Miracle-dz/UniFAR-FTUs huggingface dataset:
Initial configurations‐independent predefined performance control of robotic manipulator with input saturation

This article develops a guaranteed predefined performance control scheme for a class of robotic manipulators with input saturation and unknown uncertainties. The main advantage is that it can provide convenient and quantifiable predefined performance control, by integrating the 𝒦1 ‐class performance function in the prescribed performance control framework and designing an adaptive anti‐saturation compensator. The maximum overshoot, the settling time, and the steady‐state error can be specified independently and are not limited by the initial configurations of the robotic system, where the introduction of 𝒦1 ‐class performance function simplifies the control design. By introducing the adaptive neural network estimator and anti‐saturation compensator, the proposed robust controller is also available in the presence of dynamic uncertainties, external disturbance, and actuator saturation. The proposed adaptive anti‐saturation compensator can be easily incorporated into the guaranteed predefined performance control, which simplifies the stability analysis. Numerical results based on simulations demonstrate the effectiveness of the proposed method.
An ordered crossover based approach to designing labeling diversity mappers

Genetic algorithms (GAs) are population‐based search optimization techniques that mimic the process of evolution and natural selection. GAs are an effective way of finding feasible solutions to complex problems. Recently, GAs were applied to the labeling diversity (LD) problem that produced local optimal mappers for M‐QAM, M‐PSK, and M‐APSK constellations. However, the GA did not implement biological processes during the mating process; hence it could not be classified as a GA, but rather a genetic‐inspired algorithm (GIA). In this article, we investigate the application of six distinct crossover techniques to further improve the GIAs ability to produce more closer‐to‐optimal mapper designs. By using biological crossover techniques, offspring produced acquires genetic diversity from parent chromosomes. Single parent crossover techniques do not produce diversified offspring, thus diversity being acquired only by mutation. The Davis ordered crossover (OX1) was chosen as a suitable technique to be applied to the proposed GA. The proposed GA was tested on 16QAM, 16PSK, 16APSK, and three 16APSK constellations that do not exhibit diagonal symmetry. In the case of the 16QAM and 16PSK constellations, the proposed GA matched but did not improve upon existing mapper designs. In the case of the 16APSK and 11+5APSK constellations, the proposed GA produced mapper designs exhibited diversity gains of ≈0.5 dB over the existing GIA mapper designs at the BER of 10−6 . The asymmetric 16APSK and single symmetry 16APSK constellations exhibited diversity gains of ≈4 and ≈2 dB over existing GIA mapper designs at the BER of 10−3 and 10−5 . More significantly, the proposed GA achieved a significant improvement in time complexity. However, the proposed GA was shown to have higher computational complexity of O(M! ) over the GIA with a complexity of O(M2) . Mutation rate studies have shown that for single‐parent crossover techniques, higher mutation rates are needed, thus making the process is purely random. In the case of the two‐parent crossover technique, randomness is reduced and genetic diversity is increased, hence lower mutation rates were required due to a more guided search.
Re: Smartphone‐controlled patch electro‐acupuncture versus conventional pain relief during colonoscopy: a randomized controlled trial

We express our strong interest in the captioned article by Joan et al. who investigated the efficacy of smartphone-controlled patch electro-acupuncture as a substitute for pain relief during colonoscopy. We appreciate their study design and device application. However, we have the following concerns and suggestions from the point of view of a practitioner. First, the standardized international acupuncture nomenclature must be adopted to properly present abbreviations for meridians. Such international communication is possible only if a common language is used by all concerned. Thus, the Zusanli acupoint mentioned in the article should be professionally known as ST36 instead of S36, as Zusanli is the meridian point in the stomach meridian. Second, the locations of Zusanli acupoint were inaccurate. The authors stated that Zusanli acupuncture point is located below the knee, one-finger breadth lateral to the anterior crest of the tibia, three-finger breadth inferior to the hollow that is formed below the patella, and lateral to the patellar ligament when the knee is flexed. According to international standards, ST36 is located on the tibialis anterior muscle, on the line connecting ST35 (Dubi) with ST41 (Jiexi), 3B-cun inferior to ST35 (Fig. 1). In reality, B-cun is called proportional bone (skeletal) cun for short. The length and width between two points of particular joints are equally divided into such units. One unit is regarded as one cun. Therefore, three-finger breadth is not equal to 3B-cun. That is, the acupoint described in the article is not necessarily located on the 3B-cun inferior to ST35 and on the line connecting ST35 with ST41. On the basis of traditional Chinese medicine theory, the accuracy of acupoint location directly influences the therapeutic effect of acupuncture. Hence, the results of this study are dubious. In sum, describing the International Standard Code of acupoint and the location of points in the acupuncture clinical trials is important to improve the credibility of the final conclusion.
Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing

An ageing global population brings with it a significant burden of age-related morbidities. Recently, a novel intervention strategy to mitigate this burden has emerged, involving the use of Extracellular Vesicles (EV), comprising use of Microvesicles (MV) and Exosomes (Exo). These membranous vesicles are secreted by cells and mediate repair of cellular and tissue damage via paracrine mechanisms, involving interaction of their bioactive cargoes with stem cells. The actions of EV under normative and morbid conditions in the context of ageing remains largely unexplored. We now show that MV, but not Exo, from Pathfinder cells (PC), a putative stem cell regulatory cell type, enhance the repair of Human Dermal Fibroblast (HDF) and Mesenchymal Stem Cell (MSC) co-cultures following both mechanical and genotoxic stress. Critically, this effect was found to be both cellular age and stress-specific. Notably, MV treatment was unable to repair mechanical injury in older co-cultures, but still remained therapeutic following genotoxic stress. These observations were further confirmed in HDF and Vascular Smooth Muscle Cell (VSMC) co-cultures of increasing cellular age. In a model of comorbidity, comprising co-cultures of HDF and highly senescent Abdominal Aortic Aneurysm (AAA) VSMC, MV administration appeared to be senolytic following both mechanical and genotoxic stress, prior to enabling regeneration. To our knowledge, this is the first description of EV-based senolysis. It provides novel insight into understanding the biology of EV and the specific roles they play during tissue repair and ageing. These data will potentiate development of novel cell-free therapeutic interventions capable of attenuating age-associated morbidities and avoiding undesired effects. Ultimately, this might act as a possible intervention strategy to extend human healthspan.
Predictable Fluctuations in Excitatory Synaptic Strength Due to Natural Variation in Presynaptic Firing Rate

Many controlled in vitro studies have demonstrated how postsynaptic responses to presynaptic spikes are not constant but depend on short-term synaptic plasticity (STP) and the detailed timing of presynaptic spikes. However, the effects of short-term plasticity (depression and facilitation) are not limited to short, subsecond timescales. The effects of STP appear on long timescales as changes in presynaptic firing rates lead to changes in steady-state synaptic transmission. Here, we examine the relationship between natural variations in the presynaptic firing rates and spike transmission in vivo. Using large-scale spike recordings in awake male and female mice from the Allen Institute Neuropixels dataset, we first detect putative excitatory synaptic connections based on cross-correlations between the spike trains of millions of pairs of neurons. For the subset of pairs where a transient, excitatory effect was detected, we use a model-based approach to track fluctuations in synaptic efficacy and find that efficacy varies substantially on slow (∼1 min) timescales over the course of these recordings. For many connections, the efficacy fluctuations are correlated with fluctuations in the presynaptic firing rate. To understand the potential mechanisms underlying this relationship, we then model the detailed probability of postsynaptic spiking on a millisecond timescale, including both slow changes in postsynaptic excitability and monosynaptic inputs with short-term plasticity. The detailed model reproduces the slow efficacy fluctuations observed with many putative excitatory connections, suggesting that these fluctuations can be both directly predicted based on the time-varying presynaptic firing rate and, at least partly, explained by the cumulative effects of STP. SIGNIFICANCE STATEMENT The firing rates of individual neurons naturally vary because of stimuli, movement, and brain state. Models of synaptic transmission predict that these variations in firing rates should be accompanied by slow fluctuations in synaptic strength because of short-term depression and facilitation. Here, we characterize the magnitude and predictability of fluctuations in synaptic strength in vivo using large-scale spike recordings. For putative excitatory connections from a wide range of brain areas, we find that typical synaptic efficacy varies as much as ∼70%, and in many cases the fluctuations are well described by models of short-term synaptic plasticity. These results highlight the dynamic nature of in vivo synaptic transmission and the interplay between synaptic strength and firing rates in awake animals.
The EGFR/ErbB inhibitor neratinib modifies the neutrophil phosphoproteome and promotes apoptosis and clearance by airway macrophages

Dysregulated neutrophilic inflammation can be highly destructive in chronic inflammatory diseases due to prolonged neutrophil lifespan and continual release of histotoxic mediators in inflamed tissues. Therapeutic induction of neutrophil apoptosis, an immunologically silent form of cell death, may be beneficial in these diseases, provided that the apoptotic neutrophils are efficiently cleared from the tissue. Our previous research identified ErbB inhibitors as able to induce neutrophil apoptosis and reduce neutrophilic inflammation both in vitro and in vivo (Rahman et al., 2019). Here we extend that work using a clinical ErbB inhibitor, neratinib, which has the potential to be repurposed in inflammatory diseases. We show that neratinib reduces neutrophilic migration to an inflammatory site in zebrafish larvae. Neratinib upregulates efferocytosis and reduces the number of persisting neutrophil corpses in mouse models of acute, but not chronic, lung injury, suggesting the drug may have therapeutic benefits in acute inflammatory settings. Phosphoproteomics analysis of human neutrophils shows that neratinib modifies the phosphorylation of proteins regulating apoptosis, migration and efferocytosis. This work identifies a potential mechanism for neratinib in treating acute lung inflammation by upregulating the clearance of dead neutrophils and, through examination of the neutrophil phosphoproteome, provides important insights into the mechanisms by which this may be occurring.
Age- and episodic memory-related differences in task-based functional connectivity in women and men

Aging is associated with episodic memory decline and changes in functional brain connectivity. Understanding whether and how biological sex influences age- and memory performance-related functional connectivity has important theoretical and clinical implications for our understanding of brain and cognitive aging. Yet, little is known about the effect of sex on neurocognitive aging. Here, we scanned 161 healthy adults between 19-76 yrs of age in an event-related functional magnetic resonance imaging (fMRI) study of face-location spatial context memory. Adults were scanned while performing easy and difficult versions of the task at both encoding and retrieval. We used multivariate whole-brain partial least squares (PLS) connectivity to test the hypothesis that there are sex differences in age- and episodic memory performance-related functional connectivity. We examined how individual differences in age and retrieval accuracy correlated with task-related connectivity. We then repeated this analysis after disaggregating the data by self-reported sex. We found that increased encoding and retrieval-related connectivity within the dorsal attention network (DAN), and between DAN and frontoparietal network (FPN) and visual networks, was positively correlated to retrieval accuracy and negatively correlated with age in both sexes. We also observed sex differences in age- and performance-related functional connectivity: i) greater between-network integration was apparent at both levels of task difficulty in women only, and ii) increased DAN-DMN connectivity with age was observed in men and was correlated with poorer memory performance. Therefore, the neural correlates of age-related episodic memory decline differ in women and men and has important theoretical and clinical implications for the cognitive neuroscience of memory, aging and dementia prevention.
Tauroursodeoxycholic Acid Inhibits Clostridioides difficile Toxin-Induced Apoptosis

C. difficile infection (CDI) is a highly inflammatory disease mediated by the production of two large toxins that weaken the intestinal epithelium and cause extensive colonic tissue damage. Antibiotic alternative therapies for CDI are urgently needed as current antibiotic regimens prolong the perturbation of the microbiota and lead to high disease recurrence rates. ABSTRACT C. difficile infection (CDI) is a highly inflammatory disease mediated by the production of two large toxins that weaken the intestinal epithelium and cause extensive colonic tissue damage. Antibiotic alternative therapies for CDI are urgently needed as current antibiotic regimens prolong the perturbation of the microbiota and lead to high disease recurrence rates. Inflammation is more closely correlated with CDI severity than bacterial burden, thus therapies that target the host response represent a promising yet unexplored strategy for treating CDI. Intestinal bile acids are key regulators of gut physiology that exert cytoprotective roles in cellular stress, inflammation, and barrier integrity, yet the dynamics between bile acids and host cellular processes during CDI have not been investigated. Here we show that several bile acids are protective against apoptosis caused by C. difficile toxins in Caco-2 cells and that protection is dependent on conjugation of bile acids. Out of 20 tested bile acids, taurine conjugated ursodeoxycholic acid (TUDCA) was the most potent inhibitor, yet unconjugated UDCA did not alter toxin-induced apoptosis. TUDCA treatment decreased expression of genes in lysosome associated and cytokine signaling pathways. TUDCA did not affect C. difficile growth or toxin activity in vitro whereas UDCA significantly reduced toxin activity in a Vero cell cytotoxicity assay and decreased tcdA gene expression. These results demonstrate that bile acid conjugation can have profound effects on C. difficile as well as the host and that conjugated and unconjugated bile acids may exert different therapeutic mechanisms against CDI.
Spatial reasoning via recurrent neural dynamics in mouse retrosplenial cortex

From visual perception to language, sensory stimuli change their meaning depending on prior experience. Recurrent neural dynamics can interpret stimuli based on externally cued context, but it is unknown whether similar dynamics can compute and employ internal hypotheses to resolve ambiguities. Here, we show that mouse retrosplenial cortex (RSC) can form hypotheses over time and perform spatial reasoning through recurrent dynamics. In our task, mice navigated using ambiguous landmarks that are identified through their mutual spatial relationship, requiring sequential refinement of hypotheses. Neurons in RSC and in artificial neural networks encoded mixtures of hypotheses, location, and sensory information, and were constrained by robust low dimensional dynamics. RSC encoded hypotheses as locations in activity space with divergent trajectories for identical sensory inputs, enabling their correct interpretation. Our results indicate that interactions between internal hypotheses and external sensory data in recurrent circuits can provide a substrate for complex sequential cognitive reasoning.
The cilia enriched oxysterol 7β,27-DHC is required for polycystin activation

PC-1 and PC-2 form a heteromeric ion channel complex (hereafter called the Polycystin complex) that is abundantly expressed on primary cilia of renal epithelial cells. Mutations within the polycystin complex cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). The Polycystin complex forms a non-selective cation channel, yet the spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood, partially due to technical limitations posed by the tiny ciliary compartment. Here, we employ our novel assays to functionally reconstitute the polycystin complex in the plasma membrane. Using whole-cell and ciliary patch-clamp recordings we identified a ciliary enriched oxysterol, 7β,27-DHC, as a critical component required for activation of the polycystin complex. We identified a novel oxysterol binding pocket in PC-2 using molecular docking simulation. We also identified two amino acids within the PC-2 oxysterol binding pocket, E208 and R581, to be critical for 7β,27-DHC dependent polycystin activation in both the plasma membrane and ciliary compartment. Further, we can show that the pharmacological and genetic inhibition of oxysterol synthesis by carbenoxolone (CNX) reduces channel activity in primary cilia. Our findings identified a unique second messenger that regulates the polycystin complex. We hypothesize that cilia-enriched lipids license the polycystin complex to be functional only in the ciliary organelle, thus providing novel insights into the spatial regulation of the polycystin complex. Our results also establish a framework to target the same allosteric regulatory site in the polycystin complex to identify activators of the polycystin channels as novel therapeutic strategies for ADPKD.
Mutation of Arabidopsis SME1 and Sm core assembly improves oxidative stress resilience

Alternative splicing is a key posttranscriptional gene regulatory process, acting in diverse adaptive and basal plant processes. Splicing of precursor-messenger RNA (pre-mRNA) is catalyzed by a dynamic ribonucleoprotein complex, designated the spliceosome. In a suppressor screen, we identified a nonsense mutation in the Sm protein SME1 to alleviate photorespiratory H2O2-dependent cell death in catalase deficient plants. Similar attenuation of cell death was observed upon chemical inhibition of the spliceosome, suggesting pre-mRNA splicing inhibition to be responsible for the observed cell death alleviation. Furthermore, the sme1-2 mutants showed increased tolerance to the reactive oxygen species inducing herbicide methyl viologen. Both an mRNA-seq and shotgun proteomic analysis in sme1-2 mutants displayed a constitutive molecular stress response, together with extensive alterations in pre-mRNA splicing of transcripts encoding metabolic enzymes and RNA binding proteins, even under unstressed conditions. Using SME1 as a bait to identify protein interactors, we provide experimental evidence for almost 50 homologs of mammalian spliceosome-associated protein to reside in the Arabidopsis thaliana spliceosome complexes and propose roles in pre-mRNA splicing for four uncharacterized plant proteins. Furthermore, like in sme1-2, a mutant in the Sm core assembly protein ICLN resulted in a decreased sensitivity to methyl viologen. Taken together, these data show that both a perturbed Sm core composition and assembly results in the activation of a defense response and enhanced resilience to oxidative stress.
CanSig: Discovering de novo shared transcriptional programs in single cancer cells

Human tumors are highly heterogeneous in their cell composition; specifically, they exhibit heterogeneity in transcriptional states of malignant cells, as has been recently discovered through single-cell RNA sequencing (scRNA-seq). Distinct states of malignant cells have been linked to variability in tumorigenic properties and resistance to anti-cancer treatment. Despite the fact that scRNA-seq data contain all necessary information to uncover shared transcriptional states of malignant cells in tumors, jointly analyzing cells from multiple cancer patients comes with its set of challenges including batch correction and accounting for patient-specific genetic background driving differences between gene expression vectors. We propose CanSig, an easy-to-use approach designed to discover known and de novo shared signatures in cancer single cells. CanSig preprocesses, integrates and analyzes scRNA-seq data to provide new signatures of shared transcriptional states and links these states to known pathways. We show that CanSig successfully rediscovers ground truth pathways determining shared transcriptional states in two simulated and three experimental datasets; the latter spanning 135 patients and 72,000 cells. We then illustrate CanSig’s investigative potential by discovering novel signatures in esophageal squamous cell carcinoma possibly linked to targeted patient treatment; we also point out a de novo signature in breast cancer predictive of patients’ survival. In the cancer types studied, we juxtapose copy number variation with discovered shared transcriptional states and uncover a genetic component predisposing cancer cells to activation of specific transcriptional programs. In sum, CanSig, specifically developed to analyze shared transcriptional heterogeneity of malignant cells of different genetic backgrounds, can greatly facilitate the exploratory analysis of scRNA-seq cancer data and efficiently identify novel transcriptional signatures linked to known biological pathways.