Miracle-dz/UniFAR-FTUs huggingface dataset:
Wild and cultivated rice host different populations of the blast fungus, Pyricularia oryzae, in Mali

Blast is a devastating disease of rice caused by the fungus Pyricularia oryzae. The role of infected straw and seed as sources of primary inoculum in blast disease epidemics is well known. The role of alternative hosts is yet to be confirmed. The current study sought to assess if wild rice is a major source of inoculum for cultivated rice by comparing the genetic structure of P. oryzae populations from both hosts. Cross infectivity of P. oryzae isolates was also assessed using pathogenicity tests. Samples were collected from cultivated and wild rice organs with blast symptoms in irrigated and lowland areas of Mali in Koulikoro, Sikasso, and Ségou regions. Under controlled conditions, P. oryzae isolates from wild rice were pathogenic to cultivated rice but, on average, had a narrower range of cultivar compatibility. Results of pathogenicity tests suggest that P. oryzae isolates from wild rice have the potential to attack cultivated rice in the field. However, populations of P. oryzae on cultivated and wild rice were genetically differentiated. Thus, although physically close, each host plant hosts a different population of the pathogen, and our results support the hypothesis that wild rice is not a major source of blast inoculum for cultivated rice.
Transposon-triggered epigenetic chromatin dynamics modulate EFR-related pathogen response

Infectious diseases drive the evolution of wild plants and impact yield in crop plants. Like animals, plants can sense biotic threats via conserved pathogen-associated patterns (PAMPs). Since an overly robust immune response can harm plants, understanding the mechanisms for tuning defense responses to the appropriate level is vital as we endeavor to develop pathogen-resistant crops. In this paper, we studied the Arabidopsis pattern recognition receptor (PRR) EFR, which senses bacterial EF-Tu. An inverted-repeat transposon (Ea-IR) between EFR and the neighboring XI-k locus controls local chromatin organization, promoting the formation of a repressive chromatin loop. Upon pathogen infection, the chromatin landscape around EFR and Xl-k dynamically changes to allow for increased EFR transcription. Chromatin opening facilitates the passage of RNA polymerase II across the neighboring XI-k gene termination site, leading to a longer XI-k transcript that includes Ea-IR sequences. Dicer-like (DCL) enzymes process the longer Xl-k transcript into small RNAs (sRNAs), which reset chromatin topology to a repressive state, attenuating, in turn, the immune response, reminiscent of attenuation of receptor signaling in other systems. From an evolutionary point of view, we found that natural Arabidopsis accessions missing Ea-IR have a constitutive "EFR-open" chromatin configuration that correlates with higher basal EFR levels and higher background resistance to pathogens. Collectively, our study offers evidence for a scenario in which a transposon, chromatin organization, and gene expression interact to fine-tune immune responses, both during the course of infection and in the course of evolution. Similar gene-associated IRs in crops could provide valuable non-coding targets for genome editing or assisted plant breeding programs.
A coarse-grained model of glycosaminoglycans for biomolecular simulations

Proteoglycans contain glycosaminoglycans (GAGs), negatively charged linear polymers made of repeating disaccharide units of uronic acid and hexosamine units. They play vital roles in numerous physiological and pathological processes, particularly governing cellular communication and attachment. Depending on their sulphonation state, acetylation, and glycosidic linkages, GAGs belong to different families. The high molecular weight, heterogeneity, and flexibility of GAGs hampers their characterization at atomic resolution, but this may be circumvented via coarse-grained (CG) approaches. In this work, we report a CG model for a library of common GAG types in their isolated or proteoglycan-linked states compatible with the widely popular CG Martini forcefields (versions 2.2 and 3.0). The model reproduces conformational and thermodynamic properties for a wide variety of GAGs, as well as matching structural and binding data for selected proteoglycan test systems. The parameters developed here may thus be employed to study a range of GAG-containing biomolecular systems, benefitting from the efficiency and broad applicability of the Martini framework.
KINNTREX: A Neural Network Unveils Protein Mechanism from Time Resolved X-ray Crystallography

Here, a machine learning method based on a kinetically informed neural network (NN) is introduced. The proposed method is designed to analyze a time series of difference electron density (DED) maps from a time-resolved X-ray crystallographic experiment. The method is named KINNTREX (Kinetics Inspired NN for Time-Resolved X-ray Crystallography). To validate KINNTREX, multiple realistic scenarios were simulated with increasing level of complexity. For the simulations, time-resolved X-ray data was generated that mimic data collected from the photocycle of the photoactive yellow protein (PYP). KINNTREX only requires the number of intermediates and approximate relaxation times (both obtained from a singular valued decomposition) and does not require an assumption of a candidate mechanism. It successfully predicts a consistent chemical kinetic mechanism, together with difference electron density maps of the intermediates that appear during the reaction. These features make KINNTREX attractive for tackling a wide range of biomolecular questions. In addition, the versatility of KINNTREX can inspire more NN-based applications to time-resolved data from biological macromolecules obtained by other methods.
Correlative single-molecule and structured illumination microscopy of fast dynamics at the plasma membrane

Total internal reflection fluorescence (TIRF) microscopy offers powerful means to uncover the functional organization of proteins in the plasma membrane with very high spatial and temporal resolution. Traditional TIRF illumination, however, shows a Gaussian intensity profile, which is typically deteriorated by overlaying interference fringes hampering precise quantification of intensities – an important requisite for quantitative analyses in single-molecule localization microscopy (SMLM). Here, we combined flat-field illumination by using a standard πShaper with multi-angular TIR illumination by incorporating a spatial light modulator compatible with fast super-resolution structured illumination microscopy (SIM). This unique combination enabled quantitative multi-color SMLM with a highly homogenous illumination. By using a dual camera setup with optimized image splitting optics, we achieved versatile combination of SMLM and SIM with up to three channels. We deployed this setup for establishing robust detection of receptor stoichiometries based on single-molecule intensity analysis and single-molecule Förster resonance energy transfer (smFRET). Homogeneous illumination furthermore enabled long-term tracking and localization microscopy (TALM) of cell surface receptors identifying spatial heterogeneity of mobility and accessibility in the plasma membrane. By combination of TALM and SIM, spatially and molecularly heterogenous diffusion properties could be correlated with nanoscale cytoskeletal organization and dynamics.
A metagenomics pipeline reveals insertion sequence-driven evolution of the microbiota

Insertion sequence (IS) elements are mobile genetic elements in bacterial genomes that support adaptation. We developed a database of IS elements coupled to a computational pipeline that identifies IS element insertions in the microbiota. We discovered that diverse IS elements insert into the genomes of intestinal bacteria regardless of human host lifestyle. These insertions target bacterial accessory genes that aid in their adaptation to unique environmental conditions. Using IS expansion in Bacteroides, we show that IS activity leads to insertion “hot spots” in accessory genes. We show that IS insertions are stable and can be transferred between humans. Extreme environmental perturbations force IS elements to fall out of the microbiota and many fail to rebound following homeostasis. Our work shows that IS elements drive bacterial genome diversification within the microbiota and establishes a framework for understanding how strain level variation within the microbiota impacts human health.
Genetic and pharmacologic alterations of claudin9 levels suffice to induce functional and mature inner hair cells

Hearing loss is the most common form of sensory deficit. It occurs predominantly due to hair cell (HC) loss. Mammalian HCs are terminally differentiated by birth, making HC loss incurable. Here, we show the pharmacogenetic downregulation of Cldn9, a tight junction protein, generates robust supernumerary inner HCs (IHCs) in mice. The putative ectopic IHCs have functional and synaptic features akin to typical IHCs and were surprisingly and remarkably preserved for at least fifteen months >50% of the mouse’s life cycle. In vivo, Cldn9 knockdown using shRNA on postnatal days (P) P1-7 yielded analogous functional putative ectopic IHCs that were equally durably conserved. The findings suggest that Cldn9 levels coordinate embryonic and postnatal HC differentiation, making it a viable target for altering IHC development pre- and post-terminal differentiation.
Forest and Sea as Insurance among Fijians

This paper examines how forest and marine resources serve as insurance against a tropical cyclone using original household data gathered in rural Fiji. The fixed-effects estimator for a censored dependent variable controls for unobservable household heterogeneity that can cause bias. I propose a simple empirical strategy, which can be widely applied, to test whether a household intensifies labor activity to earn extra income to be shared under private risk-sharing arrangements. I find that while households abandon forest product gathering right after the cyclone, value-added handicrafts made of some forest products by women serve as self-insurance against crop damage after the emergency period and this is especially so among female-headed households. Fijians intensify fishing to augment mutual insurance for the recovery from village facility damage and housing damages experienced by others. I discuss how this distinct pattern emerges as private adjustments to cyclone relief delivered to the region.
Nascent Chain Ubiquitination is Uncoupled from Degradation to Enable Protein Maturation

A significant proportion of nascent proteins undergo polyubiquitination on ribosomes in mammalian cells, yet the fate of these proteins remains elusive. The ribosome-associated quality control (RQC) is a mechanism that mediates the ubiquitination of nascent chains on stalled ribosomes. Here, we find that nascent proteins ubiquitinated on stalled ribosomes by the RQC E3 ligase LTN1 are insufficient for proteasomal degradation. Our biochemical reconstitution studies reveal that ubiquitinated nascent chains are promptly deubiquitinated in the cytosol upon release from stalled ribosomes, as they are no longer associated with LTN1 E3 ligase for continuous ubiquitination to compete with cytosolic deubiquitinases. These deubiquitinated nascent chains can mature into stable proteins. However, if they misfold and expose a degradation signal, the cytosolic quality control recognizes them for re-ubiquitination and subsequent proteasomal degradation. Thus, our findings suggest that cycles of ubiquitination and deubiquitination spare foldable nascent proteins while ensuring the degradation of terminally misfolded proteins.
Improved Glucose Homeostasis Following Vertical Sleeve Gastrectomy is Associated with Alternate Wiring of the Liver Molecular Clock in a Rat Model of Spontaneously-Occurring Type 2 Diabetes

Bariatric surgery is associated with remission of type 2 diabetes (T2D). We aimed to advance fundamental understanding of mechanisms involved in improved glucose homeostasis following vertical sleeve gastrectomy (VSG). We carried out a series of pathophysiological, behavioural and liver transcriptome analyses in lean rats of the Goto-Kakizaki (GK) model of polygenic T2D following VSG or sham operation. VSG and resulting sustained reduction in glucose intolerance were associated with significant changes in liver histology and lean mass, and nycthemeral feeding patterns and activity. Liver transcriptome profiling identified differentially regulated pathways between VSG and sham GK, including inflammatory and immune processes and fatty acid metabolism. Deeper analysis of the transcriptome dataset showed that expression of almost all main regulators of the molecular clock was significantly and co-ordinately affected by VSG. Comparisons with liver transcriptome data previously generated in GK and normoglycemic rats suggested that VSG results in a profound remodelling of the regulation of the molecular clock. Our findings shed light on relationships between the molecular clock and nycthemeral feeding and activity, which may contribute to long-term therapeutic consequences of VSG in the context of polygenic T2D in the absence of confounding effects of obesity.
Interplay of RAP2 GTPase and the cytoskeleton in Hippo pathway regulation

The Hippo signaling is instrumental in regulating organ size, regeneration, and carcinogenesis. The cytoskeleton emerges as a primary Hippo signaling modulator. Its structural alterations in response to environmental and intrinsic stimuli control Hippo kinase cascade activity. However, the precise mechanisms underlying the cytoskeleton regulation of Hippo signaling are not fully understood. RAP2 GTPase is known to mediate the mechanoresponses of Hippo signaling via activating the core Hippo kinases LATS1/2 through MAP4Ks and MST1/2. Here we show the pivotal role of the reciprocal regulation between RAP2 GTPase and the cytoskeleton in Hippo signaling. RAP2 deletion undermines the responses of the Hippo pathway to external cues tied to RhoA GTPase inhibition and actin cytoskeleton remodeling, such as energy stress and serum deprivtion. Notably, RhoA inhibitors and actin disruptors fail to activate LATS1/2 effectively in RAP2-deficient cells. RNA sequencing highlighted differential regulation of both actin and microtubule networks by RAP2 gene deletion. Consistently, Taxol, a microtubule-stabilizing agent, was less effective in activating LATS1/2 and inhibiting cell growth in RAP2 and MAP4K4/6/7 knockout cells. In summary, our findings position RAP2 as a central integrator of cytoskeletal signals for Hippo signaling, which offers new avenues for understanding Hippo regulation and therapeutic interventions in Hippo-impaired cancers.
Microprism-based two-photon imaging of the lateral cortex of the mouse inferior 1 colliculus reveals novel organizational principles of the auditory midbrain. 2

24 To navigate real-world listening conditions, the auditory system relies on the integration of 25 multiple sources of information. However, to avoid inappropriate cross-talk between inputs, 26 highly connected neural systems need to strike a balance between integration and segregation. 27 Here, we develop a novel approach to examine how repeated neurochemical modules in the 28 mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. 29 The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore we 30 coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal 31 views of the LC to examine neuronal responses with respect to its neurochemical motifs under 32 anesthetized and awake conditions. This approach revealed marked differences in the acoustic 33 response properties of LC and neighboring nonlemniscal portions of the inferior colliculus. In 34 addition, we observed that the module and matrix cellular motifs of the LC displayed distinct 35 somatosensory and auditory responses. Specifically, neurons in modules demonstrated 36 primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, 37 whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses 38 to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of 39 the LC permit functional integration of multimodal inputs while retaining distinct response 40
MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death

Ferroptosis is a regulated form of cell death characterized by lipid peroxidation and lipid hydroperoxide (LOOH) generation that offers new therapeutic opportunities. However, the molecular mechanism through which LOOH accumulation leads to cell death remains poorly understood. Importantly, LOOH breakdown forms truncated phospholipids (PLs) and highly reactive lipid-derived electrophiles (LDEs) capable of altering protein function through cysteine alkylation. While truncated PLs have been shown to mediate ferroptotic membrane permeabilization, a functional role for LDEs in the ferroptotic cell death mechanism has not been established. Here, using multidrug resistance protein 1 (MRP1) activity as an example, we demonstrate that LDEs mediate altered protein function during ferroptosis. Applying live cell fluorescence imaging, we first identified that inhibition of MRP1-mediated LDE detoxification occurs across a panel of ferroptosis inducers (FINs) with differing mechanisms of ferroptosis induction (Types I-IV FINs erastin, RSL3, FIN56 and FINO2). This MRP1 inhibition was recreated by both initiation of lipid peroxidation and treatment with the LDE 4-hydroxy-2-nonenal (4-HNE). Importantly, treatment with radical-trapping antioxidants prevented impaired MRP1 activity when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of inhibited MRP1 activity during ferroptosis. Our findings, when combined with reports of widespread LDE-alkylation of key proteins during ferroptosis, sets a precedent for LDEs as critical mediators of ferroptotic cell death. LOOH breakdown to truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function during late stage ferroptosis, offering a unified explanation of the molecular ferroptotic cell death mechanism.
Transthalamic input to higher-order cortex selectively conveys state information

Communication among different neocortical areas is largely thought to be mediated by long-range synaptic interactions between cortical neurons, with the thalamus providing only an initial relay of information from the sensory periphery. Higher-order thalamic nuclei receive strong synaptic inputs from the cortex and send robust projections back to other cortical areas, providing a distinct and potentially critical route for cortico-cortical communication. However, the relative contributions of corticocortical and thalamocortical inputs to higher-order cortical function remain unclear. Using imaging of cortical neurons and projection axon terminals in combination with optogenetic manipulations, we find that the higher-order visual thalamus of mice conveys a specialized stream of information to higher-order visual cortex. Whereas corticocortical projections from lower cortical areas convey robust visual information, higher-order thalamocortical projections convey strong behavioral state information. Together, these findings suggest a key role for higher-order thalamus in providing contextual signals that flexibly modulate sensory processing in higher-order cortex.
Elucidating Compound Mechanism of Action by Network Perturbation Analysis Graphical

In Brief The mechanism of action (MoA) of smallmolecule compounds is elucidated by analyzing regulatory networks to identify proteins whose interactions are affected following compound perturbation. Experimental validation of novel MoA predictions revealed that the anticancer drug altretamine acts as an inhibitor of GPX4 lipid repair activity, revealing unexpected similarity to the activity of sulfasalazine.
Landscape of Large-Scale Somatic Genomic Insertions in Non-Small Cell Lung Carcinoma Revealed by Nanopore Sequencing

Previous NSCLC genomic studies were mostly based on the next-generation sequencing of short reads, which is an efficient approach for identifying single nucleotide variants and small indels but ineffective for identifying structural variants, especially large-scale insertions. Here, we studied 151 lung adenocarcinoma (LUAD) and 106 lung squamous cell carcinoma (LUSC) samples and paired blood samples using nanopore sequencing technology. We developed a rigorous computational pipeline and characterized the landscape of large-scale somatic insertions in NSCLC. Combining other omics data, we report three findings: 1. we identified an LUSC-enriched somatic simple repeat expansion shared by approximately 40% of LUSC patients that regulates PTPRZ1 gene expression through distal enhancers; 2. the somatic insertion of transposable elements (TEs) in NSCLC were mostly ‘complex TEs’ consisting of multiple TE elements; and 3. the insertion of short interspersed nuclear elements, especially from the Alu family in young lineages, is a frequent somatic mutation type that shapes the transcriptome of NSCLC through the expression of these elements.
Modeling of nitrogen species measured by CRISTA

We present an analysis of odd nitrogen species measured by the CRISTA experiment during the Space Shuttle mission STS 66 in November 1994. Observations of several nitrogen species are compared with modeled fields obtained from three‐dimensional simulations performed with a chemical transport model (CTM). A sequential trace gas assimilation system is used in order to constrain the simulations by CRISTA observations of long‐lived species, and total amounts of stratospheric nitrogen (NOy) derived from measurements of individual nitrogen components (NO2, N2O5, HNO3, and ClONO2). Comparisons of measured and modeled NOy species focus on significant diurnal variations and intense longitudinal variations observed by CRISTA.