Miracle-dz/UniFAR-FTUs huggingface dataset:
The aging human brain: A causal analysis of the effect of sex and age on brain volume

The goal of this work is to study how brain volume loss at old age is affected by factors such as age, APOE gene, sex, and school level. The study of brain volume loss at old age relative to young age requires at least in principle two MRI scans performed at both young and old age. There is, however, a way to address the problem by having only one MRI scan at old age. We compute the total brain loss of elderly subjects as the ratio between the estimated brain volume and the estimated total intracranial volume. Magnetic resonance imaging (MRI) scans of 890 healthy subjects aged 69 to 85 were assessed. The causal analysis of factors affecting brain atrophy was performed using Probabilistic Bayesian Modeling and the mathematics of Causal Inference. We find that healthy subjects get into their seventies with an average brain volume loss of 30% from their maximum brain volume at a young age. Both age and sex are causally related to brain atrophy, with women getting to elderly age with 1% larger brain volume relative to intracranial volume than men. How the brain ages and what are the reasons for sex differences in adult lifespan are causal questions that need to be addressed with causal inference and empirical data. The graphical causal modeling presented here can be instrumental in understanding a puzzling scientific inquiry-the biological age of the brain.
Subtractive CRISPR screen identifies factors involved in non-canonical LC3 lipidation

Although commonly associated with autophagosomes, LC3 can also be recruited to membranes in a variety of non-canonical contexts. These include responses to ionophores such as the M2 proton channel of influenza A virus. LC3 is attached to membranes by covalent lipidation that depends on recruitment of the ATG5-12-16L1 complex. Non-canonical LC3 lipidation requires the C-terminal WD40 domain of ATG16L1 that is dispensable for canonical autophagy. We devised a subtractive CRISPR knock-out screening strategy to investigate the requirements for non-canonical LC3-lipidation. This correctly identified the enzyme complexes directly responsible for LC3-lipidation. We additionally identified the RALGAP complex as important for M2-induced, but not ionophore drug induced LC3 lipidation. In contrast, we identified ATG4D as responsible for LC3 recycling in M2-induced and basal LC3-lipidation. Identification of a vacuolar ATPase subunit in the screen suggested a common mechanism for non-canonical LC3 recruitment. Influenza-induced and ionophore drug induced LC3-lipidation leads to association of the vacuolar ATPase and ATG16L1 and can be antagonised by Salmonella SopF. LC3 recruitment to erroneously neutral compartments may therefore represent a response to damage caused by diverse invasive pathogens.
Long-term stability of avalanche scaling and integrative network organization in prefrontal and premotor cortex

Ongoing neuronal activity in the brain establishes functional networks that reflect normal and pathological brain function. Most estimates of these functional networks suffer from low spatiotemporal resolution and indirect measures of neuronal population activity, limiting the accuracy and reliability in their reconstruction over time. Here, we studied the stability of neuronal avalanche dynamics and corresponding reconstructed functional networks in the adult brain. Using chronically implanted high-density microelectrode arrays, the local field potential (LFP) of resting state activity was recorded in prefrontal and premotor cortex of awake nonhuman primates. Avalanche dynamics revealed stable scaling exhibiting an inverted parabolic profile and collapse exponent of 2 in line with a critical branching process over many days and weeks. Functional networks were based on a Bayesian-derived estimator and demonstrated stable integrative properties characterized by non-trivial high neighborhood overlap between strongly connected nodes and robustness to weak link pruning. Entropy-based mixing analysis revealed significant changes in strong link weights over weeks. The long-term stability in avalanche scaling and integrative network organization in the face of individual link weight changes should support the development of non-invasive biomarkers to characterize normal and abnormal brain states in the adult brain.
ATP triggers macropinocytosis that internalizes and is regulated by PANX1

Macropinocytosis is an endocytic process that allows cells to respond to changes in their environment by internalizing nutrients and cell surface proteins, as well as modulating cell size. Here, we identify that adenosine triphosphate (ATP) triggers macropinocytosis in murine neuroblastoma cells, thereby internalizing the ATP release channel pannexin 1 (PANX1) while concurrently increasing cross-sectional cellular area. Amiloride, a potent inhibitor of macropinocytosis-associated GTPases, abolished ATP-induced PANX1 internalization and cell area expansion. Transient expression of the GTP-hydrolysis resistant GTPase ARF6 Q67L led to increased PANX1 internalization and increased cell area equivalent to levels seen with ATP stimulation. Mutation of an extracellular tryptophan (W74) in PANX1 abolished ATP-evoked cell area enlargement suggesting that PANX1 regulates this form of macropinocytosis. This novel role of PANX1 in macropinocytosis could be particularly important for disease states implicating PANX1, such as cancer, where ATP can act as a purinergic regulator of cell growth/metastasis and as a supplementary energy source following internalization.
Bat influenza vectored NS1-truncated live vaccine protects pigs against heterologous virus challenge

Swine influenza is an important disease for the swine industry. Currently used whole inactivated virus (WIV) vaccines can induce vaccine-associated enhanced respiratory disease (VAERD) in pigs when the vaccine strains mismatch with the infected viruses. Live attenuated influenza virus vaccine (LAIV) is effective to protect pigs against homologous and heterologous swine influenza virus infections without inducing VAERD, but has safety concerns due to potential reassortment with circulating viruses. Herein, we used a chimeric bat influenza Bat09:mH3mN2 virus, which contains both surface HA and NA gene open reading frames of the A/swine/Texas/4199-2/1998 (H3N2) and six internal genes from the novel bat H17N10 virus, to develop modified live-attenuated viruses (MLVs) as vaccine candidates which cannot reassort with canonical influenza A viruses by co-infection. Two attenuated MLV vaccine candidates including the virus that expresses a truncated NS1 (Bat09:mH3mN2-NS1-128, MLV1) or expresses both a truncated NS1 and the swine IL-18 (Bat09:mH3mN2-NS1-128-IL-18, MLV2) were generated and evaluated in pigs against a heterologous H3N2 virus using the WIV vaccineb as a control. Compared to the WIV vaccine, both MLV vaccines were able to reduce lesions and virus replication in lungs and limit nasal virus shedding without VAERD, also induced significantly higher levels of mucosal IgA response in lungs and significantly increased numbers of antigen-specific IFN-γ secreting cells against the challenge virus. However, no significant difference was observed in efficacy between the MLV1 and MLV2. These results indicate that bat influenza vectored MLV vaccines can be used as a safe live vaccine to prevent swine influenza.
My voice therefore I spoke: sense of agency over speech enhanced in hearing self-voice

The subjective experience of causing an action is known as the sense of agency. Dysfunction in the sense of agency has been suggested as a cause of auditory hallucinations (AHs), an important diagnostic criterion for schizophrenia. However, agency over speech has not been extensively characterized in previous empirical studies. Here, we examine both implicit and explicit measures of the sense of agency and reveal bottom-up and top-down components that constitute self-agency during speech. The first is action-outcome causality, which is perceived based on a low-level sensorimotor process when hearing their own voice following their speech. The second component is self-voice identity, which is embedded in the acoustic quality of voice and dominantly influences agency over speech at the cognitive judgment level. Our findings provide profound insight into the sense of agency over speech and present an informative perspective for understanding aberrant experience in AHs.
VirB, a Key Transcriptional Regulator of Virulence Plasmid Genes in Shigella flexneri, Forms DNA-Binding Site-Dependent Foci in the Bacterial Cytoplasm

This study reveals the subcellular localization of VirB, a key transcriptional regulator of virulence genes found on the large virulence plasmid (pINV) in Shigella. Fluorescent signals generated by an active GFP-VirB fusion form 2, 3, or 4 discrete foci in the bacterial cytoplasm, predominantly at the quarter-cell position. These signals are completely dependent upon VirB interacting with its DNA-binding site found either on the virulence plasmid or an engineered surrogate. ABSTRACT VirB is a key regulator of genes located on the large virulence plasmid (pINV) in the bacterial pathogen Shigella flexneri. VirB is unusual, as it is not related to other transcriptional regulators; instead, it belongs to a family of proteins that primarily function in plasmid and chromosome partitioning, which is exemplified by ParB. Despite this, VirB does not function to segregate DNA, but rather counters transcriptional silencing mediated by the histone-like nucleoid structuring protein, H-NS. Since ParB localizes subcellularly as discrete foci in the bacterial cytoplasm, we chose to investigate the subcellular localization of VirB to gain novel insight into how VirB functions as a transcriptional antisilencer. To do this, a green fluorescent protein (GFP)-VirB fusion that retains the regulatory activity of VirB and yet does not undergo significant protein degradation in S. flexneri was used. Surprisingly, discrete fluorescent foci were observed using fluorescence microscopy in live wild-type S. flexneri cells and in an isogenic virB mutant. In contrast, foci were rarely observed (<10%) in pINV-cured cells or in cells expressing a GFP-VirB fusion carrying amino acid substitutions in the VirB DNA-binding domain. Finally, the 25-bp VirB-binding site was demonstrated to be sufficient and necessary for GFP-VirB focus formation using a set of small surrogate plasmids. Combined, these data demonstrate that the VirB-DNA interactions required for the transcriptional antisilencing activity of VirB on pINV are a prerequisite for the subcellular localization of VirB in the bacterial cytoplasm. The significance of these findings, in light of the antisilencing activity of VirB, is discussed. IMPORTANCE This study reveals the subcellular localization of VirB, a key transcriptional regulator of virulence genes found on the large virulence plasmid (pINV) in Shigella. Fluorescent signals generated by an active GFP-VirB fusion form 2, 3, or 4 discrete foci in the bacterial cytoplasm, predominantly at the quarter-cell position. These signals are completely dependent upon VirB interacting with its DNA-binding site found either on the virulence plasmid or an engineered surrogate. Our findings (i) provide novel insight into VirB-pINV interactions, (ii) suggest that VirB may have utility as a DNA marker, and (iii) raise questions about how and why this antisilencing protein that controls virulence gene expression on pINV of Shigella spp. forms discrete foci/hubs within the bacterial cytoplasm.
TRPV channel OCR-2 is distributed along C. elegans chemosensory cilia by diffusion in a local interplay with intraflagellar transport

Sensing and reacting to the environment is essential for survival and procreation of most organisms. Caenorhabditis elegans senses soluble chemicals with transmembrane proteins (TPs) in the cilia of its chemosensory neurons. Development, maintenance and function of these cilia relies on intraflagellar transport (IFT), in which motor proteins transport cargo, including sensory TPs, back and forth along the ciliary axoneme. Here we use live fluorescence imaging to show that IFT machinery and the sensory TP OCR-2 reversibly redistribute along the cilium after exposure to repellant chemicals. To elucidate the underlying mechanisms, we performed single-molecule tracking experiments and found that OCR-2 distribution depends on an intricate interplay between IFT-driven transport, normal diffusion and subdiffusion that depends on the specific location in the cilium. These insights in the role of IFT on the dynamics of cellular signal transduction contribute to a deeper understanding of the regulation of sensory TPs and chemosensing.
Deciphering the genetic basis of wheat seminal root anatomy uncovers ancestral axial conductance alleles

Root axial conductance contributes to the rate of water uptake from the soil throughout the whole plant lifecycle. In a rainfed wheat agro-system, grain-filling is typically occurs during declining water availability (i.e. terminal drought). Therefore, preserving soil water moisture during grain filling could serve as a key adaptive trait. We hypothesized that lower wheat root axial conductance can promote higher yields under terminal drought. A segregating population derived from a cross between durum wheat and its direct progenitor wild emmer wheat was used to underpinning the genetic basis of seminal root architectural and functional traits. We detected 75 QTL associated with seminal roots morphological, anatomical and physiological traits, with several hotspots harboring co-localized QTL. We further validated the axial conductance and central metaxylem QTL using wild introgression lines. Field-based characterization of genotypes with contrasting axial conductance, suggested the contribution of low axial conductance as a mechanism for water conservation during grain filling and consequent increase in grain size and yield. Our findings underscore the potential of introducing wild alleles to reshape the wheat root system architecture for greater adaptability under changing climate.
Degradation of mixed-linkage (1,3;1,4)-β-D-glucan in maize is mediated by the CAL1 licheninase

The presence of mixed-linkage (1,3;1,4)-β-D-glucan (MLG) in plant cell walls is a key feature of grass species such as cereals - the main source of calorie intake for humans and cattle. Accumulation of this polysaccharide involves the coordinated regulation of biosynthetic and metabolic machineries. While several components of the MLG biosynthesis machinery have been identified in diverse plant species, degradation of MLG is poorly understood. A large-scale forward genetic maize screen for mutants with altered cell wall polysaccharide structural properties resulted in the identification of candy-leaf1 (cal1). Cell walls of CAL1-deficient plants contain higher amounts of MLG in several tissues, including adult leaves and senesced organs, where only trace amounts of MLG are usually detected. In addition, cal1 plants exhibit increased saccharification yields upon enzymatic digestion. Stacking cal1 with lignin-deficient mutations results in synergistic saccharification increases. Identification of the causative mutation revealed that CAL1 encodes a GH17 licheninase. Maize plants overexpressing CAL1 exhibit a 90% reduction in MLG content, indicating that CAL1 is not only required, but its expression sufficient to degrade MLG. CAL1 specifically hydrolyzes (1,3;1,4)-β-D-Glucans in vitro, and the single CAL1E262K amino acid substitution is able to block all detectable activity. Time profiling experiments indicate that wall MLG content is modulated during day/night cycles inversely correlating with CAL1 transcript accumulation. This cycling is absent in the cal1 mutant, suggesting that the mechanism involved requires MLG degradation that may in turn regulate CAL1 gene expression. One sentence summary Mixed-linkage glucan is degraded by the CAL1 licheninase in maize
Elemental analysis of airborne particles

1. Spectroscopy Methods (ICP-AES, ICP-MS, Atomic Absorption) 2. X-Ray Fluorescence 3. Neutron Activation Analysis 4. Proton-Induced X-Ray Emission 5. Source-Receptor Modeling 6. Multielemental Methods in Air Pollution Studies 7. Ion Chromatography 8. Standard Reference Materials in Quality Assurance and Quality Control Sampling Methodology 9. Data Basing of Large Sets of Environmental Measurements
AMPGAN v2: Machine Learning Guided Discovery of Anti-Microbial Peptides

Antibiotic resistance is a critical public health problem. Each year ~2.8 million resistant infections lead to more than 35,000 deaths in the U.S. alone. Anti-microbial peptides (AMPs) show promise in treating resistant infections. But, applications of known AMPs have encountered issues in development, production, and shelf-life. To drive the development of AMPbased treatments it is necessary to create design approaches with higher precision and selectivity towards resistant targets. In this paper we present AMPGAN v2, a generative adversarial network (GAN) based approach for rational AMP design. Like AMP-GAN,1 AMPGAN v2 combines data driven priors and controlled generation. These elements allow for the generation of AMP candidates tailored for specific applications. AMPGAN v2 is able to generate AMP candidates that are novel and diverse, making it an efficient AMP design tool.
Herstellung und Steuerung der Verarbeitbarkeitseigenschaften selbstverdichtender Betone

In der Arbeit wird untersucht, wie ein Mischungsentwurf fuer selbstverdichtende Betone (SVB) so zu optimieren ist, dass die geforderten Frisch- und Festbetoneigenschaften zielsicher erreicht werden. Neben der Selbstverdichtung und Selbstnivellierung muss der SVB ein auf die Einbaubedingungen abgestimmtes Fliessverhalten und eine ausreichende Verarbeitbarkeitszeit bei nur vernachlaessigbarer Sedimentationsneigung aufweisen. Als Festbeton muss der SVB die ueblichen Anforderungen an Festigkeit und Dauerhaftigkeit erfuellen, dazu sind die festgelegten Grenzen fuer Mindestzementgehalt und hoechstzulaessigen Wasserzementwert einzuhalten. Um die Empfindlichkeit des SVB gegen unvermeidbare Schwankungen der Zusammensetzung waehrend der Bauzeit gering zu halten, ist eine moeglichst hohlraumarme Sieblinie des Mehlkornanteils zu waehlen. Aufgrund der hierzu ermittelten Kenndaten kann der Startwassergehalt festgelegt werden. Die Einstellung der erforderlichen Konsistenz erfolgt dann mit hochwirksamen Fliessmitteln. Durch zeitgleiche Ermittlung von Trichterauslaufzeit und Setzfliessmass sowie der Beschaffenheit der Oberflaeche und Struktur an gesondert hergestellten Probekoerpern bei verschiedenen Wasser- und Fliessmittelgehalten kann in einem Diagramm fuer eine gegebene Kornzusammensetzung der Bereich mit selbstverdichtenden Eigenschaften ermittelt und bei Veraenderung einzelner Kenndaten waehrend der Bauzeit durch gezielte Wasser- beziehungsweise Fliessmittelgaben angesteuert werden.
Evidence for Numerous Embedded Antisense Overlapping Genes in Diverse E. coli Strains

The genetic code allows six reading frames at a double-stranded DNA locus, and many open reading frames (ORFs) overlap extensively with ORFs of annotated genes (e.g., at least 30 bp or having an embedded ORF). Currently, bacterial genome annotation systematically discards embedded overlapping ORFs of genes (OLGs) due to an assumed information-content constraint, and, consequently, very few OLGs are known. Here we use strand-specific RNAseq and ribosome profiling, detecting about 200 embedded or partially overlapping ORFs of gene candidates in the pathogen E. coli O157:H7 EDL933. These are typically short, many of them show clear promoter motifs as determined by Cappable-seq, indistinguishable from those of annotated genes, and are expressed at a low level. We could express most of them as stable proteins, and 49 displayed a potential phenotype. Ribosome profiling analyses in three other E. coli strains predicted between 84 and 190 embedded antisense OLGs per strain except in E. coli K-12, which is an atypical lab strain. We also found evidence of homology to annotated genes for 100 to 300 OLGs per E. coli strain investigated. Based on this evidence we suggest that bacterial OLGs deserve attention with respect to genome annotation and coding complexity of bacterial genomes. Such sequences may constitute an important coding reserve, opening up new research in genetics and evolutionary biology.
Mapping the common and distinct neural correlates of visual, rule and motor conflict

Flexible behaviour requires cognitive-control mechanisms to efficiently resolve conflict between competing information and alternative actions. Whether a global neural resource mediates all forms of conflict or this is achieved within domainspecific systems remains debated. We use a novel fMRI paradigm to orthogonally manipulate rule, response and stimulus-based conflict within a full-factorial design. Whole-brain voxelwise analyses show that activation patterns associated with these conflict types are distinct but partially overlapping within Multiple Demand Cortex (MDC), the brain regions that are most commonly active during cognitive tasks. Region of interest analysis shows that most MDC sub-regions are activated for all conflict types, but to significantly varying levels. We propose that conflict resolution is an emergent property of distributed brain networks, the functional-anatomical components of which place on a continuous, not categorical, scale from domain-specialised to domain general. MDC brain regions place towards one end of that scale but display considerable functional heterogeneity.
CentTracker: a trainable, machine learning-based tool for large-scale analyses of C. elegans germline stem cell mitosis

Investigating the complex interactions between stem cells and their native environment requires an efficient means to image them in situ. Caenorhabditis elegans germline stem cells (GSCs) are distinctly accessible for intravital imaging; however, long-term image acquisition and analysis of dividing GSCs can be technically challenging. Here we present a systematic investigation into the technical factors impacting GSC physiology during live imaging and provide an optimized method for monitoring GSC mitosis under minimally disruptive conditions. We describe CentTracker, an automated and generalizable image analysis tool that uses machine learning to pair mitotic centrosomes and which can extract a variety of mitotic parameters rapidly from large-scale datasets. We employ CentTracker to assess a range of mitotic features in GSCs and show that subpopulations with distinct mitotic profiles are unlikely to exist within the stem cell pool. We further find evidence for spatial clustering of GSC mitoses within the germline tissue and for biases in mitotic spindle orientation relative to the germline’s distal-proximal axis, and thus the niche. The technical and analytical tools provided herein pave the way for large-scale screening studies of multiple mitotic processes in GSCs dividing in situ, in an intact tissue, in a living animal, under seemingly physiological conditions.