Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Identifying Vulnerabilities to NSAID Adverse Events in the U.S. Population: An Analysis of Preexisting Conditions and Sex.

Purpose: In 2005, the Food and Drug Administration (FDA) issued a decision memorandum regarding nonsteroidal anti-inflammatory drugs (NSAIDs). The memorandum recommended the withdrawal of certain NSAIDs due to potential cardiovascular adverse effects. It highlighted the issue of cardiovascular risk associated with NSAIDs as a class. The NSAID medication guide includes a wide range of adverse drug reactions (ADRs), such as increased blood pressure, liver failure, allergic reactions, heart attack, and intestinal bleeding. Although both sexes have an increased risk of ADRs with NSAID use, females have a greater risk than males due to differences in pharmacodynamics and higher medication concentrations (mg/kg). In particular, females with high blood pressure, coronary heart, kidney, and liver disease are at an additional risk of harm from NSAID ADRs. This study quantifies sex-specific differences and other factors associated with prescription NSAID use. Method: The data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES), a complex survey conducted by the Centers for Disease Control and Prevention (CDC) in two-year cycles. A survey-weighted logistic regression model was utilized to investigate potential sex differences with prescription NSAIDs in the context of other factors, including kidney disease, hypertension, liver disease, insurance status, coronary heart disease, and age, within the 2011-2018 NHANES survey data. Results: Females reported a slightly higher percentage of high blood pressure and kidney disease than males, while males reported a slightly higher percentage of coronary heart and liver disease than females. Last, the model indicated that females were 58% more likely to have used a prescription NSAID than males. Conclusion: The results confirm that women and people with medical conditions, who would potentially suffer greater harm from NSAID ADRs, are more likely to use a prescription NSAID than individuals without these conditions.

Chemerin promotes invasion of oral squamous cell carcinoma by stimulating IL-6 and TNF-α production via STAT3 activation.

AIMS: Elevated levels of adipokine chemerin have been identified in oral squamous cell carcinoma (OSCC) and found to be associated with metastasis to the cervical lymph nodes. The underlying mechanism through which chemerin affects OSCC progression is unclear. The aims of this study were firstly to determine chemerin levels and cytokine concentrations in serum from patients with OSCC and in OSCC cell cultures, and secondly to observe chemerin effects on OSCC cell cytokine secretion, migration, and invasion in vitro. METHODS: Serum samples were collected from 20 patients diagnosed with OSCC, including groups with (LN+) and without (LN-) cervical lymph node metastasis. A Luminex liquid suspension assay was used to quantify serum concentrations of 27 types of cytokines. Correlations between chemerin and cytokines (i.e., IL-6, IL-15, GM-CSF, RANTES, TNF-α, and VEGF) were analyzed. ELISAs (enzyme-linked immunosorbent assays) were used to determine concentrations of chemerin and selected cytokines in serum and in supernatants of OSCC cell cultures (SCC9 and SCC25 cell lines). OSCC cells were stimulated with human recombinant chemerin, STAT3 inhibitor, or IL-6 together with TNF-α neutralizing antibodies. Phosphorylated STAT3 protein levels were measured with western blot analysis. OSCC cell migration and invasion were investigated with Transwell assays. RESULTS: Compared to the LN- group, OSCC patients with cervical lymph node metastasis had higher levels of IL-6 (P = 0.006), IL-15 (P = 0.020), GM-CSF (P = 0.036), RANTES (P = 0.032), TNF-α (P = 0.005), VEGF (P = 0.006), and chemerin (P = 0.001). Patients' serum chemerin levels correlated directly with IL-6, GM-CSF, TNF-α, and VEGF levels in OSCC patients. Exogenous recombinant chemerin treatment promoted secretion of IL-6 and TNF-α via activation of STAT3 in OSCC cells. Chemerin induced OSCC-cell migration and invasion, and these effects were reduced by IL-6 and TNF-α neutralizing antibodies. CONCLUSION: Our findings indicate that chemerin may play a role in advancing OSCC progression by increasing production of IL-6 and TNF-α, perhaps via a mechanism involving STAT3 signaling.

Phosphatase, Mg2+/Mn2+ dependent 1B regulates the hematopoietic stem cells homeostasis via the Wnt/ß-catenin signaling.

Hematopoietic stem cells (HSCs) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance. How HSCs maintain the balance between activation and quiescence remains largely unknown. Herein, we found that Phosphatase, Mg2+/Mn2+ Dependent 1B (Ppm1b) is required for the expansion of phenotypic HSCs in vitro. By using a conditional knockout mouse model in which Ppm1b was specifically depleted in hematopoietic cells, we demonstrated that loss of Ppm1b impaired the HSC homeostasis and hematopoietic reconstitution. Ppm1b deficiency mice also exhibited B-cell leukocytopenia, which is due to the compromised commitment and proliferation of B-biased lymphoid progenitor cells from CLPs. With the aid of a small molecular inhibitor, we confirmed the roles of Ppm1b in adult hematopoiesis that phenocopied the effects with loss of Ppm1b. Furthermore, transcriptome profiling of Ppm1b-deficient HSCs revealed the disruptive quiescence of HSC. Mechanistically, Ppm1b interacted with ß-catenin and mediated its dephosphorylation. Loss of Ppm1b led to the decrease of the active ß- catenin (non-phosphorylated) that interrupted the Wnt/ß-catenin signaling in HSC, which consequently suppressed HSC expansion. Together, our study identified an indispensable role of Ppm1b in regulating HSC homeostasis via Wnt/ß-catenin pathway.

Effects of Quality Enhancement of Frozen Tuna Fillets Using Ultrasound-Assisted Salting: Physicochemical Properties, Histology, and Proteomics.

Salting pretreatment is an effective method to improve the quality of frozen fish. This study investigated the quality changes and proteomic profile differences of frozen yellowfin tuna fillets pretreated with ultrasound-assisted salting (UAS) and static salting (SS). This study was centered on three aspects: physicochemical indicators' determination, histological observation, and proteomic analysis. The results showed that UAS significantly increased yield, salt content, and water-holding capacity (WHC), decreased total volatile base nitrogen (TVBN) compared to SS (p < 0.05), and significantly increased water in the protein matrix within myofibrils. Histological observations showed that the tissue cells in the UAS group were less affected by frozen damage, with a more swollen structure and rougher surface of myofibrils observed. Furthermore, 4D label-free proteomics revealed 56 differentially abundant proteins (DAPs) in UAS vs. NT comparison, mainly structural proteins, metabolic enzymes, proteasomes, and their subunits, which are associated with metabolic pathways such as calcium signaling pathway, gap junction, actin cytoskeletal regulation, and necroptosis, which are intimately associated with quality changes in freeze-stored tuna fillets. In brief, UAS enhances the potential for the application of salting pretreatment to improve frozen meat quality, and 4D label-free proteomics provides knowledge to reveal the potential links between quality and molecular changes in processed frozen meat to optimize future UAS meat processing.

All-hydrocarbon stapling enables improvement of antimicrobial activity and proteolytic stability of peptide Figainin 2.

Figainin 2 is a cationic, hydrophobic, α-helical host-defense peptide with 28 residues, which was isolated from the skin secretions of the Chaco tree frog. It shows potent inhibitory activity against both Gram-negative and Gram-positive pathogens and has garnered considerable interest in developing novel classes of natural antibacterial agents. However, as a linear peptide, conformational flexibility and poor proteolytic stability hindered its development as antibacterial agent. To alleviate its susceptibility to proteolytic degradation and improve its antibacterial activity, a series of hydrocarbon-stable analogs of Figainin 2 were synthesized and evaluated for their secondary structure, protease stability, antimicrobial, and hemolytic activities. Among them, F2-12 showed significant improvement in protease resistance and antimicrobial activity compared to that of the template peptide. This study provides a promising strategy for the development of antimicrobial drugs.

A promising approach to steady-state fusion: High-temperature superconducting strong-field stellarator with precise omnigenity.

The stellarator has inherent advantages over the tokamak in achieving steady-state operation, especially due to its absence of disruptions and lack of need for current drive and the associated recirculating power. In recent years, there have been remarkable advances in the field of stellarator optimization, where precisely quasi-symmetric and precisely quasi-isodynamic magnetic configurations have been achieved with coils, allowing the neoclassical transport and energetic particle losses of stellarators to be reduced to levels comparable to those of tokamaks. At the same time, the development of high-temperature superconducting magnet technology will potentially double the magnetic field strength of stellarators. While these strong fields are expected to introduce new challenges, and while turbulent transport remains a common challenge for both stellarators and tokamaks, the combination of these physical and technological advances results in the expectation that stellarators will become a competitive approach to tokamaks for realizing steady-state fusion.

The Genomic Characteristics of an Arthritis-Causing Salmonella pullorum.

Salmonella enterica subsp. enterica serovar Gallinarum biovar pullorum (Salmonella pullorum) is an avian-specific pathogen that has caused considerable economic losses to the poultry industry. High endemicity, poor implementation of hygiene measures, and lack of effective vaccines hinder the prevention and control of this disease in intensively maintained poultry flocks. In recent years, the incidence of arthritis in chicks caused by Salmonella pullorum infection has increased. In this study, four Salmonella pullorum strains were identified from the livers, spleens, and joint fluids of Qingjiaoma chicken breeders with arthritis clinical signs, and an arthritis model of chicks was successfully established using SP206-2. Whole genome sequencing of the SP206-2 strain showed that the genome was 4,730,579 bp, 52.16% GC content, and contained 5007 genes, including 4729 protein-coding regions. The genomic analysis of four arthritis-causing isolates and three diarrhea-causing isolates showed that the genome of arthritis-causing isolates was subject to nonsynonymous mutations, shift mutations, and gene copy deletions. An SNP phylogenetic tree analysis showed that arthritis-causing isolates are located in a different evolutionary branch from diarrhea-causing isolates. Further differential genes analysis showed that the genome of arthritis-causing isolates had missense mutations in genes related to substance metabolism and substance transport, as a result of adaptive evolution.

Loss of the vitamin D receptor triggers senescence in chronic myeloid leukemia via DDIT4-mediated DNA damage.

Chronic myeloid leukemia (CML) is a hematopoietic malignancy driven by the fusion gene BCR: ABL1. Drug resistance to tyrosine kinase inhibitors (TKIs) due to BCR: ABL1 mutation and residual leukemia stem cells (LSCs) remain major challenges for CML treatment. Here, we revealed the requirement of VDR in the progression of CML, in which VDR was upregulated by BCR: ABL1, accounting for its high expression. Interestingly, VDR knockdown inhibited the CML cell proliferation driven by BCR: ABL1 regardless of its mutations with resistance to TKIs. Mechanistically, VDR transcriptionally regulated DDIT4 expression, and the inhibition of DDIT4 triggered DNA damage-induced senescence via p53 signaling activation in CML cells. Furthermore, VDR deficiency was sufficient to not only ameliorate the disease burden and progression in primary CML mice but also reduce the self-renewal of CML-LSCs. Together, our study demonstrated that targeting VDR is a promising strategy to overcome TKI resistance and eradicate leukemia stem cells in CML.

Monoterpene indole alkaloids from Gelsemium elegans.

Two new monoterpene indole alkaloids, Eleganine A (1) and Eleganine B (2), along with 11 known compounds (3-13) were isolated from the stems and leaves of Gelsemium elegans. Compound 1 is a gelsenicine-related monoterpenoid indole alkaloid possessing an iridoid unit. Their structures and absolute configurations of 1-2 were established by UV, IR, HR-ESI-MS, NMR spectroscopy, and electronic circular dichroism data analyses. All isolated compounds were evaluated for their anti-inflammatory and inhibiting glucose-induced mesanginal cell proliferation activities. None of them showed activity with IC50 far beyond 50 µM.

Sensitivity Analysis of CMAP Scan Step Index to Different Stimulation Parameters and Examination of Muscles Affected by Spinal Cord Injury.

Step index (STEPIX) is a recently developed compound muscle action potential (CMAP) scan method for evaluating motor unit loss and remodeling changes. This study investigates the influence of different stimulation parameters during CMAP scan on STEPIX and its examination of muscles affected by spinal cord injury (SCI). CMAP scan of the first dorsal interosseous (FDI) muscle was performed using different stimulus pulse widths (0.1 ms, 0.2 ms) and different numbers of stimuli (500, 1000) in 12 neurologically intact subjects. STEPIX was derived from each CMAP scan of all subjects. A significantly higher STEPIX was obtained using 1000 stimuli than 500 stimuli, while no significant difference in STEPIX was observed using 0.1 and 0.2 ms stimulus pulse widths. STEPIX was further applied to process CMAP scans of the FDI muscle from 13 tetraplegia and 13 healthy control subjects using the same stimulation parameter setting (0.1 ms, 500 stimuli), along with other methods including MScanFit motor unit number estimation (MUNE) and D50. STEPIX was significantly lower for the SCI subjects compared with the healthy control subjects. STEPIX was significantly correlated with MscanFit MUNE and D50, but had a smaller relative width of the overlapping zone (WOZ%) between tetraplegic and healthy control groups compared with MScanFit MUNE and D50. The findings of the study highlight the importance of maintaining a consistent stimulation parameter setting in CMAP scan studies and confirm the usefulness of STEPIX as a convenient CMAP scan parameter for examination of motor unit number changes.

Monoterpene indole alkaloids from the roots of Alstonia rupestris and their anti-inflammatory activity.

Four new monoterpene indole alkaloids (1-4) together with twelve known alkaloids (5-16) were isolated from the roots of Alstonia rupestris. Compound 1 was the first example of C2-symmetric heteroyohimbine-type indole alkaloid homodimer obtained from natural plant resource. Their structures were elucidated on the basis of spectroscopic data. The absolute configuration of 1 was determined by comparison of its calculated and experimental electronic circular dichroism (ECD) spectra. All compounds were evaluated for their anti-inflammatory activities by measuring their NO inhibitory effects in LPS-stimulated RAW 264.7 cells. Compound 2 showed strong NO inhibition with IC50 value of 4.2 ± 1.3 µM. Moreover, compound 2 could decrease the expressions of cyclooxygenase-2 (COX-2) and transforming growth factor beta-1 (TGF-ß1).

IRDC-Net: An Inception Network with a Residual Module and Dilated Convolution for Sign Language Recognition Based on Surface Electromyography.

Deaf and hearing-impaired people always face communication barriers. Non-invasive surface electromyography (sEMG) sensor-based sign language recognition (SLR) technology can help them to better integrate into social life. Since the traditional tandem convolutional neural network (CNN) structure used in most CNN-based studies inadequately captures the features of the input data, we propose a novel inception architecture with a residual module and dilated convolution (IRDC-net) to enlarge the receptive fields and enrich the feature maps, applying it to SLR tasks for the first time. This work first transformed the time domain signal into a time-frequency domain using discrete Fourier transformation. Second, an IRDC-net was constructed to recognize ten Chinese sign language signs. Third, the tandem CNN networks VGG-net and ResNet-18 were compared with our proposed parallel structure network, IRDC-net. Finally, the public dataset Ninapro DB1 was utilized to verify the generalization performance of the IRDC-net. The results showed that after transforming the time domain sEMG signal into the time-frequency domain, the classification accuracy (acc) increased from 84.29% to 91.70% when using the IRDC-net on our sign language dataset. Furthermore, for the time-frequency information of the public dataset Ninapro DB1, the classification accuracy reached 89.82%; this value is higher than that achieved in other recent studies. As such, our findings contribute to research into SLR tasks and to improving deaf and hearing-impaired people's daily lives.

Comparative connectomics and escape behavior in larvae of closely related Drosophila species.

Evolution has generated an enormous variety of morphological, physiological, and behavioral traits in animals. How do behaviors evolve in different directions in species equipped with similar neurons and molecular components? Here we adopted a comparative approach to investigate the similarities and differences of escape behaviors in response to noxious stimuli and their underlying neural circuits between closely related drosophilid species. Drosophilids show a wide range of escape behaviors in response to noxious cues, including escape crawling, stopping, head casting, and rolling. Here we find that D. santomea, compared with its close relative D. melanogaster, shows a higher probability of rolling in response to noxious stimulation. To assess whether this behavioral difference could be attributed to differences in neural circuitry, we generated focused ion beam-scanning electron microscope volumes of the ventral nerve cord of D. santomea to reconstruct the downstream partners of mdIV, a nociceptive sensory neuron in D. melanogaster. Along with partner interneurons of mdVI (including Basin-2, a multisensory integration neuron necessary for rolling) previously identified in D. melanogaster, we identified two additional partners of mdVI in D. santomea. Finally, we showed that joint activation of one of the partners (Basin-1) and a common partner (Basin-2) in D. melanogaster increased rolling probability, suggesting that the high rolling probability in D. santomea is mediated by the additional activation of Basin-1 by mdIV. These results provide a plausible mechanistic explanation for how closely related species exhibit quantitative differences in the likelihood of expressing the same behavior.

Surface EMG analysis of weakness distribution in upper limb muscles post-stroke.

Weakness is a common symptom after a stroke. This study aims to depict weakness distribution among forearm muscles given that joints in the upper limb are usually driven by a group of muscles. Multi-channel electromyography (EMG) was applied to assess the muscle group, and an EMG-based index was proposed to quantify the weakness of individual muscles. By using this method, four weakness distribution patterns were observed in extensor muscles from five out of eight subjects after stroke. Complex weakness distribution patterns were observed in flexor muscles from seven out of the eight subjects when they performed grasp, tripod pinch, and hook grip. The findings can help determine the weak muscles in a clinic and facilitate the development of appropriate interventions in stroke rehabilitation targeting specific muscle weakness.

Compound muscle action potential (CMAP) scan examination of paretic and contralateral muscles reveals motor unit alterations after stroke.

This study presents a novel compound muscle action potential (CMAP) examination of motor unit changes in paretic muscle post stroke. CMAP scan of the first dorsal interosseous (FDI) muscle was performed bilaterally in 16 chronic stroke subjects. Various parameters were derived from the CMAP scan to examine paretic muscle changes, including CMAP amplitude, D50, step index (STEPIX) and amplitude index (AMPIX). A significant decrease in CMAP amplitude and STEPIX was observed in paretic muscles compared with contralateral muscles (CMAP amplitude: paretic (9.0±0.5) mV, contralateral (11.3±0.9) mV, P=0.024; STEPIX: paretic 101.2±7.6, contralateral 121.9±6.5, P=0.020). No significant difference in D50 and AMPIX was observed between the paretic and contralateral sides (P>0.05). The findings revealed complex paretic muscle changes including motor unit degeneration, muscle fiber denervation, reinnervation and atrophy, providing useful insights to help understand neuromuscular mechanisms associated with weakness and other functional deterioration post stroke. The CMAP scan experimental protocols and the applied processing methods are noninvasive, convenient, and automated, offering practical benefits for clinical application.

Research Note: Therapeutic effect of a Salmonella phage combination on chicks infected with Salmonella Typhimurium.

Antibiotic treatment failure is increasingly encountered for the emergence of pandrug-resistant isolates, including the prototypical broad-host-range Salmonella enterica serovar (S.) Typhimurium, which mainly transmitted to humans through poultry products. In this study we explored the therapeutic potential of a Salmonella phage composition containing a virulent phage and a nonproductive phage that does not produce progeny phage against chicks infected with a pandrug-resistant S. Typhimurium strain of avian origin. After approximately 107 CFU of S. Typhimurium strain ST149 were administrated to chicks by intraperitoneal injection, the phage combination (∼108 PFU) was gavaged at 8-h, 32-h, and 54-h postinfection. At d 10 postinfection, phage treatment completely protected chicks from Salmonella-induced death compared to 91.7% survival in the Salmonella challenge group. In addition, phage treatment also greatly reduced the bacterial load in various organs, with Salmonella colonization levels decreasing more significantly in spleen and bursa than in liver and cecal contents, possibly due to higher phage titers in these immune organs. However, phages could not alleviate the decreased body weight gain and the enlargement of spleen and bursa of infected chicks. Further examination of the bacterial flora in the cecal contents of chicks found that S. Typhimurium infection caused a remarkable decrease in abundance of Clostridia vadin BB60 group and Mollicutes RF39 (the dominant genus in chicks), making Lactobacillus the dominate genus. Although phage treatment partially restored the decline of Clostridia vadin BB60 group and Mollicutes RF39 and increased abundance of Lactobacillus caused by S. Typhimurium infection, Fournierella that may aggravate intestinal inflammation became the major genus, followed by increased Escherichia-Shigella as the second dominate bacterial genus. These results suggested that successive phage treatment modulated the structural composition and abundance of bacterial communities, but failed to normalize the intestinal microbiome disrupted by S. Typhimurium infection. Phages need to be combined with other means to control the spread of S. Typhimurium in poultry.

Spatial Dependence of Log-Transformed Electromyography-Force Relation: Model-Based Sensitivity Analysis and Experimental Study of Biceps Brachii.

This study investigated electromyography (EMG)-force relations using both simulated and experimental approaches. A motor neuron pool model was first implemented to simulate EMG-force signals, focusing on three different conditions that test the effects of small or large motor units located more or less superficially in the muscle. It was found that the patterns of the EMG-force relations varied significantly across the simulated conditions, quantified by the slope (b) of the log-transformed EMG-force relation. b was significantly higher for large motor units, which were preferentially located superficially rather than for random depth or deep depth conditions (p < 0.001). The log-transformed EMG-force relations in the biceps brachii muscles of nine healthy subjects were examined using a high-density surface EMG. The slope (b) distribution of the relation across the electrode array showed a spatial dependence; b in the proximal region was significantly larger than the distal region, whereas b was not different between the lateral and medial regions. The findings of this study provide evidence that the log-transformed EMG-force relations are sensitive to different motor unit spatial distributions. The slope (b) of this relation may prove to be a useful adjunct measure in the investigation of muscle or motor unit changes associated with disease, injury, or aging.