A High Precision, Wide Dynamic Range Closed-Loop Neuromodulation IC With Rapid Stimulation Artifact Recovery.

This article presents a high precision, wide dynamic range (DR) closed-loop neuromodulation (CLNM) system that can completely reject stimulation artifacts (SA) and achieve rapid SA recovery. In the recorder, a novel SA quick-blanking scheme is proposed for rail-to-rail SA rejection while minimizing SA recovery time. Besides, a new analog front-end (AFE) architecture based on a frequency-shaping (FS) technique is developed to extend DR intrinsically. In the stimulator, a stimulation driver implemented with a proposed redundant crossfire (RXF) technique is incorporated to improve the effective resolution of the stimulation current. The designed CLNM system is implemented in a 180 nm Bipolar-CMOS-DMOS (BCD) process. Measurement results show that the system is capable of tolerating rail-to-rail (5 V) SA and reducing the SA recovery time from 12 ms to 0.15 ms. The FS recorder extends the DR at low frequencies (LF) to 17.5 bits to enhance tolerance to LF interferences. The proposed stimulator adopting the 4-way RXF topology improves the effective resolution to 12.75 bits without consuming much extra area and power. Animal experiments demonstrate that the designed system can acquire high-fidelity neural signals immediately after stimulation onsets, thus supporting concurrent recording and stimulation.

A 14-Bit, 12 V-to-100 V Voltage Compliance Electrical Stimulator with Redundant Digital Calibration.

Electrical stimulation is an important technique for modulating the functions of the nervous system through electrical stimulus. To implement a more competitive prototype that can tackle the domain-specific difficulties of existing electrical stimulators, three key techniques are proposed in this work. Firstly, a load-adaptive power saving technique called over-voltage detection is implemented to automatically adjust the supply voltage. Secondly, redundant digital calibration (RDC) is proposed to improve current accuracy and ensure safety during long-term electrical stimulation without costing too much circuit area and power. Thirdly, a flexible waveform generator is designed to provide arbitrary stimulus waveforms for particular applications. Measurement results show the stimulator can adjust the supply voltage from 12 V to 100 V automatically, and the measured effective resolution of the stimulation current reaches 14 bits in a full range of 6.5 mA. Without applying charge balancing techniques, the average mismatch between the cathodic and anodic current pulses in biphasic stimulus is 0.0427%. The proposed electrical stimulator can generate arbitrary stimulus waveforms, including sine, triangle, rectangle, etc., and it is supposed to be competitive for implantable and wearable devices.

Three-dimensional solitons in Rydberg-dressed cold atomic gases with spin-orbit coupling.

We present numerical results for three-dimensional (3D) solitons with symmetries of the semi-vortex (SV) and mixed-mode (MM) types, which can be created in spinor Bose-Einstein condensates of Rydberg atoms under the action of the spin-orbit coupling (SOC). By means of systematic numerical computations, we demonstrate that the interplay of SOC and long-range spherically symmetric Rydberg interactions stabilize the 3D solitons, improving their resistance to collapse. We find how the stability range depends on the strengths of the SOC and Rydberg interactions and the soft-core atomic radius.

Gastroprotective effects of Chinese Rana chensinensis skin collagen against ethanol-induced gastric ulcer in mice.

Gastric ulcer is a common gastrointestinal disease caused by excessive gastric acid secretion, which has been recognized as one of the most common causes of morbidity and mortality in the world. The skin of Rana chensinensis is rich in collagen and many previous studies have shown that it has certain bioactivity. Therefore, we extracted and purified collagen with a molecular weight less than 10000 Da from the skin of Rana chensinensis, and studied its gastric protective mechanism through the model of ethanol-induced gastric ulcer in Balb/c mice. The results showed that through macroscopic observation and significantly reduced ulcer index, it was proved that PCRCS could protect gastric mucosa and alleviate the damage of ethanol to gastric mucosa. PCRCS reduced ethanol-induced oxidative stress by boosting depleted SOD levels and dramatically lowering MDA levels, as well as significantly reducing lipid peroxidation. Additionally PCRCS (Protein Chinese Rana chesinensis Skin) additionally decreased the launch of inflammatory mediators TNF-α and IL-6 and more desirable the content material of protective elements NO and PGE2 in gastric mucosa. Based on these findings, we believe that PCRCS has potential stomach protective effects on ethanol-induced gastric ulcer, which may be achieved by inhibiting oxidative stress and stomach inflammation.

Famine exposure during early life and risk of metabolic syndrome in adulthood in China: a meta-analysis / 中华内分泌代谢杂志

Objective:To analyze the relationship between early-life famine exposure and the risk of metabolic syndrome in Chinese population.Methods:Relevant literature on the relationship between early-life famine exposure and the risk of metabolic syndrome in the Chinese population was retrieved from databases such as CNKI, Wanfang, VIP, CBM, Web of Science, and PubMed. The search was conducted from the inception of the databases up to October 2022. Two researchers independently extracted and systematically evaluated the data from the literature, and meta-analysis was performed using Stata 16.0 software. Results:A total of 12 publications met the inclusion criteria, including 71 470 study subjects. Meta-analysis results showed that early-life famine exposure increased the risk of metabolic syndrome in the Chinese population( OR=1.28, 95% CI 1.16-1.40). Subgroup analysis showed that both fetal famine exposure( OR=1.25, 95% CI 1.03-1.52) and childhood famine exposure( OR=1.29, 95% CI 1.15-1.45) increased the risk of developing metabolic syndrome compared to the non-exposed group, and this significant association was only found in the female population. Conclusion:Early-life exposure to famine may increase the risk of developing metabolic syndrome in adulthood in the Chinese population, particularly among females.

Effect of Gualou Xiebai Decoction on pulmonary fibrosis in rats based on pyroptosis pathway / 中国中药杂志

This study investigated the effect of Gualou Xiebai Decoction on rats with bleomycin-induced pulmonary fibrosis. The rats were randomly divided into a control group, a model group, a low-dose Gualou Xiebai Decoction group(2.4 g·kg~(-1)), a high-dose Gualou Xiebai Decoction group(4.8 g·kg~(-1)), and pirfenidone group(150 mg·kg~(-1)). The model of pulmonary fibrosis was established by intratracheal instillation of bleomycin in all groups, except the control group. Since the second day of modeling, the corresponding drugs were given to rats by intragastric administration, once a day for 14 d and 28 d. The hematoxylin-eosin(HE) staining was used to evaluate the degree of inflammatory injury in lung tissues. The immunofluorescence staining was used to detect the expression of CD68 and CD163 in lung tissues of rats. The levels of tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10) in serum and brochoalveolar lavage fluid(BALF) were detected by enzyme-linked immunosorbent assay(ELISA). The expression of pyroptosis-related genes in lung tissues of rats was detected by qRT-PCR. The results of HE staining and immunofluorescence staining showed that the lung tissue structure was normal in the control group. In addition, there were alveolar collapse or even closure in lung tissues of rats in the model group, with obvious inflammatory cell infiltration, and the expression of CD68 and CD163 was significantly up-regulated. As compared with the model group, the lung tissue structure of rats in the Gualou Xiebai Decoction groups was significantly improved, with alleviated inflammation, and the expression of CD68 and CD163 was decreased. As compared with the control group, the level of TNF-α in serum and BALF of rats in the model group was significantly increased(P<0.01), the mRNA expression levels of alpha smooth muscle actin(α-SMA), collagen type Ⅰ alpha 1 chain(Col1a1), caspase-1, IL-1β, IL-18, gasdermin D(Gsdmd), and NOD-like receptor thermal protein domain associated protein 3(NLRP3) in lung tissues were significantly increased(P<0.05, P<0.01), and the mRNA expression level of E-cadherin was significantly decreased(P<0.01). As compared with the model group, the level of TNF-α in serum and BALF was significantly down-regulated in the high-dose Gualou Xiebai Decoction group(P<0.05, P<0.01), and that of IL-10 was up-regulated(P<0.05, P<0.01). The mRNA expression levels of α-SMA, Col1a1, caspase-1, IL-18, Gsdmd, NLRP3 and IL-1β in lung tissues were significantly decreased(P<0.05, P<0.01) in the high-dose Gualou Xiebai Decoction group, and the mRNA expression level of E-cadherin was significantly increased(P<0.05, P<0.01). In conclusion, Gualou Xiebai Decoction can down-regulate the levels of inflammatory factors and related genes and effectively mitigate pulmonary fibrosis by regulating the pyroptosis pathways.

Hypercalin B alleviates nonalcoholic steatohepatitis progression via suppressing mTORC1 signaling pathway / 药学学报

The global incidence rate of nonalcoholic steatohepatitis (NASH) continues to rise. The pathogenesis of NASH is complex, and there is no effective clinical treatment. Previous study has shown that DEAD box protein 5 (DDX5) can significantly alleviate the NASH process in mice. This study screened the natural product library of the research group and found that the active compound hypercalin B (HB) in Hypericum beanii N. Robson, a traditional Chinese medicine, can upregulate the expression of DDX5 protein in a dose-dependent manner. In this study, an in vitro model of NASH stimulated by palmitic acid (PA) and an animal model of NASH induced by the methionine- and choline-deficient diet (MCD) were constructed. Different concentrations of HB were used to investigate the effect and mechanism of HB in alleviating NASH progression. All animal experiments in this paper were approved by the Ethics Committee of China Pharmaceutical University (NO: 2021-02-003). In vitro model results showed that HB significantly reduced the intracellular lipid deposition induced by free fatty acid (FFA). Animal experiments showed that HB improved liver injury by significantly reducing lipid accumulation in the liver of NASH mice, and reducing serum aspartate transaminase (AST) and alanine transaminase (ALT) levels. Moreover, HB could inhibit liver inflammation by reducing the mRNA levels of liver pro-inflammatory cytokines including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNFα). Further research showed that HB could reduce the phosphorylation level of the mechanical target of rapamycin (mTOR) and reduce the expression of sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FASN), thereby improving lipid metabolism and alleviating NASH progression, and the effects of HB against NASH were dependent on DDX5. In conclusion, HB can improve lipid metabolism and inhibit inflammatory activation by suppressing mTORC1 pathway via upregulating DDX5 protein, and showed promising anti-NASH activity in vitro and in vivo.

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants following an order of BA.1>BA.2>BA.4/5. In naive animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccines targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection across all VOCs. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine- primed populations.

In vitro screening of natural compounds with antitumor activity by trypsin / 生理学报

In order to investigate the feasibility of in vitro screening the antitumor activity of natural compounds by trypsin, porcine trypsin was used to for screening test, which is marked by inhibition of enzyme activity. Four compounds, namely daidzin, genistin, matrine and oxymatrine, were selected as test subjects. The natural antitumor drug camptothecin was used as the control. The inhibitory effect was detected by two experimental methods: direct detection of trypsin activity inhibition and hydrolysis of bovine serum albumin by trypsin. The results showed the inhibitory effects of the four natural compounds on trypsin, and the inhibition rates of the four natural compounds were significantly different. The enzyme activity assay showed that the inhibitory effect of matrine was better than that of oxymatrine, indicating that trypsin had a good screening resolution. The inhibitory effect was significantly increased with the increased ratio of sample to trypsin, suggesting the structure-activity correlation and dose-effect correlation of the screening methods. Altogether, the experimental method of screening antitumor activity of natural compounds by trypsin has good application values. Since porcine trypsin is similar to human trypsin in terms of molecular structure and performance, it is more applicable for screening of antitumor efficacy of natural pharmacodynamic compounds.

Overview on diagnosis and treatment of oral diseases in the Qing Royal Court / 中华口腔医学杂志

The remained documents and archives show that the history of diagnosis and treatment of oral diseases in royal court of the Qing Dynasty was over 200 years. The departmental system of medical care in the Qing Royal Court was inherited from former Ming Dynasty. Although the departments in the system changed over reigns, the Department of Dentistry exist all the time. In a set of historical records of 38 medical cases opened to the public, the documented symptoms and diseases, in the sense of modern medical science, included periodontitis, oral mucosal diseases, dental caries, parotiditis, etc., and the patients involved various ranks in the court, showing that oral diseases were common in the Qing Royal Court. The royal doctors ranked variedly and the medication they used was diverse. Medical fuming or steaming and medical heating were some distinctive methods among the treatments. In 1600s, the western modern medical science started to be introduced into China. In the reign of Kangxi Emperor (1700s), many western doctors were employed by the royal court and they engaged in the treatment of oral diseases. The late Qing Dynasty appeared the second peak that western doctors came into China. In 1898, Dr. Jingrong Chen, a dentist who possessed knowledge of modern dentistry in Beijing city, set up a dental clinic in the royal court and gave treatment to patients in the royal members and high-ranking officials.

A randomized double-blinded placebo-controlled clinical trial of minodronate tablet in postmenopausal Chinese women with osteoporosis / 中华妇产科杂志

Objective:To verify the efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis.Methods:In this randomized, double-blinded, placebo-controlled trial, 262 postmenopausal women were enrolled. Patients were randomized to receive daily oral minodronate 1 mg with supplements of 500 mg calcium and 200 U vitamin D 3 ( n=130) or placebo ( n=132) with daily supplements of 500 mg calcium and 200 U vitamin D 3, for 48 weeks. The primary endpoint was the average bone mineral density (BMD) change in the lumbar vertebrae 48 weeks post-treatment. Secondary outcome measures was the incidence of vertebral fractures. Safety assessments included the rate of adverse events. Results:At the end of 48 weeks treatment, the average BMD change rate from baseline were: full analysis set results: (3.52±4.82)% in the minodronate group and (2.00±5.74)% in the placebo group; per-protocol set results: (3.99±5.05)% in the minodronate group and (2.07±6.20)% in the placebo group; the differences were all significant (all P<0.05). Vertebral fracture occured in 3 patients (2.3%, 3/132) in the placebo group, and 1 case (0.8%, 1/130) in the minodronate group ( P>0.05). The incidence of adverse events was 71.5% (93/130) in the minodronate group and 78.0% (103/132) in the placebo group ( P>0.05). Conclusion:Minodronate is effective and safe in the treatment of postmenopausal osteoporosis without severe side effects.

Inhibitor Binding Modulates Protonation States in the Active Site of SARS-CoV-2 Main Protease

The main protease (3CL Mpro) from SARS-CoV-2, the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mpro and to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the -ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other -ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation changes induced by inhibitors we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.

Judging the degree of brain injury after hypoxia-ischemia in living neonatal mice in the early stage / 解剖学报

Objective To explore the method of distinguishing the degree of hypoxic-ischemic brain damage ( HIBD) in living mice in early stage, so as to lay a foundation for the follow-up study of the molecular mechanism of different degrees of HIBD. Methods The modified Rice-Vannucci method was used to duplicate the HIBD model of C57BL/6 J mice. On the 1 day and 3 days after the model, the scalp of mice were cut and the brain tissue were observed to distinguish between mild and severe lesions in living mice, and then 2,3, 5-triphenyltetrazolium chloride (TTC) staining, laser speckle cerebral blood flow imaging, HE staining, Fluoro-Jade B ( FJB ) staining and body weight difference before and after operation were used to verify the reliability of observation in living mice. Results Through the gross observation of brain tissue in living mice, HIBD could be divided into mild injury (HI-M) group and severe injury (HI-S) group. On day 1 and day 3 after HIBD, a significant decrease in cerebral blood flow, obvious gray infarction and a large number of necrotic neurons were observed in the HI-S group, and the body weight was significantly lower than that before operation. In the HI-M group, the cerebral blood flow of the injured side decreased only on the 3rd day after HIBD, and the loose arrangement of neurons in the cortex and hippocampus of the injured side was observed morphologically. The body weight was lower than that before operation. Conclusion Gross observation of brain tissue by cutting the scalp is a reliable method to distinguish mild and severe brain injury in the early stage of HIBD in living mice.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons / 神经科学通报·英文版

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.

Role of the Anterior Cingulate Cortex in Translational Pain Research / 神经科学通报·英文版

As the most common symptomatic reason to seek medical consultation, pain is a complex experience that has been classified into different categories and stages. In pain processing, noxious stimuli may activate the anterior cingulate cortex (ACC). But the function of ACC in the different pain conditions is not well discussed. In this review, we elaborate the commonalities and differences from accumulated evidence by a variety of pain assays for physiological pain and pathological pain including inflammatory pain, neuropathic pain, and cancer pain in the ACC, and discuss the cellular receptors and signaling molecules from animal studies. We further summarize the ACC as a new central neuromodulation target for invasive and non-invasive stimulation techniques in clinical pain management. The comprehensive understanding of pain processing in the ACC may lead to bridging the gap in translational research between basic and clinical studies and to develop new therapies.

Growth Differentiation Factor-15 Produces Analgesia by Inhibiting Tetrodotoxin-Resistant Nav1.8 Sodium Channel Activity in Rat Primary Sensory Neurons / 神经科学通报·英文版

Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.

Comparison of efficacy and safety of insulin aspart injection Rishulin and NovoRapid for treatment of diabetes: a multicenter, randomized, open-labeled, controlled trial / 中华内科杂志

Objective:To compare the efficacy and safety of Tonghua Dongbao′s insulin aspart injection (Rishulin) and NovoRapid (Novo Nordisk) in the treatment of diabetes.Methods:A 26-week, randomized, open-label, parallel-group, positive control drug and non-inferiority trial was conducted in 23 centers in China. A total of 563 diabetes with poor blood glucose control treated with insulin for at least 3 months before were included. The subjects were randomized(stratified block random method) into those receiving Rishulin or NovoRapid at a ratio of 3∶1. Both groups were combined with basal insulin (Lantus). The primary endpoint was the change in glycosylated hemoglobin (HbA1c) from baseline to the end of 24 weeks of treatment.Results:For full analysis set, after 24 weeks of treatment, HbA1c level of Ruishulin group decreased from (8.66±1.28)% to (7.77±1.09)% ( P<0.001), and that of NovoRapid group decreased from (8.47±1.28) % to (7.65±0.97) % ( P<0.001). Treatment difference in HbA1c (NovoRapid group-Ruishulin group) was -0.061% (95% CI -0.320-0.199). HbA1c<7.0% target reacing rates were 24.26% and 21.21% ( P=0.456), and HbA1c<6.5% target reacing rates were 9.65% and 6.82% ( P=0.310) in Ruishulin group and NovoRapid group, repectively. The standard 2 hours postprandial blood glucose (2hPG) in Ruishulin group decreased from (16.23±5.22) mmol/L to (12.65±4.57) mmol/L ( P<0.001), and 2hPG in NovoRapid group decreased from (16.13±5.37) mmol/L to (11.91)±4.21) mmol/L ( P<0.001). The fingertips blood glucose at 7-point of both groups exhibited varying degrees of reduction compared with those at baseline, repectively. Positive ratios of specific antibodies were 31.68% in Ruishulin group and 36.36% in NovoRapid group ( P=0.320). Ratios of negative to positive were 7.43% and 10.61% ( P=0.360), and ratios of positive to negative were 10.40% and 7.58% ( P=0.360) in Ruishulin group and NovoRapid group, respectively. The incidence of hypoglycemia was 60.05% and 55.40% ( P=0.371), and the incidence of adverse events was 76.60% and 77.70% ( P=0.818) in Ruishulin group and NovoRapid group, respectively. Conclusions:Rishulin is not inferior to NovoRapid, and has shown good efficacy and safety. It can be an ideal choice for clinicians in patients with poor blood glucose control with insulin.

Textual Research on Ranae Oviductus / 中国实验方剂学杂志

Ranae Oviductus has a good tonic effect and is commonly used for both medicine and food. The use of Ranae Oviductus was confused because the origin of Ranae Oviductus was roughly recorded in ancient herbal literatures. In order to clarify the confusing literatures and trace the origin of Ranae Oviductus，this paper conducted a textual research on the name，origin，distribution，harvesting and processing，efficacy of the Chinese medicine by consulting ancient herbal books，modern literatures and monographs of traditional Chinese medicine. The results of the textual research showed that Ranae Oviductus belongs to Manchu medicine，which was first applied by the Manchu people because of its tonic effect. The original animal of Ranae Oviductus has many names，which are all translated from Manchu language. By analyzing the descriptions of Ranidae in various herbal books，it is concluded that the earliest description of the original animals of Ranae Oviductus appeared in the Shengjing Tongzhi compiled by Agui in the Qing dynasty. After summarization of the taxonomic changes of some species of Rana，the original animals of Ranae Oviductus were preliminarily determined as Rana dybowskii，R. amurensis and R. huanrenensis. We excluded R. huanrenensis by its size and R. amurensis by its poor quality. Therefore，the original animal of Ranae Oviductus is R. dybowskii，the main production area is northeast China and the best capture time is in October. Ranae Oviductus is often eaten after being stewed. The study can provide the effective basis for the identification of the original animal of Ranae Oviductus，the distribution of production area and the utilization of resources.

Increased expression of microRNA-34c in peripheral blood of type 2 diabetes mellitus patients associated with diabetic foot ulcer / 中华内分泌代谢杂志

Objective:To examine the correlations of microRNA-34c(miR-34c) expression in the peripheral blood with the onset of diabetic foot ulcer(DFU)and diabetic foot osteomyelitis(DFO)in patients with type 2 diabetes mellitus(T2DM).Methods:Sixty newly-diagnosed T2DM patients without DFU(T2DM group), 112 T2DM patients with DFU(DFU group), and 60 healthy controls with normal glucose tolerance(NC group)were included. The 112 T2DM patients with DFU were further divided into DFO( n=64)and NDFO( n=48)groups. The levels of miR-34c were determined by quantitative real-time PCR, while clinical features and risk factors of DFU and DFO were explored. Results:A significant increase in the expression level of miR-34c in peripheral blood was observed in T2DM group compared with NC group[2.99(1.45-6.22) vs 1.01(0.89-1.52), P<0.05], and a markedly increased miR-34c expression level was noted in DFU group compared with T2DM group [9.65(6.15-18.63) vs 2.99(1.45-6.22), P<0.01]. Additionally, the expression level of miR-34c in peripheral blood significantly increased in DFO group compared to NDFO group [13.46(8.89-19.11) vs 6.02(5.93-14.72), P<0.01]. Moreover, there was a positive correlation between the expression level of miR-34c in peripheral blood and the amputation rate in patients in DFU group( P=0.030), and a negative correlation in the expression level of miR-34c( P=0.025)with healing rate of DFU after eight weeks. The multivariate logistic regression analysis confirmed that a high expression of miR-34c was an independent risk factor for DFU and DFO( OR=3.52, 4.13; both P<0.01). Conclusion:An increased expression of miR-34c in peripheral blood of T2DM patients might be closely related to the occurrence, development, and prognosis of DFU and DFO.

Protonation states in SARS-CoV-2 main protease mapped by neutron crystallography

The main protease (3CL Mpro) from SARS-CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication, possessing an unusual catalytic dyad composed of His41 and Cys145. A long-standing question in the field has been what the protonation states of the ionizable residues in the substrate-binding active site cavity are. Here, we present the room-temperature neutron structure of 3CL Mpro from SARS-CoV-2, which allows direct determination of hydrogen atom positions and, hence, protonation states. The catalytic site natively adopts a zwitterionic reactive state where His41 is doubly protonated and positively charged, and Cys145 is in the negatively charged thiolate state. The neutron structure also identified the protonation states of other amino acid residues, mapping electrical charges and intricate hydrogen bonding networks in the SARS-CoV-2 3CL Mpro active site cavity and dimer interface. This structure highlights the ability of neutron protein crystallography for experimentally determining protonation states at near-physiological temperature - the critical information for structure-assisted and computational drug design.