Rhesus monkeys learn to control a directional-key inspired brain machine interface via bio-feedback.

Brain machine interfaces (BMI) connect brains directly to the outside world, bypassing natural neural systems and actuators. Neuronal-activity-to-motion transformation algorithms allow applications such as control of prosthetics or computer cursors. These algorithms lie within a spectrum between bio-mimetic control and bio-feedback control. The bio-mimetic approach relies on increasingly complex algorithms to decode neural activity by mimicking the natural neural system and actuator relationship while focusing on machine learning: the supervised fitting of decoder parameters. On the other hand, the bio-feedback approach uses simple algorithms and relies primarily on user learning, which may take some time, but can facilitate control of novel, non-biological appendages. An increasing amount of work has focused on the arguably more successful bio-mimetic approach. However, as chronic recordings have become more accessible and utilization of novel appendages such as computer cursors have become more universal, users can more easily spend time learning in a bio-feedback control paradigm. We believe a simple approach which leverages user learning and few assumptions will provide users with good control ability. To test the feasibility of this idea, we implemented a simple firing-rate-to-motion correspondence rule, assigned groups of neurons to virtual "directional keys" for control of a 2D cursor. Though not strictly required, to facilitate initial control, we selected neurons with similar preferred directions for each group. The groups of neurons were kept the same across multiple recording sessions to allow learning. Two Rhesus monkeys used this BMI to perform a center-out cursor movement task. After about a week of training, monkeys performed the task better and neuronal signal patterns changed on a group basis, indicating learning. While our experiments did not compare this bio-feedback BMI to bio-mimetic BMIs, the results demonstrate the feasibility of our control paradigm and paves the way for further research in multi-dimensional bio-feedback BMIs.

Gold nanorods with iron oxide dual-modal bioprobes in SERS-MRI enable accurate programmed cell death ligand-1 expression detection in triple-negative breast cancer.

The efficiency of immunotherapy for triple-negative breast cancer (TNBC) is relatively low due to the difficulty in accurately detecting immune checkpoints. The detection of TNBC-related programmed cell death ligand-1 (PD-L1) expression is important to guide immunotherapy and improve treatment efficiency. Surface-enhanced Raman spectroscopy (SERS) and magnetic resonance (MR) imaging exhibit great potential for early TNBC diagnosis. SERS, an optical imaging mode, has the advantages of high detection sensitivity, good spatial resolution, and "fingerprint" spectral characteristics; however, the shallow detection penetration of SERS bioprobes limits its application in vivo. MR has the advantages of allowing deep penetration with no radiation; however, its spatial resolution needs to be improved. SERS and MR have complementary imaging features for tumor marker detection. In this study, gold nanorod and ultrasmall iron oxide nanoparticle composites were developed as dual-modal bioprobes for SERS-MRI to detect PD-L1 expression. Anti-PD-L1 (aPD-L1) was utilized to improve the targeting ability and specificity of PD-L1 expression detection. TNBC cells expressing PD-L1 were accurately detected via the SERS imaging mode in vitro, which can image at the single-cell level. In addition, bioprobe accumulation in PD-L1 expression-related tumor-bearing mice was simply and dynamically monitored and analyzed in vivo using MR and SERS. To the best of our knowledge, this is the first time a SERS-MRI dual-modal bioprobe combined with a PD-L1 antibody has been successfully used to detect PD-L1 expression in TNBC. This work paves the way for the design of high-performance bioprobe-based contrast agents for the clinical immunotherapy of TNBC.

Dietary Folic Acid Supplementation Inhibits HighFat DietInduced Body Weight Gain through Gut Microbiota-Associated Branched-Chain Amino Acids and Mitochondria in Mice.

The effects of folic acid on body weight gain in obesity and gut microbiota-associated branched-chain amino acids (BCAAs) and mitochondrial function were investigated. Three- to four-wk-old male C57BL/6J conventional (CV) and germ-free (GF) mice were fed a high-fat diet (HD), folic acid-supplemented HD (FSHD) and a normal-fat diet (ND) for 25 wk. In CV mice, the HD-induced increases in body weight and plasma BCAA concentrations, downregulated expression of genes related to BCAA catabolism (Bcat2, Bckdha, or Ppm1k), mitochondrial biogenesis (Pgc-1α, Cox1, Nd1 or Nd6), fusion (Mfn1, Mfn2 or Opa1) and mitophagy (Pink1 or Park2), and upregulated expression of the fission-associated gene Drp1 in epididymal fat were reversely corrected with FSHD feeding. In contrast, the expression of these genes in the liver was the opposite under HD feeding or folic acid supplementation. In GF mice, plasma BCAA concentrations were much less affected by HD feeding and were reduced by FSHD feeding, with almost no alterations in the expression of genes associated with BCAA catabolism and mitochondrial function. Further analysis indicated a correlation between adipose and hepatic Mt C/N and plasma BCAA concentrations, and the latter had a close association with specific gut bacteria. Therefore, dietary folic acid supplementation differentially affected body weight gain, BCAA catabolism, and mitochondrial dynamics and metabolism under HD feeding between CV and GF mice, suggesting that gut bacteria-altered BCAAs and mitochondria might partially share the responsibility for the beneficial effects of dietary folic acid on obesity.

Hollow mesoporous organosilica nanoparticles reduced graphene oxide based nanosystem for multimodal image-guided photothermal/photodynamic/chemo combinational therapy triggered by near-infrared.

Developing a nanosystem that can perform multimodal imaging-guided combination therapy is highly desirable but challenging. In this study, we introduced multifunctional nanoparticles (NPs) consisting of graphene oxide-grafted hollow mesoporous organosilica loaded with the drug doxorubicin (DOX) and photosensitizers tetraphenylporphyrin (TPP). These NPs were encapsulated by thermosensitive liposomes that release their contents once the temperature exceeds a certain threshold. Metal oxide NPs grown on the graphene oxide (GO) surface served multiple roles, including enhancing photothermal efficiency, acting as contrast agents to improve magnetic resonance imaging, increasing the sensitivity and specificity of photoacoustic imaging, and catalysing hydrogen peroxide for the generation of reactive oxygen species (ROS). When locally injected, the HMONs-rNGO@Fe3 O4 /MnOx@FA/DOX/TPP NPs effectively enriched in subcutaneous Hela cell tumour of mice. The photothermal/photodynamic/chemo combination therapy triggered by near-infrared (NIR) successfully suppressed the tumour without noticeable side effects. This study presented a unique approach to develop multimodal imaging-guided combination therapy for cancer.

Effects of supplementation with Saccharomyces cerevisiae products on dairy calves: A meta-analysis.

Saccharomyces cerevisiae products (SCP) have the potential to promote the growth and development of the gastrointestinal tract and immunity in young livestock animals. However, the effects of SCP supplementation on calves are inconsistent among the reported studies in the literature. Hence, we performed a meta-analysis to comprehensively assess the effects of SCP on the growth performance, ruminal fermentation parameters, nutrients digestibility, ruminal histological morphology, serum immune response, and fecal pathogen colony counts in calves. We searched the Web of Science, ScienceDirect, PubMed, and China National Knowledge Infrastructure for relevant studies published up to October 1, 2021. After screening against a set of criteria, the data of 36 studies were included in our meta-analysis (2,126 calves in total). We evaluated the quality of the data using sensitivity analysis and assessed publication bias. Our meta-analysis revealed several important findings. First, SCP supplementation increased the ruminal short-chain fatty acid concentration, ruminal papilla height, and fiber digestibility, pointing toward stimulation of the development of the rumen in calves. Second, SCP supplementation increased the serum concentrations of total protein, IgA, and IgG but decreased fecal pathogen colony counts, suggesting that SCP could help calves to promote immunity (especially maintaining circulating concentrations of immunoglobulins in preweaning calves) and resistance to pathogens. Third, a subgroup analysis between preweaning and postweaning calves showed that SCP increased average daily gain and dry matter intake preweaning but not postweaning, suggesting that SCP is better supplemented to preweaning calves to achieve the best results. Forth, based on the dose-response curve, 24 to 25 g/d might be the optimal dose range of SCP supplementation (into starter feed) preweaning to achieve the best overall effect, meanwhile, we need more studies to improve the consistency and accuracy of the dose-response curve prediction. Overall, SCP supplementation improved growth performance, rumen development, and immunocompetence in calves, particularly in preweaning calves.

Reduction of lactoferrin aggravates neuronal ferroptosis after intracerebral hemorrhagic stroke in hyperglycemic mice.

Diabetic hyperglycemia aggravates the prognosis of intracerebral hemorrhagic stroke (ICH) in the clinic. In addition to hematoma expansion and increased inflammation, how diabetic hyperglycemia affects the outcomes of ICH is still unclear. We found that streptozotocin-induced diabetic hyperglycemia not only increased neutrophil infiltration, but also changed the gene expression profile of neutrophils, including lactoferrin (Ltf) encoding gene Ltf. Peroxisome proliferator-activated receptor γ (PPARγ) transcribed Ltf and the lack of neutrophilic Ltf transcription and secretion exacerbated neuronal ferroptosis by accumulating intraneuronal iron. Furthermore, the administration of recombinant Ltf protected against neuronal ferroptosis and improved neurobehavior in hyperglycemic ICH mice, and vice versa. These results indicate that supplementing Ltf or inhibiting neuronal ferroptosis are promising potential strategies to improve the acute outcomes of diabetic ICH in the clinic.

Investigating the causality of metabolites involved in one-carbon metabolism with the risk and age at onset of Parkinson's disease: A two-sample mendelian randomization study.

With the aging population and increasing life expectancy, Parkinson's disease (PD), a neurological disorder rapidly increasing in morbidity and mortality, is causing a huge burden on society and the economy. Several studies have suggested that one-carbon metabolites, including homocysteine, vitamin B6, vitamin B12 and folate acid, are associated with PD risk. However, the results remain inconsistent and controversial. Thus, we performed a two-sample Mendelian randomization (MR) study to detect the causality between one-carbon metabolites and PD susceptibility as well as age at PD onset. We collected several genetic variants as instrumental variables from large genome-wide association studies of one-carbon metabolites (homocysteine: N = 14, vitamin B6: N = 1, vitamin B12: N = 10, folate acid: N = 2). We then conducted MR analyses using the inverse variance-weighted (IVW) approach and additional MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods to further test causality. The results showed no causal association between circulating homocysteine levels and PD risk (p = 0.868) or age at PD onset (p = 0.222) with the IVW method. Meanwhile, similar results were obtained by three complementary analyses. In addition, we did not observe any evidence that the circulating levels of vitamin B6, vitamin B12 and folate acid affected the risk of PD or age at onset of PD. Our findings implied that lowering homocysteine levels through vitamin B6, vitamin B12 or folate acid supplementation may not be clinically helpful in preventing PD or delaying the age at PD onset.

Genetically Predicted Circulating Concentrations of Micronutrients and Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease with increasing incidence and high mortality, resulting in a considerable socio-economic burden. Till now, plenty of studies have explored the potential relationship between circulating levels of various micronutrients and ALS risk. However, the observations remain equivocal and controversial. Thus, we conducted a two-sample Mendelian randomization (MR) study to investigate the causality between circulating concentrations of 9 micronutrients, including retinol, folate acid, vitamin B12, B6 and C, calcium, copper, zinc as well as magnesium, and ALS susceptibility. In our analysis, several single nucleotide polymorphisms were collected as instrumental variables from large-scale genome-wide association studies of these 9 micronutrients. Then, inverse variance weighted (IVW) approach as well as alternative MR-Egger regression, weighted median and MR-pleiotropy residual sum and outlier (MR-PRESSO) analyses were performed to evaluate causal estimates. The results from IVW analysis showed that there was no causal relationship of 9 micronutrients with ALS risk. Meanwhile, the three complementary approaches obtained similar results. Thus, our findings indicated that supplementation of these 9 micronutrients may not play a clinically effective role in preventing the occurrence of ALS.

Subjective Quality of Vision in Evaporative Dry Eye Patients After Intense Pulsed Light.

Background and objective: Intense pulsed light (IPL) improves visual and clinical symptoms of dry eye disease and helps improve meibomian gland (MG) function thereby positively contributing to the tear lipid layer, a major component for a normal tear film physiology. The objective of this study was to assess the effectiveness of IPL in moderate to severe evaporative dry eye (DE) owing to meibomian gland dysfunction (MGD) on the subjective quality of vision (QOV). Methods: This is a prospective, open-label study; patients with moderate to severe evaporative DE owing to MGD were consecutively enrolled and underwent two IPL treatment sessions at 3-week intervals. Clinical assessments included: Ocular Surface Disease Index (OSDI) and QOV questionnaires, noninvasive tear breakup time (NITBUT), interferometric fringe pattern as determined by tear film lipid layer (TFLL) quality, lid margin abnormalities, corneal fluorescein staining (CFS), conjunctival hyperemia (CH) redness score, MG (evaluated with a slit-lamp microscope), best-corrected visual acuity, endothelial cell count, and intraocular pressure were conducted at pretreatment, days 21 and 42 after IPL treatment. Results: A total of 128 eyes of 64 patients (39 women, 25 men; mean age 36.09 ± 11.13 years) with moderate to severe DE owing to MGD consecutively received IPL treatment at days 1 and 21. OSDI (p < 0.05), QOV (p < 0.05), NITBUT (p < 0.05), TFLL score (p < 0.05), and MG quality and expressibility (p < 0.05) improved significantly at day 42, whereas CFS and CH showed minor not significant improvements (p > 0.05) at day 42 of assessment. Conclusions: IPL treatment reduced the severity of DE symptoms and improved the overall tear film stability in patients with moderate to severe evaporative DE owing to MGD. In addition, visual complaints experienced by DE patients secondary to MGD significantly decreased.

Astragalus polysaccharide enhanced antitumor effects of Apatinib in gastric cancer AGS cells by inhibiting AKT signalling pathway.

Apatinib has been proved effective in the treatment of advanced gastric cancer. Traditional Chinese medicine is often considered as adjuvants which could increase the effects and counteract the side effects of chemotherapy. The present study aims to explore the antitumor effects of Astragalus polysaccharide (AsPs) in combination with Apatinib in gastric cancer AGS cells. Our results demonstrated that the expression of VEGFR-2 was observed in human gastric cancer line AGS. Both Apatinib and AsPs could significantly inhibit the proliferation of AGS cells in a dose-dependent manner and Apatinib in combination with AsPs showed enhanced inhibitory effects on cell proliferation, migration and invasion compared with Apatinib monotherapy. Moreover, there was a remarkable increase in apoptosis following Apatinib treatment which could be enhanced by the addition of AsPs. Western blotting showed that the combination of Apatinib and AsPs could inhibit the expression of phosphorylated AKT (p-AKT) and MMP-9 expression. In addition, both Apatinib alone and Apatinib in combination with AsPs induced celluar autophagy which could be attenuated by the autophagy inhibitor 3-MA. The suppression of autophagy leaded to further apoptosis induction and cell proliferation suppression. In conclusion, the current study showed AsPs enhanced antitumor effects of Apatinib on AGS cells by the mechanism which includes inhibition of AKT signaling pathway. Apatinib-induced autophagy could be attenuated by 3-MA, which subsequently increased the apoptosis rate. On the basis of our study, the combination of Apatinib and AsPs could be considered as a potential candidate in the gastric cancer treatment.

Patterns of taxonomic, phylogenetic diversity during a long-term succession of forest on the Loess Plateau, China: insights into assembly process.

Quantifying the drivers underlying the distribution of biodiversity during succession is a critical issue in ecology and conservation, and also can provide insights into the mechanisms of community assembly. Ninety plots were established in the Loess Plateau region of northern Shaanxi in China. The taxonomic and phylogenetic (alpha and beta) diversity were quantified within six succession stages. Null models were used to test whether phylogenetic distance observed differed from random expectations. Taxonomic beta diversity did not show a regular pattern, while phylogenetic beta diversity decreased throughout succession. The shrub stage occurred as a transition from phylogenetic overdispersion to clustering either for NRI (Net Relatedness Index) or betaNRI. The betaNTI (Nearest Taxon Index) values for early stages were on average phylogenetically random, but for the betaNRI analyses, these stages were phylogenetically overdispersed. Assembly of woody plants differed from that of herbaceous plants during late community succession. We suggest that deterministic and stochastic processes respectively play a role in different aspects of community phylogenetic structure for early succession stage, and that community composition of late succession stage is governed by a deterministic process. In conclusion, the long-lasting evolutionary imprints on the present-day composition of communities arrayed along the succession gradient.

Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease.

Compound Formula Rehmannia has been shown to be clinically effective in treating Parkinson's disease and levodopa-induced dyskinesia; however, the mechanisms remain unclear. In this study, we established a model of Parkinson's disease dyskinesia in rats, and treated these animals with Compound Formula Rehmannia. Compound Formula Rehmannia inhibited the increase in mRNA expression of N-methyl-D-aspartate receptor subunits 1 and 2 and excitatory amino acid neurotransmitter genes, and it inhibited the reduction in expression of γ-aminobutyric acid receptor B1, an inhibitory amino acid neurotransmitter gene, in the corpus striatum. In addition, Compound Formula Rehmannia alleviated dyskinesia symptoms in the Parkinson's disease rats. These experimental findings indicate that Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease by modulating neurotransmitter signaling in the corpus striatum.

[Re-discrimination on "reinforcement can be achieved by slow-yet-rapid needling, and rapid-yet-slow needling weakens evil qi"].

OBJECTIVE: To study on the original meanings of "reinforcement can be achieved by slow-yet-rapid needling, and rapid-yet-slow needling weakens evil-qi", one of important bases of reinforcing-reducing in acupuncture. METHODS: Using the principle of knowledge archaeology and through structure an d through structure analysis on the subjects described by "slow" and "rapid" and the papers appearing the words, the meanings of this sentence are re-discriminated. CONCLUSION: "Slow-rapid" prescribed in the reinforcing-reducing needling method in Huangdi's Internal Classic includes 3 subjects: pulse condition, needle-retained time, and velocity of withdrawing the needle. The "slow-rapid" in "reinforcement can be achieved by slow-yet-rapid needling, and rapid-yet-slow needling weakens evil-qi" should be pulse condition, but was not needling method, which means that the pulse changes from slow to rapid, marked by transformation of channels from deficiency to excess; the transform of the pulse from rapid to slow means that the channel transforms from excess to deficiency.