Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanotaxis directs Pseudomonas aeruginosa twitching motility

Significance Single cells across kingdoms of life explore, prey, escape, or congregate using surface-specific motility. Motile eukaryotic cells use chemotaxis to direct migration on surfaces. However, how bacteria control surface motility remains underexplored. Pseudomonas aeruginosa twitches on surfaces by successive extension and retraction of extracellular filaments called type IV pili. Here, we show that P. aeruginosa directs twitching by sensing mechanical input generated by type IV pili. The Chp sensory system performs spatially resolved mechanosensing by harnessing two response regulators with antagonistic functions. Our results demonstrate that sensory systems, whose input often remains elusive, can sense mechanical signals to actively steer motility. Furthermore, Chp establishes a signaling principle shared with higher-order organisms, identifying a conserved strategy to transduce spatially resolved signals. The opportunistic pathogen Pseudomonas aeruginosa explores surfaces using twitching motility powered by retractile extracellular filaments called type IV pili (T4P). Single cells twitch by sequential T4P extension, attachment, and retraction. How single cells coordinate T4P to efficiently navigate surfaces remains unclear. We demonstrate that P. aeruginosa actively directs twitching in the direction of mechanical input from T4P in a process called mechanotaxis. The Chp chemotaxis-like system controls the balance of forward and reverse twitching migration of single cells in response to the mechanical signal. Collisions between twitching cells stimulate reversals, but Chp mutants either always or never reverse. As a result, while wild-type cells colonize surfaces uniformly, collision-blind Chp mutants jam, demonstrating a function for mechanosensing in regulating group behavior. On surfaces, Chp senses T4P attachment at one pole, thereby sensing a spatially resolved signal. As a result, the Chp response regulators PilG and PilH control the polarization of the extension motor PilB. PilG stimulates polarization favoring forward migration, while PilH inhibits polarization, inducing reversal. Subcellular segregation of PilG and PilH efficiently orchestrates their antagonistic functions, ultimately enabling rapid reversals upon perturbations. The distinct localization of response regulators establishes a signaling landscape known as local excitation–global inhibition in higher-order organisms, identifying a conserved strategy to transduce spatially resolved signals.
Validation of the Munich Actimetry Sleep Detection Algorithm for estimating sleep-wake patterns from activity recordings

Periods of sleep and wakefulness can be estimated from wrist-locomotor activity recordings via algorithms that identify periods of relative activity and inactivity. Here, we evaluated the performance of our Munich Actimetry Sleep Detection Algorithm (MASDA). MASDA uses a moving 24-hour-threshold and correlation procedure estimating relatively consolidated periods of sleep and wake. MASDA was validated against sleep logs and polysomnography. Sleep-log validation was performed on 2 field samples collected over 54 and 34 days (median) in 34 adolescents and 28 young adults. Polysomnographic validation was performed on a clinical sample of 23 individuals undergoing 1 night of polysomnography. Epoch-by-epoch analyses were conducted and comparisons of sleep measures via Bland-Altman plots and correlations. Compared with sleep logs, MASDA classified sleep with a median sensitivity of 80% (IQR = 75-86%) and specificity of 91% (87-92%). Mean onset and offset times were highly correlated (r = 0.86-0.91). Compared with polysomnography, MASDA reached a median sensitivity of 92% (85-100%), but low specificity of 33% (10-98%), owing to the low frequency of wake episodes in the nighttime polysomnographic recordings. MASDA overestimated sleep onset (~21 min) and underestimated wake after sleep onset (~26 min), while not performing systematically different from polysomnography in other sleep parameters. These results demonstrate the validity of MASDA to faithfully estimate sleep-wake patterns in field studies. With its good performance across day- and nighttime, it enables analyses of sleep-wake patterns in long recordings performed to assess circadian and sleep regularity and is therefore an excellent objective alternative to sleep logs in field settings.
Sauna-like conditions or menthol treatment reduce tau phosphorylation through mild hyperthermia

In Alzheimer’s disease (AD), hyper-phosphorylation and aggregation of tau correlates with clinical progression and represents a valid therapeutic target. A recent 20-year prospective study revealed an association between moderate to high frequency of Finnish sauna bathing and a lower incidence of dementia and AD, but the molecular mechanisms underlying these benefits remain uncertain. Here, we tested the hypothesis that sauna-like conditions could lower tau phosphorylation by increasing body temperature. We observed a decrease in tau phosphorylation in wild-type and hTau mice as well as in neuron-like cells when exposed to higher temperatures. These effects were correlated with specific changes in phosphatase and kinase activities, but not with inflammatory or heat-shock responses. We also used a drug strategy to promote thermogenesis. Topical application of menthol led to a sustained increase in body temperature in hTau mice concomitant with a significant decrease in tau phosphorylation. Our results suggest that sauna-like conditions or menthol treatment could lower tau pathology through mild hyperthermia, and may provide promising therapeutic strategies for AD and other tauopathies.
Genome-wide analysis of mobile element insertions in human genomes

Mobile element insertions (MEIs) are a major class of structural variants (SVs) and have been linked to many human genetic disorders, including hemophilia, neurofibromatosis, and various cancers. However, human MEI resources from large-scale genome sequencing are still lacking compared to those for SNPs and SVs. Here, we report a comprehensive map of 36,699 non-reference MEIs constructed from 5,675 genomes, comprising 2,998 Chinese samples (∼26.2X, NyuWa) and 2,677 samples from the 1000 Genomes Project (∼7.4X, 1KGP). We discovered that LINE-1 insertions were highly enriched at centromere regions, implying the role of chromosome context in retroelement insertion. After functional annotation, we estimated that MEIs are responsible for about 9.3% of all protein-truncating events per genome. Finally, we built a companion database named HMEID for public use. This resource represents the latest and largest genomewide study on MEIs and will have broad utility for exploration of human MEI findings.
Neutralization of UK-variant VUI-202012/01 with COVAXIN vaccinated human serum

We performed the plaque reduction neutralization test (PRNT50) using sera collected from the recipients of BBV152/COVAXIN™ against hCoV-19/India/20203522 (UK-variant) and hCoV27 19/India/2020Q111 (heterologous strain). A comparable neutralization activity of the vaccinated individuals sera showed against UK-variant and the heterologous strain with similar efficiency, dispel the uncertainty of possible neutralization escape.
Circuit organization of the excitatory sensorimotor loop through hand/forelimb S1 and M1

Sensory-guided limb control relies on communication across sensorimotor loops. For active touch with the hand, the longest loop is the transcortical continuation of ascending pathways, particularly the lemnisco-cortical and corticocortical pathways carrying tactile signals via the cuneate nucleus, ventral posterior lateral (VPL) thalamus, and primary somatosensory (S1) and motor (M1) cortices to reach corticospinal neurons and influence descending activity. We characterized excitatory connectivity along this pathway in the mouse. In the lemnisco-cortical leg, disynaptic cuneate→VPL→S1 connections excited mainly layer (L) 4 neurons. In the corticocortical leg, S1→M1 connections from L2/3 and L5A neurons mainly excited downstream L2/3 neurons, which excite corticospinal neurons. The findings provide a detailed new wiring diagram for the hand/forelimb-related transcortical circuit, delineating a basic but complex set of cell-type-specific feedforward excitatory connections that selectively and extensively engage diverse intratelencephalic projection neurons, thereby polysynaptically linking subcortical somatosensory input to cortical motor output to spinal cord.
Resource selection by the Endangered Arabian tahr: identifying critical habitats for conservation and climate change adaptation

The Arabian tahr is an Endangered mountain ungulate endemic to the Hajar Mountains of Arabia. The Arabian tahr population is in decline and threats to tahr habitat are intensifying, in addition new potential challenges from climate change are emerging. Fundamental to future conservation planning is understanding tahr habitat selection patterns, so we can prioritise habitat protection, and understand how habitat may be used to provide thermal refuge and allow adaptation to climate change impacts. We used GPS collars and resource selection functions to characterise Arabian tahr habitat preferences in Wadi Sareen Nature Reserve, Oman. We found tahr habitat selection was dependent on scale, sex and season. Vegetation resources were only selected at the smallest scales of selection and avoided at other scales. Habitat providing low heat load and thermal refuge were intensely selected at small and medium scales, by both sexes and in both seasons, suggesting the importance of thermal refuges in facilitating thermoregulation. Higher elevations, steep slopes and rugged habitats were selected across all scales tested here, and in previous landscape-scale studies, indicating the fundamental importance of these habitats in supporting Arabian tahr populations. Our results identified critical habitats required to sustain Arabian tahr, and demonstrated the importance of thermal refuges to species living in the hot climates such as the Arabian Peninsula. Given the accessibility of habitat layers, and ease in which the identified habitats can be mapped using a geographical information system, understanding the habitat selection of tahr and other species is a crucial step to increasing conservation management capacity of threatened species. Given our uncertainty of how to conserve wildlife under future climate change, understanding the availability and distribution of wildlife habitat is an important baseline from where we can plan, connect and preserve the resources necessary for wildlife conservation.
Comprehensive analysis of male-free reproduction in Monomorium triviale (Formicidae: Myrmicinae)

We report comprehensive evidence for obligatory thelytokous parthenogenesis in an ant Monomorium triviale. This species is characterized by distinct queen–worker dimorphism with strict reproductive division of labor: queens produce both workers and new queens without mating, whereas workers are completely sterile. We collected 333 nests of this species from 14 localities and three laboratory-reared populations in Japan. All wild queens dissected had no sperm in their spermathecae. Laboratory observation confirmed that virgin queens produced workers without mating. Furthermore, microsatellite genotyping showed identical heterozygous genotypes between mothers and their respective daughters, suggesting an extremely low probability of sexual reproduction. Microbial analysis detected no bacterial genera that are known to induce thelytokous parthenogenesis in Hymenoptera. Finally, the lack of variation in partial sequences of mitochondrial DNA among individuals sampled from across Japan suggests recent rapid spread or selective sweep. M. triviale would be a promising model system of superorganism-like adaptation through comparative analysis with well-studied sexual congeners, including the pharaoh ant M. pharaonis.
Reliance on polyfunctional tissue leads to a reproduction-immunity tradeoff due to inherent constraint

The use of one tissue for multiple purposes can result in constraints, impaired function, and tradeoffs. The insect fat body performs remarkably diverse functions including metabolic control, reproductive provisioning, and systemic immune responses. Immunity and reproduction are observed to trade off in many organisms, although the mechanistic basis for the tradeoff is generally unknown. More generally, how do polyfunctional tissues simultaneously execute multiple distinct physiological functions? Using single-nucleus sequencing, we determined the Drosophila melanogaster fat body executes diverse basal functions with heterogenous cellular subpopulations. However, as an emergency function, the immune response engages the entire tissue. We found that reproductively active females exhibit impaired capacity to produce new protein in response to infection, resulting in the reproduction-immunity tradeoff. We suggest that such inherent internal limitations may provide a general explanation for the wide prevalence of physiological and evolutionary tradeoffs.
In-frame deletion of SPECC1L microtubule binding domain results in embryonic tissue movement and fusion defects

Embryonic morphogenesis of the neural tube, palate, ventral body wall and optic fissure require precise sequence of tissue movement and fusion, which if incomplete, leads to anencephaly/exencephaly, cleft palate, omphalocele and coloboma, respectively. These are genetically heterogeneous birth defects, so there is a continued need to identify etiologic genes. Patients with autosomal dominant SPECC1L mutations show syndromic malformations, including hypertelorism, cleft palate and omphalocele. These SPECC1L mutations cluster in the second coiled-coil domain (CCD2), which facilitates association with microtubules. To study SPECC1L function in mice, we first generated a null allele (Specc1lΔEx4) lacking the entire SPECC1L protein. Homozygous mutants for these truncations died perinatally without cleft palate or exencephaly. Given the clustering of human mutations in CCD2, we hypothesized that targeted perturbation of CCD2 may be required. Indeed, homozygotes for in-frame deletions involving CCD2 (Specc1lΔCCD2) resulted in ~50% exencephaly and ~50% cleft palate. Interestingly, these two phenotypes are never observed in the same embryo. Examination of embryos with and without exencephaly revealed that the oral cavity was narrower in exencephalic embryos, which allowed palatal shelves to elevate despite their defect. In contrast to an evenly distributed subcellular expression pattern, mutant SPECC1L-ΔCCD2 protein showed abnormal subcellular localization, decreased overlap with microtubules, increased actin bundles, and dislocated non-muscle myosin II to the cell cortex. Thus, we show that perturbations of CCD2 in the context of full SPECC1L protein affects tissue fusion dynamics, indicating that human SPECC1L CCD2 mutations are gain-of-function. Improper SPECC1L subcellular localization appears to disrupt connections between actomyosin and microtubule networks, which in turn may affect cell alignment and coordinate movement during tissue morphogenesis.
The neural response to the temporal fine structure of continuous musical pieces is not affected by selective attention

Speech and music are spectro-temporally complex acoustic signals that a highly relevant for humans. Both contain a temporal fine structure that is encoded in the neural responses of subcortical and cortical processing centres. The subcortical response to the temporal fine structure of speech has recently been shown to be modulated by selective attention to one of two competing voices. Music similarly often consists of several simultaneous melodic lines, and a listener can selectively attend to a particular one at a time. However, the neural mechanisms that enable such selective attention remain largely enigmatic, not least since most investigations to date have focussed on short and simplified musical stimuli. Here we study the neural encoding of classical musical pieces in human volunteers, using scalp electroencephalography (EEG) recordings. We presented volunteers with continuous musical pieces composed of one or two instruments. In the latter case, the participants were asked to selectively attend to one of the two competing instruments and to perform a vibrato identification task. We used linear encoding and decoding models to relate the recorded EEG activity to the stimulus waveform. We show that we can measure neural responses to the temporal fine structure of melodic lines played by one single instrument, at the population level as well as for most individual subjects. The neural response peaks at a latency of 7.6 ms and is not measurable past 15 ms. When analysing the neural responses elicited by competing instruments, we find no evidence of attentional modulation. Our results show that, much like speech, the temporal fine structure of music is tracked by neural activity. In contrast to speech, however, this response appears unaffected by selective attention in the context of our experiment.
Enhanced Cas12a multi-gene regulation using a CRISPR array separator

The type V-A Cas12a protein can process its CRISPR array, a feature useful for multiplexed gene editing and regulation. However, CRISPR arrays often exhibit unpredictable performance due to interference between multiple crRNAs. Here, we report that Cas12a array performance is hypersensitive to the GC content of crRNA spacers, as high-GC spacers can impair activity of the downstream crRNA. We analyzed naturally occurring CRISPR arrays and observed that repeats always contain an AT-rich fragment that separates crRNAs; we term this fragment a CRISPR separator. Inspired by this observation, we designed short, AT-rich synthetic separators (synSeparators) that successfully removed the disruptive effects between crRNAs. We demonstrate enhanced simultaneous activation of seven endogenous genes in human cells using an array containing the synSeparator. These results elucidate a previously unknown feature of natural CRISPR arrays and demonstrate how nature-inspired engineering solutions can improve multi-gene control in mammalian cells.
A novel swine model of the acute respiratory distress syndrome using clinically relevant injury exposures

To date, existing animal models of the acute respiratory distress syndrome (ARDS) have failed to translate preclinical discoveries into effective pharmacotherapy or diagnostic biomarkers. To address this translational gap, we developed a high-fidelity swine model of ARDS utilizing clinically-relevant lung injury exposures. Fourteen male swine were anesthetized, mechanically ventilated, and surgically instrumented for hemodynamic monitoring, blood, and tissue sampling. Animals were allocated to one of three groups: 1) Indirect lung injury only: animals were inoculated by direct injection of E. coli into the kidney parenchyma, provoking systemic inflammation and distributive shock physiology; 2) Direct lung injury only: animals received volutrauma, hyperoxia, and bronchoscope-delivered gastric particles; 3) Combined indirect and direct lung injury: animals were administered both above-described indirect and direct lung injury exposures. Animals were monitored for up to 12 hours, with serial collection of physiologic data, blood samples, and radiographic imaging. Lung tissue was acquired post-mortem for pathological examination. In contrast to indirect lung injury only and direct lung injury only groups, animals in the combined indirect and direct lung injury group exhibited all of the physiological, radiographic, and histopathologic hallmarks of human ARDS: impaired gas exchange (mean PaO2/FiO2 ratio 124.8 ± 63.8), diffuse bilateral opacities on chest radiographs, and extensive pathologic evidence of diffuse alveolar damage. Our novel porcine model of ARDS, built on clinically-relevant lung injury exposures, faithfully recapitulates the physiologic, radiographic, and histopathologic features of human ARDS, and fills a crucial gap in the translational study of human lung injury.
CONTROLLING COCKROACH POPULATIONS IN HUMAN AND ANIMAL HABITATIONS BY REDUCING FOOD AVAILABILITY

Background Cockroaches, carriers of pathogenic organisms that cause human and animal disease, typically have access to human or pet food in bowls, allowing cockroaches to expand their colonies and infestations. Hypothesis We hypothesized that existing anti-ant technology could be converted to anti-cockroach technology by simple design changes. Methods A base of various heights was affixed to the bottom of an anti-ant bowl to increase the distance of the anti-ant shield from the native height “x” to the hypothesized cockroach-resistant height “z”. The effects of z =0, 12.7, 15.9, 19.1, 25.4, 44.5, and 57.2 mm were studied. 118.3 cc (4 oz) of dry cat food was used as cockroach bait. The modified anti-ant bowls were placed in a high-intensity cockroach environment during summer nights where the temperatures varied between 23.9-29.4 degrees Celsius for 3 hours and then cockroach counts were performed. Ten runs at each height z were performed. Results Mean numbers of infesting cockroaches ± SD at each height z were 21.3±2.9 at 0 mm, 22.0±2.9 at 12.7 mm, 11.2±2.6 at 15.9 mm, 0.9±0.8 at 19.1mm, 0.4±0.5 at 25.4 mm, 0±0 at 44.5 mm, and 0±0 at 57.2 mm (p<0.001 with z≥15.9 mm for all). Cockroach numbers began declining when z = 15.9 mm and declined to only large cockroaches at z = 25.4 mm. The cockroaches that were able to overcome the z =25.4 mm were the larger American cockroaches that can exceed 76.2 mm (3 inch) in length. However, at z = 44.5 mm and 57.2 mm no cockroaches penetrated the modified bowl. Conclusions To defeat the majority of species of cockroaches the anti-insect shield should be at a height of at least 25.4 mm and to defeat the larger American cockroaches preferably greater than 25.4 mm with 44.5 mm and 57.2 mm defeating all tested cockroaches
Fish primary embryonic stem cells self-assemble into retinal tissue mirroring in vivo early eye development

Organoids derived from pluripotent stem cells promise the solution to current challenges in basic and biomedical research. Further progress and widespread applications are however limited by long developmental time, variable success, and lack of direct comparison to an in vivo reference. To overcome those limitations, we derived organoids from rapidly developing teleosts. We demonstrate how primary embryonic stem cells from zebrafish and medaka efficiently self-organize into anterior neural structures, particularly retina. Within four days, blastula-stage cell aggregates reproducibly execute key steps of eye development: retinal specification, morphogenesis and differentiation. The number of aggregated cells as well as genetic factors crucially impacted upon the concomitant morphological changes that were intriguingly reflecting the in vivo situation. High reproducibility and rapid development of fish-derived organoids in combination with advanced genome editing techniques immediately allow addressing aspects of development and disease, and systematically probing the impact of the physical environment on morphogenesis and differentiation.