Non-pharmacological therapies for the management of the cognitive dysfunctions in post-stroke patients: a systematic review and network meta-analysis.

OBJECTIVE: To investigate the comparative effects of non-pharmacological therapies for managing global, attention, memory and execution cognitive functions in stroke patients. DESIGN: We searched PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science, PEDro and Google Scholar for randomized controlled trials (RCTs) that evaluated the effects of non-pharmacological therapies for treating stroke cognitive dysfunctions. We performed a network meta-analysis (NMA) to estimate the mean treatment effect of 95% credible interval (CrI). RESULTS: 73 RCTs were included in the NMA for evidence syntheses. All therapies had significant effects than control on global cognition in stroke patients. Combined therapy was superior to other therapies for global cognition of all patients (vs cognitive task therapy: 0.71, 95%CrI 0.14 to 1.29; vs exercise: 0.88, 95%CrI 0.31 to 1.45, vs physical modality therapy: 0.77, 95%CrI 0.16 to 1.40). Different therapies have effects on specific cognitive domains in stroke patients. CONCLUSIONS: Our findings suggest that non-pharmacological therapies are effective in improving global cognitive function in stroke patients, with cognitive task therapy, exercise therapy, physical modality therapy, and combined therapy being viable options (most optimal approach: combined therapy). Precise selection of therapies based on the time since stroke onset and specific cognitive domains can further enhance treatment outcomes.

Biosynthesis and engineering of the nonribosomal peptides with a C-terminal putrescine.

The broad bioactivities of nonribosomal peptides rely on increasing structural diversity. Genome mining of the Burkholderiales strain Schlegelella brevitalea DSM 7029 leads to the identification of a class of dodecapeptides, glidonins, that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus. The N-terminal diversity originates from the wide substrate selectivity of the initiation module. The C-terminal putrescine moiety is introduced by the unusual termination module 13, the condensation domain directly catalyzes the assembly of putrescine into the peptidyl backbone, and other domains are essential for stabilizing the protein structure. Swapping of this module to another two nonribosomal peptide synthetases leads to the addition of a putrescine to the C-terminus of related nonribosomal peptides, improving their hydrophilicity and bioactivity. This study elucidates the mechanism for putrescine addition and provides further insights to generate diverse and improved nonribosomal peptides by introducing a C-terminal putrescine.

Heterologous Biosynthesis of Complex Bacterial Natural Products in Burkholderia gladioli.

Bacterial natural products (NPs) are an indispensable source of drugs and biopesticides. Heterologous expression is an essential method for discovering bacterial NPs and the efficient biosynthesis of valuable NPs, but the chassis for Gram-negative bacterial NPs remains inadequate. In this study, we built a Burkholderiales mutant Burkholderia gladioli Δgbn::attB by introducing an integrated site (attB) to inactivate the native gladiolin (gbn) biosynthetic gene cluster, which stabilizes large foreign gene clusters and reduces the native metabolite profile. The growth and successful heterologous production of high-value NPs such as phylogenetically close Burkholderiales-derived antitumor polyketides (PKs) rhizoxins, phylogenetically distant Gammaproteobacteria-derived anti-MRSA (methicillin-resistant Staphylococcus aureus) antibiotics WAP-8294As, and Deltaproteobacteria-derived antitumor PKs disorazols demonstrate that this strain is a potential chassis for Gram-negative bacterial NPs. We further improved the yields of WAP-8294As through promoter insertions and precursor pathway overexpression based on heterologous expression in this strain. This study provides a robust bacterial chassis for genome mining, efficient production, and molecular engineering of bacterial NPs.

Biosynthesis of cyanobacterin, a paradigm for furanolide core structure assembly.

The γ-butyrolactone motif is found in many natural signaling molecules and other specialized metabolites. A prominent example is the potent aquatic phytotoxin cyanobacterin, which has a highly functionalized γ-butyrolactone core structure. The enzymatic machinery that assembles cyanobacterin and structurally related natural products (herein termed furanolides) has remained elusive for decades. Here, we elucidate the biosynthetic process of furanolide assembly. The cyanobacterin biosynthetic gene cluster was identified by targeted bioinformatic screening and validated by heterologous expression in Escherichia coli. Full functional evaluation of the recombinant key enzymes in vivo and in vitro, individually and in concert, provided in-depth mechanistic insights into a streamlined C-C bond-forming cascade that involves installation of compatible reactivity at seemingly unreactive Cα positions of amino acid precursors. Our work extends the biosynthetic and biocatalytic toolbox for γ-butyrolactone formation, provides a general paradigm for furanolide biosynthesis and sets the stage for their targeted discovery, biosynthetic engineering and enzymatic synthesis.

Epidemiological Characteristics and Factors Associated with Alzheimer's Disease and Mild Cognitive Impairment among the Elderly in Urban and Rural Areas of Hubei Province.

Utilize the prevalence, associated factors and population distribution of AD and MCI among residents of the Hubei province aged 60 years or over to prove that elderly people who study and communicate with others, take part in regular physical exercise and choose a healthy lifestyle, will prevent or slow the decline in cognitive ability. If elderly people study and communicate with others, take part in regular physical exercise and choose a healthy lifestyle, can prevent or slow the decline in cognitive ability. A cross-sectional study was used for the recruitment of subjects. The screened patients with AD and MCI were then selected as patients in a case−control study. A total of 4314 subjects were recruited into the study. The prevalence of AD and MCI was 1.44% and 10.04%, respectively. The prevalence of AD and MCI differed significantly as a function of age and gender (p < 0.05). The preventative factors for AD and MCI, separately, included a happy marriage (OR = 0.69, 95%CI: 0.36−1.35) and higher education (OR = 0.65, 95%CI: 0.55−0.78). The risk factors for AD and MCI, separately, included infrequent participation in social activities (OR = 1.00, 95%CI: 0.60−1.66) and infrequent communication with children (OR = 1.35, 95%CI: 1.09−1.69). The prevalence of AD for people aged 60 or over in the Hubei province was lower than the national average of 3.06%. The prevalence of MCI was within the national range (5.2−23.4%). The influencing factors of AD and MCI were associated with the participants' social connections, lifestyle behaviors, somatic diseases and so on. The elderly people who study and communicate with others, take part in regular physical exercise and choose a healthy lifestyle will prevent or slow the decline in cognitive ability. The conclusion section has been replaced.

A High Neutrophil-to-Lymphocyte Ratio Predicts Higher Risk of Poststroke Cognitive Impairment: Development and Validation of a Clinical Prediction Model.

OBJECTIVE: Poststroke cognitive impairment (PSCI) is a serious complication of stroke. The neutrophil-to-lymphocyte ratio (NLR) is a marker of peripheral inflammation. The relationship between the NLR and PSCI is far from well studied, and the thesis of this study was to assess the predictive value of the NLR in patients with PSCI, and establish and verify the corresponding prediction model based on this relationship. METHODS: A total of 367 stroke patients were included in this study. Neutrophils, lymphocytes, and NLRs were measured at baseline, and clinical and neuropsychological assessments were conducted 3 months after stroke. The National Institutes of Health Scale (NIHSS) was used to assess the severity of stroke. A Chinese version of the Mini Mental State Examination (MMSE) was used for the assessment of cognitive function. RESULTS: After three months of follow-up, 87 (23.7%) patients were diagnosed with PSCI. The NLR was significantly higher in PSCI patients than in non-PSCI patients (P < 0.001). Patient age, sex, body mass index, NIHSS scores, and high-density lipoprotein levels also differed in the univariate analysis. In the logistic regression analysis, the NLR was an independent risk factor associated with the patients with PSCI after adjustment for potential confounders (OR = 1.67, 95%CI: 1.21-2.29, P = 0.002). The nomogram based on patient sex, age, NIHSS score, and NLR had good predictive power with an AUC of 0.807. In the validation group, the AUC was 0.816. CONCLUSION: An increased NLR at admission is associated with PSCI, and the model built with NLR as one of the predictors can increase prognostic information for the early detection of PSCI.

An Updated Understanding of the Current Emerging Respiratory Infection: COVID-19.

According to the World Health Organization (WHO), the COVID-19 pandemic has been declared as a priority disease. Some patients with COVID-19 had symptoms of multiple organ failure and death. The published articles on COVID-19 infection were reviewed. The origin of SARS-CoV-2 is still not completely established. Person-to-person transmission via droplets, probable aerosols, or close contact is considered as the main mode of transmission. With increased mortality due to SARS-CoV-2, valuable clinical indicators or treatments should be further identified and summarized. CT scanning plays an important role in the diagnosis and evaluation of COVID-19 in asymptomatic patients or those with initially negative RT-PCR results. No specific antiviral therapy is recommended, except the main supportive treatments, and effective measures should be taken into consideration to protect important organs and prevent the development of acute respiratory distress syndrome (ARDS) in patients with severe infection.

Elucidation of the Tailoring Steps in Julichrome Biosynthesis by Marine Gastropod Mollusk-Associated Streptomyces sampsonii SCSIO 054.

The biosynthetic gene cluster governing the production of antibacterial julichromes was identified from marine gastropod mollusk-associated Streptomyces sampsonii SCSIO 054. Post-PKS assembly/tailoring enzymes JuiL, JuiM, JuiI, and JuiN represent key assembly enzymes. JuiL serves as a ketoreductase. JuiM is an acetyltransferase. JuiI carries out an intriguing biaryl coupling of two julichrome Q6 units (immediate JuiL, JuiM product) to afford julichrome Q6-6. JuiN carries out tailoring steps on julichrome Q6-6, transforming Q6-6 into Q3-3.

Nonspecific Heme-Binding Cyclase, AbmU, Catalyzes [4 + 2] Cycloaddition during Neoabyssomicin Biosynthesis.

Diels-Alder (DA) [4 + 2]-cycloaddition reactions rank among the most powerful transformations in synthetic organic chemistry; biosynthetic examples, however, are few and far between. We report here a heme-binding cyclase, AbmU, that catalyzes an essential [4 + 2] cycloaddition during neoabyssomicin scaffold assembly. In vivo genetic and in vitro biochemical analyses strongly suggest that AbmU catalyzes an intramolecular and stereoselective [4 + 2] cycloaddition to form a spirotetronate skeleton from an acyclic substrate featuring both a terminal 1,3-diene and an exo-methylene group. Biochemical assays and X-ray diffraction analyses reveal that AbmU binds nonspecifically to a heme b cofactor and that this association does not play a catalytic role in AbmU catalysis. A detailed study of the AbmU crystal structure reveals a unique mode of substrate binding and reaction catalysis; His160 forms a H-bond with the C-1 carbonyl O-atom of the acyclic substrate, and the imidazole of the same amino acid directs the tetronate moiety of acyclic substrate toward the terminal Δ10,11, Δ12,13-diene moiety, thereby facilitating intramolecular DA chemistry. Our findings expand upon what is known about mechanistic diversities available to biosynthetic [4 + 2] cyclases and help to lay the foundation for the use of AbmU in possible industrial applications.

Neuroprotective functions of calycosin against intracerebral hemorrhage-induced oxidative stress and neuroinflammation.

Aim: To investigate whether calycosin affects the brain damages induced by intracerebral hemorrhage (ICH). Methods: ICH mouse model was established by injection of collagenase type VII. Results: 50 mg/kg calycosin showed significant inhibitory effects on ICH-induced brain impairment evaluated by modified neurologic severity scores and water content. In addition, the lesion volumes, blood accumulation and hemispheric enlargement were all dramatically reduced by calycosin treatment compared with those of vehicles. It was observed that calycosin repressed oxidative stress by enhancing Nrf2 anti-oxidative pathway and suppressed inflammation by blocking NACHT, NALP3 inflammasome and NF-κB pathway activation. Conclusion: Calycosin could protect the brain against the damages induced by ICH via inhibiting oxidative damages and inflammation.

Efficient synthesis of ß-lactam antibiotics with in situ product removal by a newly isolated penicillin G acylase.

A penicillin G acylase (PGA) from Achromobacter xylosoxidans PX02 was newly isolated, and site-directed mutagenesis at three important positions αR141, αF142, ßF24 was carried out for improving the enzymatic synthesis of ß-lactam antibiotics. The efficient mutant ßF24A was selected, and the (Ps/Ph)ini (ratio between the initial rate of synthesis and hydrolysis of the activated acyl donor) dramatically increased from 1.42-1.50 to 23.8-24.1 by means of the optimization of reaction conditions. Interestingly, the efficient enzymatic synthesis of ampicillin (99.1% conversion) and amoxicillin (98.7% conversion) from a high concentration (600 mM) of substrate 6-APA in the low acyl donor/nucleus ratio (1.1:1) resulted in a large amount of products precipitation from aqueous reaction solution. Meanwhile, the by-product D-phenylglycine was hardly precipitated, and 93.5% yield of precipitated ampicillin (561 mM) and 94.6% yield of precipitated amoxicillin (568 mM) were achieved with high purity (99%), which significantly simplified the downstream purification. This was the first study to achieve efficient ß-lactam antibiotics synthesis process with in situ product removal, with barely any by-product formation. The effect enzymatic synthesis of antibiotics in aqueous reaction solution with in situ product removal provides a promising model for the industrial semi-synthesis of ß-lactam antibiotics.

Julichrome Monomers from Marine Gastropod Mollusk-Associated Streptomyces and Stereochemical Revision of Julichromes Q3 ⋠5 and Q3 ⋠3.

Two julichrome monomers, julichromes Q11 (1) and Q12 (2), along with five known julichromes (Q10 , Q3 ⋅ 5 , Q3 ⋅ 3 , Q6 ⋅ 6 , Q6 , 3-7) and four known anthraquinones (chrysophanol, 4-acetylchrysophanol, islandicin, huanglongmycin A, 8-11), were isolated from the marine gastropod mollusk Batillaria zonalis-associated Streptomyces sampsonii SCSIO 054. This is the first report of julichromes isolated from a marine source. Extensive dissection of 1D and 2D NMR datasets combined with X-ray crystallography enabled rigorous elucidation of the previously reported configurations of julichrome Q3 ⋅ 5 (4) and related julichrome Q3 ⋅ 3 (5); both of the configuration at C(9) needs to be revised. In addition, julichrome Q12 (2) was found to display antibacterial activity against Micrococcus luteus and Bacillus subtilis with MICs of 2.0 and 8.0 µg mL-1 ; four compounds (1, 3, 6, 7) also showed inhibitory activities against an array of methicillin-resistant Staphylococcus aureus, S. aureus and S. simulans AKA1 with MIC values ranging from 8 to 64 µg mL-1 .

[Effects of early intervention training on cognitive impairment in critical patients].

OBJECTIVE: To investigate the characteristics of cognitive impairment in critical patients, and to explore the role of early cognitive intervention training in improving cognitive impairment in critical patients. METHODS: A prospective cohort study was conducted. 133 patients in conscious and normal intelligence admitted to intensive care unit (ICU) of Hefei Second People's Hospital from January 2015 to June 2018 were enrolled. The patients were divided into control group (n = 66) and cognitive intervention group (n = 67) according to random number table based on chronological number for entry into the study. Cognitive function was assessed by Montreal cognitive assessment scale (MoCA scale) within 24 hours after ICU admission. The patients in the cognitive intervention group received a series of scientifically designed cognitive training sessions (playing electronic musical keyboard, learning simple Spanish, clock-drawing, psychological intervention) for 2 months, and follow-up was completed if the patient was discharged from ICU. While the patients in the control group did not undertake any cognitive training. After 2 months, the cognitive function of patients in both groups were assessed with MoCA scale. Subgroup analysis was conducted according to different age groups (20-40 years old, 41-60 years old, 61-80 years old) to explore the effect of cognitive intervention training in different age groups. According to the subjective evaluation of the patient's ability to live 2 months after cognitive intervention by the patient or his relatives, receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of the total score of MoCA for patients' ability to live after cognitive intervention. RESULTS: 133 critical patients were enrolled in the final analysis. There was no significant difference in gender, age, education, complications, ICU hospitalization, sedative or analgesic drug usage between the two groups, indicating that the data of the two groups were balanced and comparable. No significant difference in MoCA scale total score or sub-item cognitive domain score within 24 hours of ICU admission was found between the two groups. After 2 months of intervention, the incidence of cognitive impairment in the cognitive intervention group was significantly lower than that in the control group [38.8% (26/67) vs. 60.6% (40/66), χ2 = 6.321, P = 0.015]. The total score of MoCA scale and four sub-item cognitive domain scores including visual space and execution power, protection of memory, attention execution, and orientation in the cognitive intervention group were significant higher than those in the control group (MoCA scale total score: 26.73±1.92 vs. 24.95±2.26, visual space and executive power score: 4.39±0.70 vs. 3.95±0.88, protection of memory score: 8.91±1.03 vs. 8.24±1.37, attention execution score: 5.21±0.77 vs. 4.79±1.00, orientation score: 5.67±0.53 vs. 5.44±0.68, all P < 0.05), but no significant difference was found in verbal skills score (2.55±0.56 vs. 2.53±0.56, P > 0.05). Subgroup analysis showed that the total MoCA scale score of the younger sample (20-40 years old, n = 20) was recovered by 2.10±1.55 in the cognitive intervention group after 2 months of cognitive intervention, which was significantly higher than that in the control group (n = 21; 0.24±2.76, P < 0.05). In the middle-aged and the older population [aged 41-60 years old (n = 20) and 61-80 years old (n = 27)], the total MoCA scale scores were recovered slightly after cognitive intervention as compared with those in the younger sample (0.43±1.47, -1.91±2.20 vs. 2.10±1.55, both P < 0.05), which were significantly lower than those in the control group [aged 41-60 years old (n = 21) and 61-80 years old (n = 24), -0.78±1.38, -4.41±2.17, both P < 0.01]. It was suggested that cognitive intervention training played an active role in the recovery of cognitive function in young critical patients. It was shown by ROC curve analysis that the area under ROC curve (AUC) of MoCA scale total score for predicting daily life ability after cognitive intervention was 0.732 with 95% confidence interval (95%CI) of 0.646-0.819. When the best cut-off value was 24.5, the sensitivity was 89.3%, the specificity was 60.2%, the positive predictive value was 85.7%, and the negative predictive value was 80.8%. CONCLUSIONS: Early cognitive intervention could efficiently abate the deterioration of cognitive function in critical patients in ICU and had significant effects on the visual space and executive power, protection of memory, attention execution and orientation. Cognitive intervention exerted significantly positive effects on the recovery of cognitive function in the younger sample population (aged 20-40 years old).

Analysis of HYAL3 gene mutations in Chinese lung squamous cell carcinoma patients.

PURPOSE: In a previous study, we found a hyaluronidase 3 (HYAL3) gene mutation in exon 2 at position 188 by genome sequencing in a lung squamous cell carcinoma patient. The mutation results in substitution of serine for alanine. The aim of the study was to screen the HYAL3 gene mutation in Chinese lung squamous cell carcinoma patients and explore the correlation between mutation of HYAL3 with clinical and pathological characteristics in lung squamous cell carcinoma patients in China. METHODS: We applied polymerase chain reaction to examine the HYAL3 gene mutations in cancer tissues and their adjacent normal tissues from 39 cases of lung squamous cell carcinoma patients. RESULTS: 1) The incidence rate of HYAL3 mutation in 39 cases of lung squamous cell carcinoma was 10.26% (4/39) and none in adjacent normal lung tissues (0/39). 2) The mutations of HYAL3 in the 4 cases were all heterozygous: 3 of them were located in exon 1 (G-T) and one in exon 2 (G-T). 3) Mutations of the HYAL3 gene were not correlated with the distribution of patient gender, age, tumor size, histological grade, smoking history, TNM stage or distant metastasis (P >0.05). The gene mutation was correlated with lymph node status (P = 0.044). CONCLUSION: Mutations of the HYAL3 gene are rare in Chinese lung squamous cell carcinoma patients and might contribute to lymph node metastasis.

Demethylzeylasteral exhibits strong inhibition towards UDP-glucuronosyltransferase (UGT) 1A6 and 2B7.

Inhibition of UDP-glucuronosyltransferase (UGT) isoforms can result in severe clinical results, including clinical drug-drug interactions (DDI) and metabolic disorders of endogenous substances. The present study aims to investigate the inhibition of demethylzeylasteral (an important active component isolated from Tripterygium wilfordii Hook F.) towards three important UGT isoforms UGT1A6, UGT1A9 and UGT2B7. The results showed that 100 µM of demethylzeylasteral exhibited strong inhibition towards UGT1A6 and UGT2B7, with negligible influence towards UGT1A9. Furthermore, Dixon and Lineweaver-Burk plots showed the inhibition of UGT1A6 and UGT2B7 by demethylzeylasteral was best fit to competitive inhibition, and the inhibition kinetic parameters (Ki) were calculated to be 0.6 µM and 17.3 µM for UGT1A6 and UGT2B7, respectively. This kind of inhibitory effect need much attention when demethylzeylasteral and demethylzeyasteral-containing herbs (e.g., Tripterygium wilfordii Hook F.) were co-administered with the drugs mainly undergoing UGT1A6, UGT2B7-catalyzed metabolism. However, when extrapolating the in vivo clinical results using our present in vitro data, many complex factors might affect final results, including the contribution of UGT1A6 and UGT2B7 to the metabolism of compounds, and the herbal or patients' factors affecting the in vivo concentration of demethylzeylasteral.