Miracle-dz/UniFAR-FTUs huggingface dataset:
Uneven distribution of Purkinje cell injury in the cerebellar vermis of term neonates with hypoxic-ischemic encephalopathy

Introduction In term neonates with hypoxic-ischemic encephalopathy (HIE), cerebellar injury is becoming more and more acknowledged. Animal studies demonstrated that Purkinje cells (PCs) are especially vulnerable for hypoxic-ischemic injury. In neonates, however, the extent and pattern of PC injury has not been investigated. The aim of this study was to determine the distribution of PC injury in the cerebellar vermis of term born neonates with HIE. Methods Term born neonates with HIE that underwent post-mortem autopsy of the cerebellar vermis were included. Haematoxylin & Eosin (H&E) stained sections of the vermis were used to determine total PC count and morphology (normal, abnormal or non-classified) at the bases and crown of the folia and of the lobules in both the anterior and posterior lobes. Differences in PC count and PC morphology between the anterior and posterior lobe and between the bases and crown were calculated using the paired samples T-test or Wilcoxon-signed rank test. Results The total number of PCs were significantly higher at the crown compared to the bases (p<0.001) irrespective of the precise location. Besides, PCs at the bases more often had an abnormal morphology. No significant difference between the total number of PCs in the anterior and posterior lobe was observed. Conclusion The abnormal PC count and morphology in term neonates with HIE resembles supratentorial ulegyria.
Consequences of population structure for sex allocation and sexual conflict

Both sex allocation and sexual conflict can be modulated by spatial structure. However, how the interplay between the type of dispersal and the scale of competition simultaneously affects these traits in sub-divided populations is rarely considered. We investigated sex allocation and sexual conflict evolution in meta-populations of the spider mite Tetranychus urticae evolving under budding (pairing females from the same patch) or random (pairing females from different patches) dispersal and either local (fixed sampling from each subpopulation) versus global (sampling as a function of subpopulation productivity) competition. Females evolving under budding dispersal produced less female-biased offspring sex ratios than those from the random dispersal selection regimes, contradicting theoretical predictions. In turn, the scale of competition did not have a strong effect on sex allocation. Males evolved under budding dispersal induced less female harm than those exposed to random dispersal, but there was no reduction in female fitness following exposure to multiple mates from either selection regime. This work highlights that population structure can impact the evolution of sex allocation and sexual conflict. We also discuss how selection on either trait may reciprocally affect the evolution of the other, for example via effects on fecundity.
Regulation of Olfactory Associative Memory by the Circadian Clock Output Signal Pigment-Dispersing Factor (PDF)

Dissociation between the output of the circadian clock and external environmental cues is a major cause of human cognitive dysfunction. While the effects of ablation of the molecular clock on memory have been studied in many systems, little has been done to test the role of specific clock circuit output signals. To address this gap, we examined the effects of mutations of Pigment-dispersing factor (Pdf) and its receptor, Pdfr, on associative memory in male and female Drosophila. Loss of PDF signaling significantly decreases the ability to form associative memory. Appetitive short-term memory (STM), which in wild-type (WT) is time-of-day (TOD) independent, is decreased across the day by mutation of Pdf or Pdfr, but more substantially in the morning than in the evening. This defect is because of PDFR expression in adult neurons outside the core clock circuit and the mushroom body (MB) Kenyon cells (KCs). The acquisition of a TOD difference in mutants implies the existence of multiple oscillators that act to normalize memory formation across the day for appetitive processes. Interestingly, aversive STM requires PDF but not PDFR, suggesting that there are valence-specific pathways downstream of PDF that regulate memory formation. These data argue that the circadian clock uses circuit-specific and molecularly diverse output pathways to enhance the ability of animals to optimize responses to changing conditions. SIGNIFICANCE STATEMENT From humans to invertebrates, cognitive processes are influenced by organisms' internal circadian clocks, the pace of which is linked to the solar cycle. Disruption of this link is increasingly common (e.g., jetlag, social jetlag disorders) and causes cognitive impairments that are costly and long lasting. A detailed understanding of how the internal clock regulates cognition is critical for the development of therapeutic methods. Here, we show for the first time that olfactory associative memory in Drosophila requires signaling by Pigment-dispersing factor (PDF), a neuromodulatory signaling peptide produced only by circadian clock circuit neurons. We also find a novel role for the clock circuit in stabilizing appetitive sucrose/odor memory across the day.
Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro

Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.
Multi-Scale Variability Analysis of Wheat Straw-Based Ethanol Biorefineries Identifies Bioprocess Designs Robust Against Process Input Variations

Bioprocesses based on (ligno-)cellulosic biomass are highly prone to batch-to-batch variations. Varying raw material compositions and enzyme activities hamper the prediction of process yields, economic feasibility and environmental impacts. Commonly, these performance indicators are averaged over several experiments to select suitable process designs. The variabilities in performance indicators resulting from variable process inputs are often neglected, causing a risk for faulty performance predictions and poor process design choices during scale-up. In this paper, a multi-scale variability analysis framework is presented that quantifies the effects of process input variations on performance indicators. Using the framework, a kinetic model describing simultaneous saccharification and ethanol fermentation was integrated with a flowsheet process model, techno-economic analysis and life cycle assessment in order to evaluate a wheat straw-based ethanol biorefinery. Hydrolytic activities reported in the literature for the enzyme cocktail Cellic® CTec2, ranging from 62 to 266 FPU·mL−1, were used as inputs to the multi-scale model to compare the variability in performance indicators under batch and multi-feed operation for simultaneous saccharification and fermentation. Bioprocess simulations were stopped at ethanol productivities ≤0.1 g·L−1·h−1. The resulting spreads in process times, hydrolysis yields, and fermentation yields were incorporated into flowsheet, techno-economic and life cycle scales. At median enzymatic activities the payback time was 7%, equal to 0.6 years, shorter under multi-feed conditions. All other performance indicators showed insignificant differences. However, batch operation is simpler to control and well-established in industry. Thus, an analysis at median conditions might favor batch conditions despite the disadvantage in payback time. Contrary to median conditions, analyzing the input variability favored multi-feed operation due to a lower variability in all performance indicators. Variabilities in performance indicators were at least 50% lower under multi-feed operation. Counteracting the variability in enzymatic activities by adjusting the amount of added enzyme instead resulted in higher uncertainties in environmental impacts. The results show that the robustness of performance indicators against input variations must be considered during process development. Based on the multi-scale variability analysis process designs can be selected which deliver more precise performance indicators at multiple system levels.
Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.
Identification of super-transmitters of SARS-CoV-2

A newly emerged coronavirus, SARS-CoV-2, caused severe outbreaks of pneumonia in China in December 2019 and has since spread to various countries around the world. To probe the origin and transmission dynamics of this virus, we performed phylodynamic analysis of 247 high quality genomic sequences of viruses available in the GISAID platform as of March 05, 2020. A substantial number of earliest sequences reported in Wuhan in December 2019, including those of viruses recovered from the Huanan Seafood Market (HNSM), the site of the initial outbreak, were genetically diverse, suggesting that viruses of multiple sources were involved in the original outbreak. The viruses were subsequently disseminated to different parts of China and other countries, with diverse mutational profiles being recorded in strains recovered subsequently. Interestingly, four genetic clusters defined as Super-transmitters (STs) were found to become dominant and were responsible for the major outbreaks in various countries. Among the four clusters, ST1 is widely disseminated in Asia and the US and mainly responsible for outbreaks in the states of Washington and California in the US as well as those in South Korea at the end of February and early March, whereas ST4 contributed to the pandemic in Europe. Each ST cluster carried a signature mutation profile which allowed us to trace the origin and transmission patterns of specific viruses in different parts of the world. Using the signature mutations as markers of STs, we further analysed 1539 genome sequences reported after February 29, 2020. We found that around 90% of these genomes belonged to STs with ST4 being the dominant one and their contribution to pandemic in different continents were also depicted. The identification of these super-transmitters provides insight into the control of further transmission of SARS-CoV-2.
Mapping the human praxis network: an investigation of white matter disconnection in apraxia

Left hemispheric cerebral stroke can cause apraxia, a motor-cognitive disorder characterised by deficits of higher-order motor skills such as the failure to accurately produce meaningful gestures. This disorder provides unique insights into the anatomical and cognitive architecture of the human praxis system. The present study aimed to map the structural brain network that is damaged in apraxia. We assessed the ability to perform meaningful gestures with the hand in 101 patients with chronic left hemisphere stroke. Structural white matter fibre damage was directly assessed by diffusion tensor imaging and fractional anisotropy mapping. We used multivariate topographical inference on tract-based fractional anisotropy topographies to identify white matter disconnection associated with apraxia. We found relevant pathological white matter alterations in a densely connected fronto-temporo-parietal network of short and long association fibres. Hence, the findings suggest that heterogeneous topographical results in previous lesion mapping studies might not only result from differences in study design, but also from the general methodological limitations of univariate topographical mapping in uncovering the structural praxis network. A striking role of middle and superior temporal lobe disconnection, including temporo-temporal short association fibres, was found, suggesting strong involvement of the temporal lobe in the praxis network. Further, the results stressed the importance of subcortical disconnections for the emergence of apractic symptoms. Our study provides a fine-grain view into the structural connectivity of the human praxis network and suggests a potential value of disconnection measures in the clinical prediction of behavioural post-stroke outcome.
CD209 C-Type Lectins Promote Host Invasion, Dissemination, and Infection of Toxoplasma gondii

Toxoplasma gondii, the causative agent of toxoplasmosis and a major opportunistic parasite associated with AIDS, is able to invade host cells of animals and humans. Studies suggested that the ability of host invasion by the tachyzoite, the infectious form of T. gondii, is essential for the pathogenicity to promote its dissemination to other parts of animal hosts. However, the detailed molecular mechanisms for host invasion and dissemination of the parasites are not clear. On the other hand, viruses and bacteria are able to interact with and hijack DC-SIGN (CD209) C-type lectin on antigen presenting cells (APCs), such as dendritic cells and macrophages as the Trojan horses to promote host dissemination. In this study, we showed that invasion of T. gondii into host cells was enhanced by this parasite-CD209 interaction that were inhibited by ligand mimicking-oligosaccharides and the anti-CD209 antibody. Furthermore, covering the exposures of DC-SIGN by these oligosaccharides reduced parasite burden, host spreading and mortality associated with T. gondii infection. These results suggested that interaction of T. gondii to APCs expressing DC-SIGN might promote host dissemination and infection. Can the blockage of this interaction with Mannan and/or anti-CD209 antibody be developed as a prevention or treatment method for T. gondii infection?
Recent advances in 3D printing of pure proteinaceous microstructures by femtosecond laser direct write

Recent advances in three-dimensional (3D) printing of pure proteinaceous microstructures by femtosecond laser direct write (fs-LDW) are presented. Fs-LDW utilizes light-matter interaction to fabricate micro- and nanostructures along the designated path of the focused laser light. Extremely short pulses suppress heat effects while enhancing the likelihood of non-linear light absorption processes. Fs-LDW thereby allows the fabrication with spatially well-confined features and nearly arbitrary shapes in 3D with a high resolution for diverse materials including protein. Mixtures of protein and photoactivator were usually used so far as precursors to fabricate proteinaceous 3D microstructures. Here, we show that proteinaceous 3D microstructure can be fabricated using the precursor without photoactivator. Such omission of photoactivator might be relevant for biomedical and microfluidic applications because the use of photoactivator is accompanied with the undesired side-effects of photoactivator molecules leaching from created structures and cause physical alteration in the device or allergic reactions for medical use. Raman spectroscopy reveals the absence of photoactivator in the created structures and acid-catalyzed hydrolysis verifies covalent cross-linking as the printing mechanism. We further demonstrate our recent findings in terms of function retention by antibody staining. Due to the diverse abundance of proteins with different native protein functions, we believe fs-LDW of pure proteinaceous microstructures offers many applications in biological studies and medical applications.
Effects of Field and Landscape Scale Habitat on Insect and Bird Damage to Sunflowers

Agriculture-dominated landscapes harbor significantly diminished biodiversity. Woody vegetation along field margins can provide farmers with ecosystem services and benefit biodiversity. However, when crops are damaged by the biodiversity harbored in such vegetation, farmers are reluctant to incorporate field margin habitat onto their land and may even actively remove such habitats. We investigated how damage by both insect pests (sunflower moth, Homoeosoma electellum) and avian pests to sunflower (Helianthus annuus) seed crops varied as a function of field-margin and landscape-scale habitat, as well as by bird abundance and diversity. Surveys for insect damage, avian abundance, and bird damage were carried out over 2 years in 30 different fields. The mean percentage of moth-damaged sunflowers sampled was nearly four times higher in fields that had bare or weedy margins (23.5%; $877/ha) compared to fields with woody vegetation (5.9%; $220/ha) and was positively associated with landscape-scale habitat complexity. Birds damaged significantly fewer sunflower seeds (2.7%) than insects, and bird damage was not affected by field margin habitat type, landscape-scale habitat variables, or avian abundance, but was significantly higher along field edges compared to ≥ 50 m from the field edge. Avian species richness nearly doubled in fields with woody margin habitat compared to fields with bare/weedy margins in both the breeding season and in fall. These results indicate that the benefits of planting or retaining woody vegetation along sunflower field margins could outweigh the ecosystem disservices related to bird damage, while simultaneously increasing the biodiversity value of intensively farmed agricultural landscapes.
DTA expression in mTas1r3+ cells lead to male infertility

TAS1R taste receptors and their associated heterotrimeric G protein gustducin are strongly expressed in testis and sperm, but their functions and distribution in these tissues were unknown. Using transgenic mouse models, we show that taste signal transduction cascades (mTas1r3-Gnat3-Trmp5) are observed in testis form GFP transgenic mice. It is mTas1rs and mTas2rs, not Gnat3, that was expressed in leydig and sertoli cells. The pattern of mTas1r3 expression was different from that of mTas2r105 expression in seminiferous epithelium. Analysis of the seminiferous epithelium cycle show that both mTas1r3 and mTas2r105 is expressed in the spermatid stage, but mTas2r5 expression is found in spermatocyte stage. Conditional deletion of mTas1r3+ cells leads to male infertility, but do not affect the expression of taste signal transduction cascade during the spermatogenesis. The current results indicate a critical role for mTas1r3+ cell in sperm development and maturation.
Flow over seal whiskers: Importance of geometric features for force and frequency response

The complex undulated geometry of seal whiskers has been shown to substantially modify the turbulent structures directly downstream, resulting in a reduction of hydrodynamic forces as well as modified vortex-induced-vibration response when compared with smooth whiskers. Although the unique hydrodynamic response has been well documented, an understanding of the fluid flow effects from each geometric feature remains incomplete. In this computational investigation, nondimensional geometric parameters of the seal whisker morphology are defined in terms of their hydrodynamic relevance, such that wavelength, aspect ratio, undulation amplitudes, symmetry and undulation off-set can be varied independently of one another. A two-factor fractional factorial design of experiments procedure is used to create 16 unique geometries, each of which dramatically amplifies or attenuates the geometric parameters compared with the baseline model. The flow over each unique topography is computed with a large-eddy simulation at a Reynolds number of 500 with respect to the mean whisker thickness and the effects on force and frequency are recorded. The results determine the specific fluid flow impact of each geometric feature which will inform both biologists and engineers who seek to understand the impact of whisker morphology or lay out a framework for biomimetic design of undulated structures.