invaded in vivo by Salmonella Typhimurium even when depleted of all known invasion factors

Salmonella are among the most important foodborne pathogens and contaminated poultry meat and eggs are the main source of human infection. Infected poultry are a major problem as they are asymptomatic, thus rendering the identification of infected poultry farms difficult. In this context, controlling animal infections is of primary importance. It is known that cell and tissue tropism govern disease in many infectious models, our aim was therefore to identify the infected host-cell types in chicks and the role of the three known bacterial invasion factors in this process (T3SS-1, Rck and PagN). Chicks were inoculated with wild-type or isogenic fluorescent Salmonella Typhimurium mutant strains via the intraperitoneal route. Then infected cells in the liver, spleen, gall bladder and aortic vessels were identified using flow-cytometric analyses and invasion confirmed by confocal microscopy. Our results show that all these organs could be foci of infection and that a wide array of phagocytic and non-phagocytic cells is invaded in vivo in each organ. These cells include immune cells and also epithelial and endothelial cells. Moreover, we demonstrated that, despite the invalidation of the three known invasion factors (T3SS-1, Rck and PagN), S. Typhimurium remained able to colonize internal organs and invade non-phagocytic cells in each organ studied. In line with this result, the mutant strains colonized these organs more efficiently than the wild-type strain. S. Typhimurium invasion of gall bladder cells was confirmed by immunohistochemistry and infection was shown to last several weeks after inoculation of chicks and at a level similar to that observed in the spleen. All together, these findings provide new insights into the dynamics of Salmonella spread in vivo in chicks at the organ and cellular levels. Author summary In many infectious models, cell and tissue tropism govern disease. Moreover, depending on the entry process, both bacterial behavior and host response are different. It is therefore important to identify the host cells targeted in vivo by a pathogen and the entry routes used by this pathogen to invade the different host cells. This is all the more important with a pathogen that enters cells in several ways like Salmonella, which is responsible for human and animal salmonellosis. As poultry meat and eggs are the main sources of human contamination, controlling animal infections is of primary importance. In this paper, we identified a large array of phagocytic and non-phagocytic cells targeted in vivo using fluorescent Salmonella Typhimurium strains inoculated by the intraperitoneal route. Surprisingly, the same host cells were infected by the wild-type strain or its isogenic mutants deleted of either the T3SS-1 or of the three known invasion factors (T3SS-1, Rck and PagN). These cells were immune cells but also epithelial and endothelial cells. Moreover, we demonstrated for the first time that the gall bladder and the aortic vessels could be foci of infection in chicks in addition to the liver and spleen.
Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

Multiple molecular features, such as activation of specific oncogenes (e. g. MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with – and most likely a driver of – gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation of MYC and BCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset. Statement of significance This work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.