Frequency dependent whole-brain coactivation patterns analysis in Alzheimer's disease.

Background: The brain in resting state has complex dynamic properties and shows frequency dependent characteristics. The frequency-dependent whole-brain dynamic changes of resting state across the scans have been ignored in Alzheimer's disease (AD). Objective: Coactivation pattern (CAP) analysis can identify different brain states. This paper aimed to investigate the dynamic characteristics of frequency dependent whole-brain CAPs in AD. Methods: We utilized a multiband CAP approach to model the state space and study brain dynamics in both AD and NC. The correlation between the dynamic characteristics and the subjects' clinical index was further analyzed. Results: The results showed similar CAP patterns at different frequency bands, but the occurrence of patterns was different. In addition, CAPs associated with the default mode network (DMN) and the ventral/dorsal visual network (dorsal/ventral VN) were altered significantly between the AD and NC groups. This study also found the correlation between the altered dynamic characteristics of frequency dependent CAPs and the patients' clinical Mini-Mental State Examination assessment scale scores. Conclusion: This study revealed that while similar CAP spatial patterns appear in different frequency bands, their dynamic characteristics in subbands vary. In addition, delineating subbands was more helpful in distinguishing AD from NC in terms of CAP.

Antitoxin MqsA decreases antibiotic susceptibility through the global regulator AgtR in Pseudomonas fluorescens.

Type II toxin-antitoxin systems are highly prevalent in bacterial genomes and play crucial roles in the general stress response. Previously, we demonstrated that the type II antitoxin PfMqsA regulates biofilm formation through the global regulator AgtR in Pseudomonas fluorescens. Here, we found that both the C-terminal DNA-binding domain of PfMqsA and AgtR are involved in bacterial antibiotic susceptibility. Electrophoretic mobility shift assay (EMSA) analyses revealed that AgtR, rather than PfMqsA, binds to the intergenic region of emhABC-emhR, in which emhABC encodes an resistance-nodulation-cell division efflux pump and emhR encodes a repressor. Through quantitative real-time reverse-transcription PCR and EMSA analysis, we showed that AgtR directly activates the expression of the emhR by binding to the DNA motif [5´-CTAAGAAATATACTTAC-3´], leading to repression of the emhABC. Furthermore, we demonstrated that PfMqsA modulates the expression of EmhABC and EmhR. These findings enhance our understanding of the mechanism by which antitoxin PfMqsA contributes to antibiotic susceptibility.

Effects of the Severe Acute Respiratory Syndrome Coronavirus 2 Inactivated Vaccine on the Outcome of Frozen Embryo Transfers: A Large Scale Clinical Study.

Background: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a life-threatening infectious disease that has become a global pandemic. Objective: This study aimed to explore the effects of SARS-CoV-2 inactivated vaccine on the outcome of frozen embryo transfer (FET). Methods: We grouped patients who underwent FET between August 2021 and March 2022 based on their vaccination status, number of doses, and the interval between the last dose and the FET, and then compared the differences in pregnancy outcomes among the groups. Results: There were 1084 vaccinated patients and 1228 non-vaccinated ones. There were significant differences in the live birth rate between the vaccination and non-vaccination groups (16.61% vs 28.26%), among the one-dose, two-dose, and three-dose groups (22.28% vs 19.51% vs 7.27%), and among the groups with interval ≤ 1 month, 1-2 months, and ≥ 2 months (38.38% vs 27.27% vs 12.03%). There were significant differences in the persistent pregnancy rate between the vaccination and non-vaccination groups (22.88% vs 14.09%), among the one-dose, two-dose, and three-dose groups (14.51% vs 23.80% vs 38.18%), and among the groups with interval ≤ 1 month, 1-2 months, and ≥ 2 months (1.01% vs 8.44% vs 28.16%). There were significant differences in the neonatal weight between the vaccination and non-vaccination groups [3805.50 (3746.00-3863.50) vs 2970.00 (2500.00-3400.00)]. There were significant differences in the premature birth rate among the one-dose, two-dose, and three-dose groups (23.26% vs 34.59% vs 100.00%), and among the groups with interval ≤ 1 month, 1-2 months, and ≥ 2 months (15.79% vs 21.43% vs 37.00%). Conclusion: Pregnancy outcomes were not affected by taking the SARS-CoV-2 inactivated vaccine before FET, the number of doses, and the interval between doses. These findings provide evidence supporting the safety of administering the SARS-CoV-2 inactivated vaccine during pregnancy, which can be used as a guide for vaccinating patients undergoing ART.

Proteomic analysis reveals the mechanism of different environmental stress-induced tolerance of Pseudomonas aeruginosa to monochloramine disinfection.

Although drinking water disinfection proved to be an effective strategy to eliminate many pathogens, bacteria can still show disinfection tolerance in drinking water distribution systems. To date, the molecular mechanisms on how environmental stress affects the tolerance of Pseudomonas aeruginosa to monochloramine are not well understood. Here, we investigated how three stress conditions, namely starvation, low temperature, and starvation combined with low temperature, affected the monochloramine tolerance of Pseudomonas aeruginosa, an opportunistic pathogen commonly found in drinking water distribution systems. All stress conditions significantly promoted monochloramine tolerance, among which starvation had the most drastic effects. Proteomic analyses suggested that the three conditions not only triggered a positive antioxidant defense against oxidative damages but also prepared the bacteria to employ a passive defense mechanism against disinfectants via dormancy. Moreover, the expression of antioxidant enzymes reached the maximum under the starvation condition and further low temperature treatment had little effect on bacterial response to oxidative stress. Instead, we found further treatment of the starved cells with low temperature decreased the osmotic stress response and the stringent response, which generally play pivotal roles in disinfection tolerance. Taken together, these findings shed light on how abiotic factors influence the bacterial disinfection tolerance and will aid design of efficient strategies to eliminate Pseudomonas aeruginosa from drinking water.

Bacterial type II toxin-antitoxin systems acting through post-translational modifications.

The post-translational modification (PTM) serves as an important molecular switch mechanism to modulate diverse biological functions in response to specific cues. Though more commonly found in eukaryotic cells, many PTMs have been identified and characterized in bacteria over the past decade, highlighting the importance of PTMs in regulating bacterial physiology. Several bacterial PTM enzymes have been characterized to function as the toxin component of type II TA systems, which consist of a toxin that inhibits cell growth and an antitoxin that protects the cell from poisoning by the toxin. While TA systems can be classified into seven types based on nature of the antitoxin and its activity, type II TA systems are perhaps the most studied among the different TA types and widely distributed in eubacteria and archaea. The type II toxins possessing PTM activities typically modify various cellular targets mostly associated with protein translation and DNA replication. This review mainly focuses on the enzymatic activities, target specificities, antitoxin neutralizing mechanisms of the different families of PTM toxins. We also proposed that TA systems can be conceptually viewed as molecular switches where the 'on' and 'off' state of the system is tightly controlled by antitoxins and discussed the perspective on toxins having other physiologically roles apart from growth inhibition by acting on the nonessential cellular targets.

The Regulator PltZ Regulates a Putative ABC Transporter System PltIJKNOP of Pseudomonas aeruginosa ATCC 27853 in Response to the Antimicrobial 2,4-Diacetylphloroglucinol.

Pseudomonas aeruginosa is an opportunistic pathogen commonly infecting immunocompromised patients with diseases like cystic fibrosis (CF) and cancers and has high rates of recurrence and mortality. The treatment efficacy can be significantly worsened by the multidrug resistance (MDR) of P. aeruginosa, and there is increasing evidence showing that it is easy for this pathogen to develop MDR. Here, we identified a gene cluster, pltZ-pltIJKNOP, which was originally assumed to be involved in the biosynthesis of an antimicrobial pyoluteorin, significantly contributing to the antibiotic resistance of P. aeruginosa ATCC 27853. Moreover, the TetR family regulator PltZ binds to a semi-palindromic sequence in the promoter region of the pltIJKNOP operon and recognizes the antimicrobial 2,4-diacetylphloroglucinol (2,4-DAPG), which in turn induces the expression of the pltIJKNOP operon. Using quantitative proteomics method, it was indicated that the regulator PltZ also plays an important role in maintaining metabolic hemostasis by regulating the transporting systems of amino acids, glucose, metal ions, and bacteriocins.

Understanding collective behaviors in reinforcement learning evolutionary games via a belief-based formalization.

Collective behaviors by self-organization are ubiquitous in nature and human society and extensive efforts have been made to explore the mechanisms behind them. Artificial intelligence (AI) as a rapidly developing field is of great potential for these tasks. By combining reinforcement learning with evolutionary game (RLEG), we numerically discover a rich spectrum of collective behaviors-explosive events, oscillation, and stable states, etc., that are also often observed in the human society. In this work, we aim to provide a theoretical framework to investigate the RLEGs systematically. Specifically, we formalize AI-agents' learning processes in terms of belief switches and behavior modes defined as a series of actions following beliefs. Based on the preliminary results in the time-independent environment, we investigate the stability at the mixed equilibrium points in RLEGs generally, in which agents reside in one of the optimal behavior modes. Moreover, we adopt the maximum entropy principle to infer the composition of agents residing in each mode at a strictly stable point. When the theoretical analysis is applied to the 2×2 game setting, we can explain the uncovered collective behaviors and are able to construct equivalent systems intuitively. Also, the inferred composition of different modes is consistent with simulations. Our work may be helpful to understand the related collective emergence in human society as well as behavioral patterns at the individual level and potentially facilitate human-computer interactions in the future.

Analysis of Drought Tolerance and Associated Traits in Upland Cotton at the Seedling Stage.

(1) Background: Upland cotton (Gossypium hirsutum L.) is the most important natural fiber worldwide, and it is extensively planted and plentifully used in the textile industry. Major cotton planting regions are frequently affected by abiotic stress, especially drought stress. Drought resistance is a complex, quantitative trait. A genome-wide association study (GWAS) constitutes an efficient method for dissecting the genetic architecture of complex traits. In this study, the drought resistance of a population of 316 upland cotton accessions was studied via GWAS. (2) Methods: GWAS methodology was employed to identify relationships between molecular markers or candidate genes and phenotypes of interest. (3) Results: A total of 8, 3, and 6 SNPs were associated with the euphylla wilting score (EWS), cotyledon wilting score (CWS), and leaf temperature (LT), respectively, based on a general linear model and a factored spectrally transformed linear mixed model. For these traits, 7 QTLs were found, of which 2 each were located on chromosomes A05, A11, and D03, and of which 1 was located on chromosome A01. Importantly, in the candidate regions WRKY70, GhCIPK6, SnRK2.6, and NET1A, which are involved in the response to abscisic acid (ABA), the mitogen-activated protein kinase (MAPK) signaling pathway and the calcium transduction pathway were identified in upland cotton at the seedling stage under drought stress according to annotation information and linkage disequilibrium (LD) block analysis. Moreover, RNA sequencing analysis showed that WRKY70, GhCIPK6, SnRK2.6, and NET1A were induced by drought stress, and the expression of these genes was significantly different between normal and drought stress conditions. (4) Conclusions: The present study should provide some genomic resources for drought resistance in upland cotton. Moreover, the germplasm of the different phenotypes, the detected SNPs and, the potential candidate genes will be helpful for molecular marker-assisted breeding studies about increased drought resistance in upland cotton.

Reinforcement learning meets minority game: Toward optimal resource allocation.

The main point of this paper is to provide an affirmative answer through exploiting reinforcement learning (RL) in artificial intelligence (AI) for eliminating herding without any external control in complex resource allocation systems. In particular, we demonstrate that when agents are empowered with RL (e.g., the popular Q-learning algorithm in AI) in that they get familiar with the unknown game environment gradually and attempt to deliver the optimal actions to maximize the payoff, herding can effectively be eliminated. Furthermore, computations reveal the striking phenomenon that, regardless of the initial state, the system evolves persistently and relentlessly toward the optimal state in which all resources are used efficiently. However, the evolution process is not without interruptions: there are large fluctuations that occur but only intermittently in time. The statistical distribution of the time between two successive fluctuating events is found to depend on the parity of the evolution, i.e., whether the number of time steps in between is odd or even. We develop a physical analysis and derive mean-field equations to gain an understanding of these phenomena. Since AI is becoming increasingly widespread, we expect our RL empowered minority game system to have broad applications.

Macrophages participate in the immunosuppression of condyloma acuminatum through the PD-1/PD-L1 signaling pathway.

BACKGROUND: The aim of this study was to investigate whether macrophages can participate in the immunosuppression of condyloma acuminatum (CA) by expressing PD-1/PD-L1. METHODS: The infiltration of macrophages and expression of programmed death-1 (PD-1) and PD-1 ligand 1 (PD-L1) on wart lesions and in normal skin tissues were detected by immunohistochemistry assay. The amounts of M1- and M2-type macrophages derived from THP-1 cells were measured by flow cytometry. The expression of cytokines on macrophages was examined by using enzyme-linked immunosorbent assay (ELISA). The protein expression of PD-1 and PD-L1 on macrophages was detected by western blotting. RESULTS: The macrophages were significantly increased, while PD-1 and PD-L1 were highly expressed on wart lesions compared to normal controls. More M2-like macrophages than M1-type macrophages were present on wart lesions. The M2-like macrophages in the CA groups showed high expression of interleukin-10 (IL-10), transforming growth factor (TGF-ß), PD-1, and PD-L1 compared to normal controls. CONCLUSION: Macrophages participate in the immunosuppression of CA by expressing PD-1/PD-L1.

Discovery and structural analysis of a phloretin hydrolase from the opportunistic human pathogen Mycobacterium abscessus.

The family of PhlG proteins catalyses the hydrolysis of carbon-carbon bonds and is widely distributed across diverse bacterial species. Two members of the PhlG family have been separately identified as 2,4-diacetylphloroglucinol (2,4-DAPG) hydrolase and phloretin hydrolase; however, the extent of functional divergence and catalytic substrates for most members of this family is still unknown. Here, using sequence similarity network and gene co-occurrence analysis, we categorized PhlG proteins into several subgroups and inferred that PhlG proteins from Mycobacterium abscessus (MaPhlG) are likely to be functionally equivalent to phloretin hydrolase. Indeed, we confirmed the hydrolytic activity of MaPhlG towards phloretin and its analog monoacetylphloroglucinol (MAPG), and the crystal structure of MaPhlG in complex with MAPG revealed the key residues involved in catalysis and substrate binding. Through mutagenesis and enzymatic assays, we demonstrated that H160, I162, A213 and Q266, which are substituted in 2,4-DAPG hydrolase, are essential for the activity towards phloretin. Based on the conservation of these residues, potential phloretin hydrolases were identified from Frankia, Colletotrichum tofieldiae and Magnaporthe grisea, which are rhizosphere inhabitants. These enzymes may be important for rhizosphere adaptation of the producing microbes by providing a carbon source through anaerobic degradation of flavonoids. Taken together, our results provided a framework for understanding the mechanism of functional divergence of PhlG proteins.

The antitoxin MqsA homologue in Pseudomonas fluorescens 2P24 has a rewired regulatory circuit through evolution.

The mqsRA operon encodes a toxin-antitoxin pair that was characterized to participate in biofilm and persister cell formation in Escherichia coli. Notably, the antitoxin MqsA possesses a C-terminal DNA-binding domain that recognizes the [5'-AACCT(N)2-4 AGGTT-3'] motif and acts as a transcriptional regulator controlling multiple genes including the general stress response regulator RpoS. However, it is unknown how the transcriptional circuits of MqsA homologues have changed in bacteria over evolutionary time. Here, we found mqsA in Pseudomonas fluorescens (PfmqsA) is acquired through horizontal gene transfer and binds to a slightly different motif [5'-TACCCT(N)3 AGGGTA-3'], which exists upstream of the PfmqsRA operon. Interestingly, an adjacent GntR-type transcriptional regulator, which was termed AgtR, is under negative control of PfMqsA. It was further demonstrated that PfMqsA reduces production of biofilm components through AgtR, which directly regulates the pga and fap operons involved in the synthesis of extracellular polymeric substances. Moreover, through quantitative proteomics analysis, we showed AgtR is a highly pleiotropic regulator that influences up to 252 genes related to diverse processes including chemotaxis, oxidative phosphorylation and carbon and nitrogen metabolism. Taken together, our findings suggest the rewired regulatory circuit of PfMqsA influences diverse physiological aspects of P. fluorescens 2P24 via the newly characterized AgtR.

Analysis of quality of life and influencing factors in 197 Chinese patients with port-wine stains.

Port-wine stains (PWS) are congenital capillary malformations, usually occurring on the face, neck, and other exposed parts of the skin, that have serious psychological and social impact on the patient. Most researchers focus on the treatment of PWS, but the quality of life (QoL) of PWS patients is seldom researched. The objective of this study is to evaluate the QoL of patients with PWS on exposed parts and explore the factors influencing the QoL of PWS patients. The QoL of 197 cases with PWS on exposed parts were prospectively studied using the Dermatology Life Quality Index questionnaire (DLQI), and the factors influencing the patients' QoL were analyzed by single-factor analysis and multiple-factor logistic regression analysis. The reliability and validity of the QoL of PWS patients were then assessed by DLQI. A total of 197 valid questionnaires were collected. The DLQI scores in PWS cases ranged from 2 to 16, with 2 to 5 in 52.29% (103/197), 6 to 10 in 42.13% (83/197), and 11 to 20 in 5.58% (11/197). The main score elements of the DLQI focused on symptoms and feelings, daily activities, and social entertainment. Single-factor analysis and multiple-factor logistic regression analysis showed that the main influencing factors were female sex, skin hypertrophy, and lesion area >30 cm. The inter-item correlation averaged 47.46% and the Cronbach α was 0.740, indicating high internal consistency. Correlation of the 6 dimensions of the DLQI questionnaires with the total scores showed that the Spearman correlation coefficient r ranged from 0.550 to 0.782 (P < .001), with symptoms and feelings having a correlation coefficient of 0.782 and a high correlation with total scores. This study shows that PWS has mild to moderate influence on the QoL of most patients, mainly on daily activities, social entertainment, and feelings.

A novel MVK missense mutation in one Chinese family with disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. mevalonate kinase, (MVK) a gene know to play an important role in regulation of calcium-induced keratinocyte differentiation and proliferation, has recently been suggested as the disease-causing gene for DSAP. Here we report a direct sequencing analysis of this gene in 3 DSAP families, 6 sporadic cases, and 100 unrelated healthy controls. We detected a heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene in one familial case. This mutation will result in an amino acid change at codon 69 (P.Ser69Thr), which is from a serine codon (TCA) to a threonine codon (ACA). No such mutation was detected in the unaffected family members or the 100 unrelated healthy controls. Our results demonstrated a novel missense mutation in MVK gene. This will be valuable for the diagnosis of DSAP as well as for genetic counseling and prenatal diagnosis of affected families.

[Dynamics of peripheral blood B lymphocytes and natural killer cells in patients with severe acute respiratory syndrome].

OBJECTIVE: To study the dynamics of peripheral blood B lymphocytes and natural killer (NK) cells in patients with severe acute respiratory syndrome (SARS). METHODS: The absolute numbers of peripheral blood B lymphocytes and NK cells in 602 serial samples from 240 patients with SARS were counted, using flow cytometry, and compared with that of normal population. RESULTS: The absolute numbers of peripheral blood B lymphocytes and NK cells in SARS patients were significantly lower than that of the normal population (P < 0.001) and were much lower in SARS patients with severe or extremely severe types, as compared with that of moderate or mild type cases (P < 0.001). The amount of B lymphocytes in recovery SARS patients increased at the 2nd week after onset, and gradually becoming normal at the 5th week of the disease onset. The number of NK cells was in the low level at onset, and keep decreasing at the 2nd week. However, it was increasing with the recovery of the disease, but did not reach to normal level at the 5th week after onset. CONCLUSION: The absolute numbers of peripheral blood B lymphocytes and NK cells were associated with the severity of the disease, and detection of these two kinds of cells was useful for predicting the prognosis of SARS.