Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of a rapid, sensitive detection method for SARS‐CoV‐2 and influenza virus based on recombinase polymerase amplification combined with CRISPR‐Cas12a assay

Respiratory tract infections are associated with the most common diseases transmitted among people and remain a huge threat to global public health. Rapid and sensitive diagnosis of causative agents is critical for timely treatment and disease control. Here, we developed a novel method based on recombinase polymerase amplification (RPA) combined with CRISPR‐Cas12a to detect three viral pathogens, including SARS‐CoV‐2, influenza A, and influenza B, which cause similar symptom complexes of flu cold in the respiratory tract. The detection method can be completed within 1 h, which is faster than other standard detection methods, and the limit of detection is approximately 102 copies/μL. Additionally, this detection system is highly specific and there is no cross‐reactivity with other common respiratory tract pathogens. Based on this assay, we further developed a more simplified RPA/CRISPR‐Cas12a system combined with lateral flow assay on a manual microfluidic chip, which can simultaneously detect these three viruses. This low‐cost detection system is rapid and sensitive, which could be applied in the field and resource‐limited areas without bulky and expensive instruments, providing powerful tools for the point‐of‐care diagnostic.
sPDGFRβ and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study

Abstract INTRODUCTION There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high‐risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle‐aged Black/African American (B/AA) and non‐Hispanic White (NHW) participants. METHODS Adults (45–65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS CSF total tau (t‐tau), phosphorylated tau (p‐tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet‐derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t‐tau, p‐tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW. DISCUSSION Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race‐related differences in these relationships. Highlights Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high‐risk middle‐aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non‐Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.
An Effective and Universal Long-Read Sequencing-Based Approach for SMN1 2 + 0 Carrier Screening through Family Trio Analysis.

BACKGROUND Population-wide carrier screening for spinal muscular atrophy (SMA) is recommended by professional organizations to facilitate informed reproductive options. However, genetic screening for SMN1 2 + 0 carriers, accounting for 3%-8% of all SMA carriers, has been challenging due to the large gene size and long distance between the 2 SMN genes. METHODS Here we repurposed a previously developed long-read sequencing-based approach, termed comprehensive analysis of SMA (CASMA), to identify SMN1 2 + 0 carriers through haplotype analysis in family trios (CASMA-trio). Bioinformatics pipelines were developed for accurate haplotype analysis and SMN1 2 + 0 deduction. Seventy-nine subjects from 24 families composed of, at the minimum, 3 were enrolled, and CASMA-trio was employed to determine whether an index subject with 2 SMN1 copies was a 2 + 0 carrier in these families. For the proof-of-principle, SMN2 2 + 0 was also analyzed. RESULTS Among the 16 subjects with 2 SMN1 copies, CASMA-trio identified 5 subjects from 4 families as SMN1 2 + 0 carriers, which was consistent with pedigree analysis involving an affected proband. CASMA-trio also identified SMN2 2 + 0 in six out of 43 subjects with 2 SMN2 copies. Additionally, CASMA-trio successfully determined the distribution pattern of SMN1 and SMN2 genes on 2 alleles in all 79 subjects. CONCLUSIONS CASMA-trio represents an effective and universal approach for SMN1 2 + 0 carriers screening, as it does not reply on the presence of an affected proband, certain single-nucleotide polymorphisms, ethnicity-specific haplotypes, or complicated single-nucleotide polymorphism analysis across 3 generations. Incorporating CASMA-trio into existing SMA carrier screening programs will greatly reduce residual risk ratio.
Effect of collateral circulation in patients with multiple craniocervical artery stenoses

Based on previous findings, collateral circulation in the brain is vital in mitigating cerebral ischemia's effects and influencing stroke risk. This retrospective study examined collateral circulation, admission ischemic stroke status, and long‐term recurrence in patients with multiple craniocervical artery stenoses. Consecutive symptomatic internal carotid artery (ICA) stenosis patients from the First Affiliated Hospital of Soochow University were recruited. Baseline data including medical histories and neurological function at admission were collected. Imaging techniques assessed collateral compensative capacity. Multivariate logistic regression analysis was used to investigate the association between collateral circulation and case status. A total of 559 patients with symptomatic ICA stenosis were included, among whom 153 (27.4%) had concurrent moderate to severe vertebro‐basilar artery (VBA) stenosis. Dizziness, weakness/numbness, and slurring of speech were the primary symptoms in all patients. Over 36 months, 71 (12.7%) patients experienced a recurrence of acute ischemic stroke (AIS). In multivariate analysis, collateral circulation was found to be negatively associated with AIS (regional leptomeningeal collateral [rLMC] scores: OR: 0.798, 95% CI: 0.743–0.857, p < 0.001; Tan scores: OR: 0.478, 95% CI: 0.336–0.679, p < 0.001). Meanwhile, the collateral circulation scores were significantly associated with the recurrence of AIS within 3 years (rLMC scores: OR: 0.926, 95% CI: 0.860–0.997, p = 0.042; Tan scores: OR: 0.467, 95% CI: 0.306–0.712, p < 0.001). Most associations remained significant in the subgroup of patients with VBA stenosis. Favorable collateral circulation in multiple craniocervical artery stenosis patients reduced long‐term ischemic event recurrence. Stratifying treatment risks is essential for optimizing outcomes.
Vascular protection with rivaroxaban in the comprehensive management of atrial fibrillation

ABSTRACT Introduction In addition to an increased risk of thromboembolic complications, patients with atrial fibrillation (AF) are at risk for vascular events. Consequently, complete vascular protection is warranted in these patients. Areas covered A narrative search was conducted on PubMed (MEDLINE), using the MeSH terms [Rivaroxaban] + [Atrial fibrillation] + [Cardiovascular] + [Vascular] + [Treatment]. Original data from clinical trials, prospective and retrospective studies, useful reviews and experimental studies, were selected. Expert opinion The ROCKET-AF trial showed that rivaroxaban is effective in reducing the risk of stroke, with a lower risk of fatal and intracranial bleeding compared to warfarin. Remarkably, experimental data have provided a number of pathogenic mechanisms through which rivaroxaban could provide beneficial vascular properties beyond its antithrombotic activity. Moreover, in the AF population, additional to its ability to reduce the risk of thromboembolic complications, rivaroxaban is associated with a lower risk of myocardial infarction, major adverse cardiac and limb events, and vascular mortality in patients with diabetes, also attenuating renal impairment during follow-up. These findings suggest that rivaroxaban may provide a comprehensive vascular protection in patients with AF.
Endoscopic ultrasound-guided ethanol ablation versus surgical resection of insulinomas

Abstract Purpose Insulinoma is a rare tumor of the pancreas that can lead to hypoglycemia. To date, the standard therapy is surgical resection. After the first case report of successful endoscopic ultrasound-guided (EUS) ethanol injection 16 years ago, the need for establishing an alternative treatment method remains unchanged given the high morbidity rates of surgery and its unsuitability in some patients. Materials and Methods Here, we provide retrospective data from 33 insulinoma patients that were treated at our center between 2010 and 2021. Of these, 9 patients were treated with EUS-guided ethanol injection and 24 underwent pancreatic surgery. Results The ethanol group was older (ethanol: mean ± SE 67.8±11.2 years vs. surgery: 52.3±15.7, p=0.014) with a higher Charlson Comorbidity Index (3.0 (1.0;4.0) vs. 1.0 (0.0;2.0), p=0.008). The lowest glucose values were similar between groups before (ethanol: 2.09±0.17 mmol/l vs. surgery: 1.81±0.08, p=0.158) and after (4.95±0.74 vs. 5.41±0.28, p=0.581) the respective treatments. Complications occurred more frequently in the surgery group (11 % vs. 54 %, p=0.026). One patient after prior partial pancreatectomy died postoperatively. The hospitalization time was significantly shorter in the ethanol group (4.78±0.78 days vs. 19.88±4.07, p<0.001). Conclusion EUS-guided ethanol injection can be similarly effective for the treatment of hyperinsulinemic hypoglycemia compared with pancreatic surgery but seems to be associated with less severe complications. This implies the need for prospective randomized trials in insulinoma patients with a low risk for malignancy.
Stacked fibula flap for unilateral total maxillectomy reconstruction with orbital preservation

Unilateral total maxillectomy is indicated for locally advanced maxillary tumors that require complete removal of the midface bony structure and inferior orbital rim. Reconstruction of this defect is challenging due to aesthetic and functional concerns. A retrospective review of patients at two tertiary‐care institutions undergoing unilateral total maxillectomy reconstruction with a stacked fibula flap from 2018 to 2022 was performed. Each patient's clinical course was reviewed, and attention was focused on the demonstration of surgical steps with photos. Twenty patients underwent stacked fibula flap reconstruction for unilateral total maxillectomy orbital preservation defects. Surgical extirpation was performed for malignancy (80%, 16/20) and for osteoradionecrosis or benign tumor in 20% (4/20). The complication rate was 30% (6/20). Most flaps survived (95%, 19/20). We present a modified, reproducible method of fibula flap reconstruction for unilateral total maxillectomy with orbital preservation that only requires two segments and maintains positive aesthetic and functional results.
Nestin Regulates Müller Glia Proliferation After Retinal Injury

Purpose The proliferative and neurogenic potential of retinal Müller glia after injury varies widely across species. To identify the endogenous mechanisms regulating the proliferative response of mammalian Müller glia, we comparatively analyzed the expression and function of nestin, an intermediate filament protein established as a neural stem cell marker, in the mouse and rat retinas after injury. Methods Nestin expression in the retinas of C57BL/6 mice and Wistar rats after methyl methanesulfonate (MMS)-induced photoreceptor injury was examined by immunofluorescence and Western blotting. Adeno-associated virus (AAV)-delivered control and nestin short hairpin RNA (shRNA) were intravitreally injected to rats and Müller glia proliferation after MMS-induced injury was analyzed by BrdU incorporation and immunofluorescence. Photoreceptor removal and microglia/macrophage infiltration were also analyzed by immunofluorescence. Results Rat Müller glia re-entered the cell cycle and robustly upregulated nestin after injury whereas Müller glia proliferation and nestin upregulation were not observed in mice. In vivo knockdown of nestin in the rat retinas inhibited Müller glia proliferation while transiently stimulating microglia/macrophage infiltration and phagocytic removal of dead photoreceptors. Conclusions Our findings suggest a critical role for nestin in the regulation of Müller glia proliferation after retinal injury and highlight the importance of cross species analysis to identify the molecular mechanisms regulating the injury responses of the mammalian retina.
A Novel Sensory Feedback Approach to Facilitate Both Predictive and Corrective Control of Grasping Force in Myoelectric Prostheses

Reliable force control is especially important when using myoelectric upper-limb prostheses as the force defines whether an object will be firmly grasped, damaged, or dropped. It is known from human motor control that the grasping of non-disabled subjects is based on a combination of anticipation and feedback correction. Inspired by this insight, the present study proposes a novel approach to provide artificial sensory feedback to the user of a myoelectric prosthesis using vibrotactile stimulation to facilitate both predictive and corrective processes characteristic of grasping in non-disabled people. Specifically, the level of EMG was conveyed to the subjects while closing the prosthesis (predictive strategy), whereas the actual grasping force was transmitted when the prosthesis closed (corrective strategy). To investigate if this combined EMG and force feedback is indeed an effective method to explicitly close the control loop, 16 non-disabled and 3 transradial amputee subjects performed a set of functional tasks, inspired by the “Box and Block” test, with six target force levels, in three conditions: no feedback, only EMG feedback, and combined feedback. The highest overall performance in non-disabled subjects was obtained with combined feedback (79.6±9.9%), whereas the lowest was achieved with no feedback (53±11.5%). The combined feedback, however, increased the task completion time compared to the other two conditions. A similar trend was obtained also in three amputee subjects. The results, therefore, indicate that the feedback inspired by human motor control is indeed an effective approach to improve prosthesis grasping in realistic conditions when other sources of feedback (vision and audition) are not blocked.
Establishing the link between motivational disturbances and behavioural rigidity in frontotemporal dementia

Rigid and inflexible behaviours are common in frontotemporal dementia (FTD), manifesting in compulsive pursuit of specific interests, routines, and rituals. Paradoxically, these changes occur alongside profound motivational disturbances including apathy and anhedonia. While posited to be related, no study to date has explored the link between motivational changes and behavioural rigidity in FTD.
A freak wave in the Black Sea: Observations and simulation

Recently, the problem of the generation of anomalous high waves of unusual form on the ocean surface has been at the center of intense theoretical and applied work. The phenomenon of anomalously high waves (often called freak waves) is related to the sudden generation of intense waves that can be two or more times as high as the significant wave height. The suddenness and large energy of these waves have resulted in numerous shipwrecks and deaths, and the history of such disasters is described, for example, in [1]. Researchers have suggested the following possible mechanisms for the generation of such waves: linear (or linear with account for nonlinear corrections) focusing of wave groups as a result of dispersion, variable conditions of wave propagation (variable bathymetry, change in direction, and trapping by currents), variable atmospheric forcing, nonlinear modulation instability, and interaction of soliton-type wave groups (see review [2]). In this paper, we give an example of a recorded wave in the Black Sea that is undoubtedly anomalous. We carried out analysis and numerical simulation of this wave, which allowed us to make a judgment about this wave’s spatial dynamics. An attempt was made to determine the mechanism of the formation of such waves. The results are compared with the numerical simulation of the evolution of the so-called New Year Wave that was performed in [3]. The New Year Wave became a popular object of investigation after being registered on an oil platform on January 1, 1995. The anomalous wave described in the present communication was characterized by specific features (in addition to those typical of previously recorded anomalous waves) that provided its more significant intensification relative to the New Year Wave. 1. Experimental data. Waves on the open part of the Black Sea are have been virtually unexplored using instrumental measurements (except for occasional onboard reports). The available coastal observations mostly represent short-term and episodic data. In 1996, a Directional Waverider Buoy (DATAWELL Co., Netherlands) was deployed in the open sea ( 44°30 ′ 40 N, 37°58 ′ 70 E; depth 85 m) near Gelendzhik [5, 6]. The buoy was intended for making direct measurements of wave parameters, including direction of propagation, preprocessing, and transfer of gathered data to a coastal receiving device. The data were transferred from the buoy to the coastal device via a radio channel every 3 h (every 1 h when the significant wave height exceeded 1.5 m). To date, the available volume and composition (dataset) of the software programmable information includes more than 15 000 wave records.
Establishing the Roles of the Dorsal and Ventral Striatum in Humor Comprehension and Appreciation with fMRI

Humor comprehension (i.e., getting a joke) and humor appreciation (i.e., enjoying a joke) are distinct, cognitively complex processes. Functional magnetic resonance imaging (fMRI) investigations have identified several key cortical regions but have overlooked subcortical structures that have theoretical importance in humor processing. The dorsal striatum (DS) contributes to working memory, ambiguity processing, and cognitive flexibility, cognitive functions that are required to accurately recognize humorous stimuli. The ventral striatum (VS) is critical in reward processing and enjoyment. We hypothesized that the DS and VS play important roles in humor comprehension and appreciation, respectively. We investigated the engagement of these regions in these distinct processes using fMRI. Twenty-six healthy young male and female human adults completed two humor-elicitation tasks during a 3 tesla fMRI scan consisting of a traditional behavior-based joke task and a naturalistic audiovisual sitcom paradigm (i.e., Seinfeld viewing task). Across both humor-elicitation methods, whole-brain analyses revealed cortical activation in the inferior frontal gyrus, the middle frontal gyrus, and the middle temporal gyrus for humor comprehension, and the temporal cortex for humor appreciation. Additionally, with region of interest analyses, we specifically examined whether DS and VS activation correlated with these processes. Across both tasks, we demonstrated that humor comprehension implicates both the DS and the VS, whereas humor appreciation only engages the VS. These results establish the role of the DS in humor comprehension, which has been previously overlooked, and emphasize the role of the VS in humor processing more generally. SIGNIFICANCE STATEMENT Humorous stimuli are processed by the brain in at least two distinct stages. First, humor comprehension involves understanding humorous intent through cognitive and problem-solving mechanisms. Second, humor appreciation involves enjoyment, mirth, and laughter in response to a joke. The roles of smaller subcortical brain regions in humor processing, such as the DS and VS, have been overlooked in previous investigations. However, these regions are involved in functions that support humor comprehension (e.g., working memory ambiguity resolution, and cognitive flexibility) and humor appreciation (e.g., reward processing, pleasure, and enjoyment). In this study, we used neuroimaging to demonstrate that the DS and VS play important roles in humor comprehension and appreciation, respectively, across two different humor-elicitation tasks.
Tuning the potency and selectivity of ImmTAC molecules by affinity modulation

Abstract T-cell-engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T-cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using immune mobilizing monoclonal TCRs against cancer (ImmTAC) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the redirected T-cell response. This class of bispecifics binds specific target peptides presented by human leukocyte antigen on the cell surface via an affinity-enhanced T-cell receptor and can redirect T-cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T-cell activation, while strong affinity of both targeting and effector domains significantly reduces maximum cytokine release. Moreover, by optimizing the affinity of both parts of the molecule, it is possible to improve the selectivity. These results could be effectively modelled based on kinetic proofreading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark state. These findings have important implications for the design of anti-CD3-based bispecifics with optimal biophysical parameters for both activity and specificity.
SCAN: Spatiotemporal Cloud Atlas for Neural cells

Abstract The nervous system is one of the most complicated and enigmatic systems within the animal kingdom. Recently, the emergence and development of spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq) technologies have provided an unprecedented ability to systematically decipher the cellular heterogeneity and spatial locations of the nervous system from multiple unbiased aspects. However, efficiently integrating, presenting and analyzing massive multiomic data remains a huge challenge. Here, we manually collected and comprehensively analyzed high-quality scRNA-seq and ST data from the nervous system, covering 10 679 684 cells. In addition, multi-omic datasets from more than 900 species were included for extensive data mining from an evolutionary perspective. Furthermore, over 100 neurological diseases (e.g. Alzheimer's disease, Parkinson's disease, Down syndrome) were systematically analyzed for high-throughput screening of putative biomarkers. Differential expression patterns across developmental time points, cell types and ST spots were discerned and subsequently subjected to extensive interpretation. To provide researchers with efficient data exploration, we created a new database with interactive interfaces and integrated functions called the Spatiotemporal Cloud Atlas for Neural cells (SCAN), freely accessible at http://47.98. 139.124:8799 or http://scanatlas.net. SCAN will benefit the neuroscience research community to better exploit the spatiotemporal atlas of the neural system and promote the development of diagnostic strategies for various neurological disorders.