Catalytic conversion of furfural into a 2,5-furandicarboxylic acid-based polyester with total carbon utilization.
One divided into two combined into one: The catalytic conversion of furfural into a 2,5-furandicarboxylic acid-based polyester, linked by the disproportionation of furoate to furan and 2,5-furandicarboxylate, is reported. In this manner, all carbons are utilized, demonstrating the success of combining a platform molecule from C(5) sugars (furfural) to one from C(6) sugars (2,5-FDCA).


Distant heart procurement for human transplantation. Ultrastructural studies.
The paucity of donor hearts for human transplantation can be remedied by distant heart procurement. In the present study, 12 donor hearts obtained at distant locatins were preserved by infusion with 500 ml of cardioplegic solution at 4 degrees C at 150 mm Hg and immersion in 4 degrees C saline for rapid transmural cooling. They were transported in ice-cold saline. Maximal ischemic times were 110-182 minutes. Septal biopsies before coronary reperfusion showed normal mitochondria (11 and 12), normal nuclei (seven of 12), myofibrillar I-bands (six of 12), and capillary endothelial swelling (12 of 12). Septal biopsies 30 minutes after reperfusion showed mitochondrial swelling (six of 10), nuclear damage (10 of 10), myofibrillar contraction (10 of 10), and endothelial swelling (eight of 10). All grafts functioned satisfactorily. Eight of the 12 patients were alive 6-15 months later; four patients died (one of pulmonary hypertension and three of infection). We concluded that (1) human hearts show significant ultrastructural changes after 3 hours of ischemia, but (2) these worsen after reperfusion, and (3) distant heart procurement is feasible for human transplantation.


Metabolomic analysis of pressure-overloaded and infarcted mouse hearts.
Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism. Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction [MI]). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated with myocardial insulin resistance. Longer duration of transverse aortic constriction and MI led to a decrease in purines, acylcarnitines, fatty acids, and several lysolipid and sphingolipid species but a marked increase in pyrimidines as well as ascorbate, heme, and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline. These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism.


Randomized, double-blind, placebo-controlled, multicentered trial of the efficacy of a single dose of live oral cholera vaccine CVD 103-HgR in preventing cholera following challenge with Vibrio cholerae O1 El tor inaba three months after vaccination.
CVD 103-HgR is a live oral cholera vaccine strain constructed by deleting 94% of the gene for the enzymatically active A subunit of cholera toxin from classical Inaba Vibrio cholerae O1 569B; the strain also contains a mercury resistance gene as an identifying marker. This vaccine was well tolerated and immunogenic in double-blind, controlled studies and was protective in open-label studies of volunteers challenged with V. cholerae O1. A randomized, double-blind, placebo-controlled, multicenter study of vaccine efficacy was designed to test longer-term protection of CVD 103-HgR against moderate and severe El Tor cholera in U.S. volunteers. A total of 85 volunteers (50 at the University of Maryland and 35 at Children's Hospital Medical Center/University of Cincinnati) were recruited for vaccination and challenge with wild-type V. cholerae El Tor Inaba. Volunteers were randomized in a double-blind manner to receive, with buffer, a single oral dose of either CVD 103-HgR (2 x 10(8) to 8 x 10(8) CFU) or placebo (killed E. coli K-12). About 3 months after immunization, 51 of these volunteers were orally challenged with 10(5) CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Ninety-one percent of the vaccinees had a >/=4-fold rise in serum vibriocidal antibodies after vaccination. After challenge, 9 (39%) of the 23 placebo recipients and 1 (4%) of the 28 vaccinees had moderate or severe diarrhea (>/=3-liter diarrheal stool) (P < 0.01; protective efficacy, 91%). A total of 21 (91%) of 23 placebo recipients and 5 (18%) of 28 vaccinees had any diarrhea (P < 0.001; protective efficacy, 80%). Peak stool V. cholerae excretion among placebo recipients was 1.1 x 10(7) CFU/g and among vaccinees was 4.9 x 10(2) CFU/g (P < 0.001). This vaccine could therefore be a safe and effective tool to prevent cholera in travelers.


Update on cobalamin, folate, and homocysteine.
Three topics affecting cobalamin, folate, and homocysteine that have generated interest, activity, and advances in recent years are discussed. These are: (I). the application of an expanded variety of tools to the diagnosis of cobalamin deficiency, and how these affect and are affected by our current understanding of deficiency; (II). the nature of the interaction between homocysteine and vascular disease, and how the relationship is affected by vitamins; and (III). the improved understanding of relevant genetic disorders and common genetic polymorphisms, and how these interact with environmental influences. The diagnostic approach to cobalamin deficiency now allows better diagnosis of difficult and atypical cases and more confident rejection of the diagnosis when deficiency does not exist. However, the process has also become a complex and sometimes vexing undertaking. Part of the difficulty derives from the lack of a diagnostic gold standard among the many available tests, part from the overwhelming numerical preponderance of patients with subclinical deficiency (in which isolated biochemical findings exist without clinical signs or symptoms) among the cobalamin deficiency states, and part from the decreased availability of reliable tests to identify the causes of a patient's cobalamin deficiency and thus a growing deemphasis of that important part of the diagnostic process. In Section I, Dr. Carmel discusses the tests, the diagnostic issues, and possible approaches to the clinical evaluation. It is suggested no single algorithm fits all cases, some of which require more biochemical proof than others, and that differentiating between subclinical and clinical deficiency, despite their overlap, may be a helpful and practical point of departure in the evaluation of patients encountered in clinical practice. The arguments for and against a suggested expansion of the cobalamin reference range are also weighed. The epidemiologic data suggest that homocysteine elevation is a risk factor for vascular and thrombotic disease. In Section II, Dr. Green notes that the interactions of metabolism and clinical risk are not well understood and a causative relationship remains unproven despite new reports that lowering homocysteine levels may reduce vascular complications. Genetic and acquired influences may interact in important ways that are still being sorted out. The use of vitamins, especially folate, often reduces homocysteine levels but also carries potential disadvantages and even risks. Folate fortification of the diet and supplement use have also markedly reduced the frequency of folate deficiency, and cobalamin deficiency is now the more common deficiency state, especially among the elderly. Although genetic disorders are rare, they illuminate important metabolic mechanisms and pose diagnostic challenges, especially when clinical presentation occurs later in life. In Section III, Drs. Rosenblatt and Watkins use selected disorders to illustrate the subject. Imerslund-Gräsbeck syndrome, a hereditary disorder of cobalamin absorption at the ileal level, demonstrates genetic heterogeneity. Finnish patients show mutation of the gene for cubilin, the multiligand receptor for intrinsic factor. Surprisingly, Norwegian and other patients have been found recently to have mutations of the AMN (amnionless) gene, mutations that are lethal in mice at the embryonic stage. Two disorders of cobalamin metabolism, cblG and cblE, are now known to arise from mutations of the methionine synthase and methionine synthase reductase genes, respectively. These disorders feature megaloblastic anemia and neurologic manifestations. The folate disorder selected for illustration, methylenetetrahydrofolate reductase (MTHFR) deficiency, paradoxically causes neurological problems but no megaloblastic anemia. This rare deficiency is the most common inborn error of folate metabolism. It is distinct from the very common MTHFR gene polymorphisms, mutations that cause mild to moderate reductions in MTHFR activity but no direct clinical manifestations. The MTHFR polymTHFR polymorphisms, especially the 677C-->T mutation, may contribute to vascular and birth defect risks, while reducing the risk of certain malignancies, such as colon cancer. These polymorphisms and those of genes for other enzymes and proteins related to cobalamin, folate, and homocysteine metabolism may be important role players in frequent interactions between genes and the environment.


[Heterogeneity of the morpho-functional organization of bushy interoceptors as one of the factors of their resistance].
Bush interoceptors reveal their obvious heterogeneity of morphofunctional organization through non-standard responses of their units and elements to adequate and extreme irritants, the responses involving different degree of receptor resistance upon change of ionic power and in anoxia, and non-standard spikes of biopotentials. The morpho-functional heterogeneity of bush receptors seems to enlarge considerably the scope of adequate responses of reflexogenic areas to stimuli, thus raising the functional resistance of sensory system in unfavourable conditions.


Bayesian decision-making under stress-preserved weighting of prior and likelihood information.
A rich body of empirical work has addressed the question of how stress changes the way we memorize, learn, and make high-level decisions in complex scenarios. There is evidence that stress also changes the way we perceive the world, indicating influences on decision-making at lower levels. Surprisingly, as of yet, little research has been conducted in this domain. A few studies suggest that under stress, humans tend to eschew existing knowledge, and instead focus on novel input or information from bottom-up. Decision-making in the perceptual domain has been modeled with Bayesian frameworks. Here, existing knowledge about structures and statistics of our environment is referred to as prior, whereas sensory data are termed likelihood. In this study, we directly assessed whether stress, as induced by the socially evaluated cold pressure task (SECPT), would modulate low-level decisions, specifically the weight given to sensory information, and how people reacted to changes in prior and sensory uncertainty. We found that while the stress-inducing procedure successfully elicited subjective stress ratings as well as stress relevant physiological paramters, it did not change participants' average reliance on sensory information. Furthermore, it did not affect participants' sensitivity to changes in prior and sensory uncertainty, with both groups able to detect it and modulate their behavior accordingly, in a way predicted by Bayesian statistics. Our results suggest that, contrary to our predictions, stress may not directly affect lower-level sensory-motor decisions. We discuss the findings in context of time scales of the stress reaction, linked to different neural and functional consequences.


Cell-mediated immunity in Herpesvirus hominis infections.
The cell-mediated and antibody responses to Herpesvirus hominis type 1 were investigated in patients with primary and recurrent herpetic infections. Stimulation of lymphocyte transformation with the virus and the complement fixing antibody titre did not differ significantly between patients and controls. However, macrophage migration inhibition and lymphocyte cytotoxicity were impaired in patients. The defects were specific to H. hominis, as Candida oblicans, which was used as an unrelated antigen, failed to show a similar abnormality. These results and preliminary sequential studies suggest that the susceptibility to recurrent herpesvirus infection may be due to an impaired production of macrophage migration inhibition factor and lymphocyte cytotoxicity in the presence of intact lymphocyte sensitization and antibody formation.


[Responses of soybean cultivar Dongsheng-1 to different O3 concentrations in northeast China].
Soybean cultivar Dongsheng No. 1 [Glycine max (L.) Mer.] was exposed to charcoal-filtered air (CFA), non-filtered air (NFA) and non-filtered air with ozone addition (NFA + O3) in nine open-top chambers. Individual yield and yield components at maturity, C, N concentration in leaf and seed, gas exchange, chlorophyll a fluorescence and pigments content at the full bloom stage were measured with an AOT40 value of 10.6 microL x L(-1) x h during the growing season. Compared to CFA, NFA reduced individual yield and 100-seed weight by 4.5% and 4% respectivley, while NFA + O3 treatment significantly reduced each of them by 34% and 18%. However, plant height, node numbers of main stem, pods per plant and number of seeds per pod remained unchanged by O3 addition. Leaf C, N concentrations at the seed filling stage under NFA + O3 also significantly increased by 3% and 26%, respectively, while the CN ratio significantly decreased by 18%. Moreover, compared to CFA and NFA, NFA + O3 caused significant reductions in the photosynthetic parameters at the full bloom stage, e.g. significant declines in net photosynthetic rates, stomatal conductance, water use efficiency, fluorescence parameters of F'(v)/F'(m) and phi(PS II). It is proposed that lower photosynthetic rates, reduced photochemical efficiency in PS II and the decline in 100-seed weight might be the main reasons contributing to the lower individual yield of soybean plant by elevated O3.


Assessment of Inter-Laboratory Variation in the Characterization and Analysis of the Mucosal Microbiota in Crohn's Disease and Ulcerative Colitis.
In studies evaluating the microbiome, numerous factors can contribute to technical variability. These factors include DNA extraction methodology, sequencing protocols, and data analysis strategies. We sought to evaluate the impact these factors have on the results obtained when the sequence data are independently generated and analyzed by different laboratories. To evaluate the effect of technical variability, we used human intestinal biopsy samples resected from individuals diagnosed with an inflammatory bowel disease (IBD), including Crohn's disease (n = 12) and ulcerative colitis (n = 10), and those without IBD (n = 10). Matched samples from each participant were sent to three laboratories and studied using independent protocols for DNA extraction, library preparation, targeted-amplicon sequencing of a 16S rRNA gene hypervariable region, and processing of sequence data. We looked at two measures of interest - Bray-Curtis PERMANOVA R 2 values and log2 fold-change estimates of the 25 most-abundant taxa - to assess variation in the results produced by each laboratory, as well the relative contribution to variation from the different extraction, sequencing, and analysis steps used to generate these measures. The R 2 values and estimated differential abundance associated with diagnosis were consistent across datasets that used different DNA extraction and sequencing protocols, and within datasets that pooled samples from multiple protocols; however, variability in bioinformatic processing of sequence data led to changes in R 2 values and inconsistencies in taxonomic assignment and abundance estimates. Although the contribution of DNA extraction and sequencing methods to variability were observable, we find that results can be robust to the various extraction and sequencing approaches used in our study. Differences in data processing methods have a larger impact on results, making comparison among studies less reliable and the combined analysis of bioinformatically processed samples nearly impossible. Our results highlight the importance of making raw sequence data available to facilitate combined and comparative analyses of published studies using common data processing protocols. Study methodologies should provide detailed data processing methods for validation, interpretability, reproducibility, and comparability.


KAI1 is unchanged in metastatic and nonmetastatic esophageal and gastric cancers.
Down-regulation of KAI1 mRNA expression has been shown to be associated with the formation of metastases or disease progression in pancreatic cancer. Whether KAI1 possesses similar characteristics in other malignancies of the gastrointestinal tract is not known. Here, we compared the patterns of KAI1 mRNA expression in 41 esophageal cancers and 35 stomach cancers to assess whether KAI1 might also be of biological relevance in the metastatic ability of these tumors. By Northern blot analysis, KAI1 mRNA levels ranged widely in both normal and cancerous esophageal and gastric tissue samples, with no statistical differences. No association between KAI1 mRNA expression and tumor stage or tumor differentiation was seen in these tumors. In addition, KAI1 mRNA expression was similar in primary esophageal and gastric cancer samples with or without metastases. By in situ hybridization, KAI1 mRNA expression was evident in the cytoplasm of most squamous epithelial cells in the normal esophagus and in nonmucosal epithelial cells of the normal stomach. The staining intensity in the esophageal and gastric cancer cells was similar to that in the normal controls. This differential pattern of KAI1 mRNA expression in esophageal and gastric cancers in comparison to pancreatic cancer indicates that KAI1 seems to influence the potential of gastrointestinal cancer cells to metastasize differently. In esophageal and gastric cancers, the formation of metastases is not dependent on the reduction of KAI1 in the cancer cells.


Cognitive and linguistic abilities and perceptual restoration of missing speech: Evidence from online assessment.
When speech is clear, speech understanding is a relatively simple and automatic process. However, when the acoustic signal is degraded, top-down cognitive and linguistic abilities, such as working memory capacity, lexical knowledge (i.e., vocabulary), inhibitory control, and processing speed can often support speech understanding. This study examined whether listeners aged 22-63 (mean age 42 years) with better cognitive and linguistic abilities would be better able to perceptually restore missing speech information than those with poorer scores. Additionally, the role of context and everyday speech was investigated using high-context, low-context, and realistic speech corpi to explore these effects. Sixty-three adult participants with self-reported normal hearing completed a short cognitive and linguistic battery before listening to sentences interrupted by silent gaps or noise bursts. Results indicated that working memory was the most reliable predictor of perceptual restoration ability, followed by lexical knowledge, and inhibitory control and processing speed. Generally, silent gap conditions were related to and predicted by a broader range of cognitive abilities, whereas noise burst conditions were related to working memory capacity and inhibitory control. These findings suggest that higher-order cognitive and linguistic abilities facilitate the top-down restoration of missing speech information and contribute to individual variability in perceptual restoration.


Functional analysis of the Mycobacterium tuberculosis MprAB two-component signal transduction system.
The mechanisms utilized by Mycobacterium tuberculosis to establish, maintain, or reactivate from latent infection in the host are largely unknown but likely include genes that mediate adaptation to conditions encountered during persistence. Previously, a two-component signal transduction system, mprAB, was found to be required in M. tuberculosis for establishment and maintenance of persistent infection in a tissue- and stage-specific fashion. To begin to characterize the role of this system in M. tuberculosis physiology and virulence, a functional analysis of the mprA and mprB gene products was initiated. Here, evidence is presented demonstrating that sensor kinase MprB and response regulator MprA function as an intact signal-transducing pair in vitro and in vivo. Sensor kinase MprB can be autophosphorylated, can donate phosphate to MprA, and can act as a phospho-MprA phosphatase in vitro. Correspondingly, response regulator MprA can accept phosphate from MprB or from small phosphodonors including acetyl phosphate. Mutagenesis of residues His249 in MprB and Asp48 in MprA abolished the ability of these proteins to be phosphorylated in vitro. Introduction of these alleles into Mycobacterium bovis BCG attenuated virulence in macrophages in vivo. Together, these results support a role for the mprAB two-component system in M. tuberculosis physiology and pathogenesis. Characterization of two-component signal transduction systems will enhance our understanding of processes regulated by M. tuberculosis during acute and/or persistent infection in the host.


Long-term and short-term survivors after pancreatectomy for pancreatic cancer.
Out of 63 Japanese patients with pancreatic carcinoma who underwent surgical resection, 8 short-term survivors who died within 3 months after resection and 6 long-term survivors who were alive for more than 3 years after resection were compared regarding 26 clinicopathological parameters. The 8 short-term survivors were significantly older than the 6 long-term survivors (63.7 versus 47.8 years, P = 0.0099). The mean peripheral lymphocyte count was significantly smaller in the short-term survivors than in the long-term survivors (1,212 versus 2,115 /microl, P = 0.0459). Operative blood loss was significantly larger in the short-term survivors than in the long-term survivors (2,393 versus 1,043 g, P = 0.0157). The surgical margin was affected by malignant cells in 7 of the 8 short-term survivors, but in only 2 of the 6 long-term survivors (P = 0.0362). Of the 8 short-term survivors, 5 were in comprehensive stage IV and 3 in stage III, while 3 of the 6 long-term survivors were in stage III, two in stage II, and one in stage I (P = 0.0487). All the 8 short-term survivors were of the comprehensive curability C, while 3 of the 6 long-term survivors were of A, one B and the other two C (P = 0.0239). Multiple regression analysis of these 6 profound factors showed that the peripheral lymphocyte count was an independent significant parameter to differentiate the short-term and long-term survivors. These findings suggest that, although the aggressive nature of pancreatic cancer has been accepted, the clinical course after pancreatectomy would also depend upon the immunological state of the patient.


Blood Viral Load in Symptomatic Congenital Cytomegalovirus Infection.
Viral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear. Post hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy. Higher baseline VL was associated with central nervous system involvement (3.82 log, range 1-5.65 vs 3.32 log, range 1-5.36; P = .001), thrombocytopenia (3.68 log, range 1-5.65 vs 3.43 log, range 1-5.36; P = .03), and transaminitis at presentation (3.73 log, range 1-5.60 vs 3.39 log, range 1-5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing. In infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes.


Has COVID-19 changed the workload for primary care physicians? The case of Spain.
The COVID-19 pandemic has led to a massive over-exertion of doctors, multiplying their work intensity, overload and stress. Yet no studies have been conducted on the changes in primary care physician overload during the pandemic. To address this research gap, the aim of this article is to document the subjective dimensions of physicians' work during the peak of the pandemic for comparison with a pre-COVID-19 situation. In addition, the relationship between workload and the individual characteristics of the physician or the percentage of tele-assistance is examined. This study performs a subjective measurement procedure for the analysis of work overload through the NASA-TLX questionnaire, with a total of 102 records from 16 doctors from a Primary Health Centers of the Granada-Metropolitan Health district (Andalusia, Spain). The results reflect a significantly higher workload during COVID-19 in relation to a previous situation (66.1% versus 48.6% before COVID-19). All the dimensions of the NASA-TLX test suffered an increase during the COVID-19, this increase being higher in the physical, temporal and frustration levels. Interestingly, the findings reflect the higher the percentage of telematic consultations, the lower workload. Work overload and the emotional state of health workers is one of the many repercussions of the COVID-19 pandemic. The results derived from this study may be useful in formulating policies and practices related to the workforce development, funding streams to prepare for the next wave of COVID-19 infections as well as for future public health emergencies.


The immunobiology of low-dose total-body irradiation: more questions than answers.
Low-dose total-body irradiation (TBI) is used in the treatment of chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma. The usual practice is to give very low individual fractions (0.1 to 0.25 Gy) several times a week, to a total dose of 1.5 to 2 Gy. Despite this low dose, low-dose TBI can induce long-term remissions in the majority of patients. Immune enhancement, rather than direct radiation cell killing, is one of the suggested mechanisms by which low-dose TBI can exert its effect. Data from animal experiments have shown that low-dose TBI could enhance the immune response through (1) augmenting the proliferative reactive response of the T cells to mitogenic stimulation; (2) altering cytokine release, particularly the activation of interferon gamma and Il2 production; (3) increasing the expression of Il2 receptors on the T-cell surface; (4) facilitating signal transduction in T lymphocytes; (5) increasing splenic catecholamine content and lowering the serum corticosterone level; and (6) eliminating a particularly radiosensitive subset of the suppressor T cells. Data for humans, though scarce, suggest that at least some of these mechanisms occur in patients treated with low-dose TBI. Whether these immunomodulatory effects are responsible for the clinical outcome is not yet clear. Much is still unknown about the immunobiology of low-dose TBI, its clinical potential, and the possible synergism with chemotherapy, biological response modifiers, or immunotherapy. This lack of comprehensive knowledge hampers the optimal and widespread use of this intriguing and potentially useful treatment modality in clinical practice.


Licochalcone A Prevents the Loss of Dopaminergic Neurons by Inhibiting Microglial Activation in Lipopolysaccharide (LPS)-Induced Parkinson's Disease Models.
The neuroprotective effects of Licochalcone A (Lico.A), a flavonoid isolated from the herb licorice, in Parkinson's disease (PD) have not been elucidated. The prominent pathological feature of PD is the loss of dopaminergic neurons. The crucial role of neuroinflammation induced by activated microglia in dopaminergic neurodegeneration has been validated. In this study, we explore the therapeutic effects of Lico.A in lipopolysaccharide (LPS)-induced PD models in vivo and in vitro. We find that Lico.A significantly inhibits LPS-stimulated production of pro-inflammatory mediators and microglial activation by blocking the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and nuclear factor κB (NF-κB) p65 in BV-2 cells. In addition, through cultured primary mesencephalic neuron-glia cell experiments, we illustrate that Lico.A attenuates the decrease in [³H] dopamine (DA) uptake and the loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in LPS-induced PD models in vitro. Furthermore, LPS intoxication in rats results in microglial activation, dopaminergic neurodegeneration and significant behavioral deficits in vivo. Lico.A treatment prevents microglial activation and reduction of dopaminergic neuron and ameliorates PD-like behavioral impairments. Thus, these results demonstrate for the first time that the neuroprotective effects of Lico.A are associated with microglia and anti-inflammatory effects in PD models.


[Clinical manifestations and treatment of sweat gland carcinoma--analysis of 22 cases].
Twenty-two patients with sweat gland carcinoma treated during the past 8 years are reported. They constitute 4.4% of malignant lesions of the skin during the same period. Of these 22 patients, 2 were apocrine gland carcinoma, 15 eccrine carcinoma, 4 hidradenocarcinoma and 1 cylindroma. In 11 patients with distant metastasis, 90.9% had lymphatic metastasis and 36.3% had blood metastasis. Vascular disseminations were mainly to the bone, lung and skin in order of incidence. Sweat gland carcinoma is rare and of low malignancy with evident tendency of recurrence. Prognosis was mainly related to the presence of distant metastasis. It is believed that the enlarged local resection should be given to patients without metastasis. On the other hand, local resection plus regional dissection should be performed on patients with metastasis. Post-operative irradiation may be helpful to prevent distant metastasis.


Expression of TIGAR and its correlation with clinicopathology, prognosis, and 18F-FDG PET/CT parameters in patients with resectable pancreatic ductal adenocarcinoma.
The aim of this study was to investigate the expression of TP53-inducible glycolysis and apoptosis regulator (TIGAR) and its relationship with clinical pathology and prognosis; and to analyze the correlation between TIGAR expression and 18F-labeled fluoro-2-deoxyglucose (18F-FDG) PET/computed tomography (CT) parameters in patients with pancreatic ductal adenocarcinoma (PDAC). We retrospectively analyzed the data of 23 patients who underwent preoperative 18F-FDG PET/CT examinations and were confirmed to have PDAC by postoperative pathology. TIGAR was detected using immunohistochemistry. The relationships between TIGAR expression and clinicopathology and its value in predicting the prognosis of patients with PDAC were analyzed. The correlations between TIGAR expression and 18F-FDG PET/CT parameters [standard uptake value (SUV) max, SUVmean, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)] were analyzed. The expression of TIGAR was low in 34.8% of patients and high in 65.2% of patients. There was no correlation between TIGAR expression and clinicopathology. The overall survival of patients with high TIGAR expression was significantly shorter than that of patients with low TIGAR expression (11.2 vs. 35.4 months). The 18F-FDG PET/CT parameters: SUVmax, SUVmean, SUVpeak, MTV, and TLG were positively correlated with TIGAR expression, but only the MTV correlation with TIGAR expression was statistically significant. TIGAR is highly expressed in PDAC. Its expression is independent of clinicopathological data and can be used as an independent prognostic factor. TIGAR expression was significantly positively correlated with the 18F-FDG PET/CT parameter MTV.


Emergency mental health: lessons learned from flight 3407.
Emergency mental health (EMH), a field that is often not well represented when considering emergency preparedness, is nonetheless a vital component to any disaster response. Emergency mental health issues must be considered not only for victims of disasters and their families, friends, and coworkers but also for both on-scene and off-scene responders and members of the community who may have witnessed the disaster. This article describes the EMH preparation for and response to the crash of Continental Airlines flight 3407 in western New York on February 12, 2009, killing all 49 crew and passengers on board and 1 person on the ground. It describes aspects of the response that went as planned and highlights areas for improvement. The lessons learned from this EMH preparation and response can be used to inform future planning for disaster response.


Interleukin-10 and prostaglandin E2 have complementary but distinct suppressive effects on Toll-like receptor-mediated dendritic cell activation in ovarian carcinoma.
Dendritic cells (DC) have the potential to instigate a tumour-specific immune response, but their ability to prime naïve lymphocytes depends on their activation status. Thus, for tumour immunotherapy to be effective, the provision of appropriate DC activation stimuli such as Toll-like receptor (TLR) agonists is crucial in order to overcome immunosuppression associated with the tumour microenvironment. To address this, we investigated how ovarian carcinoma (OC)-associated ascites impedes activation of DC by TLR agonists. Our results show that ascites reduces the TLR-mediated up-regulation of CD86 and partially inhibits the production of the pro-inflammatory cytokines interleukin 6 (IL-6), IL-12 and tumour necrosis factor α (TNFα) in monocyte-derived DC from healthy controls. We further observe an impaired T cell stimulatory capacity of DC upon activation with TLR agonists in the presence of ascites, indicating that their functionality is affected by the immunosuppressive factors. We identify IL-10 and prostaglandin E2 (PGE2) as the pivotal immunosuppressive components in OC-associated ascites compromising TLR-mediated DC activation. Interestingly, IL-10 is present in both ascites from patients with malignant OC and in peritoneal fluid from patients with benign ovarian conditions and both fluids have similar ability to reduce TLR-mediated DC activation. However, depletion of IL-10 from ascites revealed that the presence of paracrine IL-10 is not crucial for ascites-mediated suppression of DC activation in response to TLR activation. Unlike IL-10, PGE2 is absent from peritoneal fluid of patients with benign conditions and selectively reduces TNFα induction in response to TLR-mediated activation in the presence of OC-associated ascites. Our study highlights PGE2 as an immunosuppressive component of the malignant OC microenvironment rendering PGE2 a potentially important target for immunotherapy in OC.


Noninvasive measurement of cardiac output: two methods compared in patients with mitral regurgitation.
In search for the origin of the less reliable cardiac output (CO) estimations by means of electrical impedance cardiography (EIC), the authors hypothesized that cardiac valve pathology might be one of the reasons. Twenty-six patients were examined by means of echo Doppler (ED) and EIC. The cardiac valve status was obtained by means of echocardiography and color Doppler flow, while CO was obtained by means of both methods. Seventeen patients had no valve pathology (nVP) while nine patients had mild to moderate mitral regurgitation (MVR). The overall correlation between the calculation of CO by means of the two methods was good (r = 0.85, p < 0.001, mean difference and standard deviation: 0.20+/-0.74 L/min), while there was no significant difference between the paired values. After division into an nVP and an MVR population, the results showed an even closer agreement between the CO values in the nVP population (r = 0.88, p < 0.001, mean difference and standard deviation: 0.15+/-0.68 L/min). Furthermore, significant differences were found in the first derivative of the impedance (dZ/dt) signals of these groups. Although the agreement between ED and EIC was slightly lower in the MVR population, EIC reliably estimated CO, even in case of MVR. The impedance signal itself gave an indication for the existence of MVR.


Annealing vs. invasion in phage lambda recombination.
Genetic recombination catalyzed by lambda's Red pathway was studied in rec+ and recA mutant bacteria by examining both intracellular lambda DNA and mature progeny particles. Recombination of nonreplicating phage chromosomes was induced by double-strand breaks delivered at unique sites in vivo. In rec+ cells, cutting only one chromosome gave nearly maximal stimulation of recombination; the recombinants formed contained relatively short hybrid regions, suggesting strand invasion. In contrast, in recA mutant cells, cutting the two parental chromosomes at non-allelic sites was required for maximal stimulation; the recombinants formed tended to be hybrid over the entire region between the two cuts, implying strand annealing. We conclude that, in the absence of RecA and the presence of non-allelic DNA ends, the Red pathway of lambda catalyzes recombination primarily by annealing.


[Epithelial tumors of the thymus gland].
A classification of thymomas is proposed based on rich authors' material. The classification allows one to reveal correlations between the malignancy grade, clinical manifestations and postoperative prognosis.


Transforming growth factor (TGF)-β levels and unprovoked recurrent venous thromboembolism.
Prediction of recurrence in patients with unprovoked venous thromboembolism (VTE) remains a challenge. Studies of atherosclerosis suggest a protective role of transforming growth factor (TGF)-β. However, the role of TGF-β has not been studied in VTE. The aim of this study was to investigate TGF-β as a predictive marker of recurrent VTE in patients with a first episode of unprovoked VTE. Patients in the Malmö Thrombophilia Study (MATS) were followed after the discontinuation of anticoagulant treatment until the diagnosis of recurrent VTE or the end of the study in December 2008 (mean ± SD 38.5 months ± 27). Among patients with a first episode of unprovoked VTE, we identified 42 patients with recurrent VTE during the follow-up period. Two age- and sex-matched control subjects without recurrent VTE were selected for each patient (n = 84). Plasma levels of the three isoforms of TGF-β (TGF-β1, TGF-β2 and TGF-β3) were quantified simultaneously by TGF-β 3-plex immunoassay. Compared to controls, plasma levels of TGF-β1 and TGF-β2 were significantly lower in patients with recurrent VTE (p < 0.05), whereas no difference was found for TGF-β3. In a multivariate Cox regression analyses, adjusted for inherited thrombophilia, age, sex and BMI, low levels of TGF-β1 [hazard ratio (HR) = 2.2, 95% confidence interval (CI) 1.1-4.3; p = 0.02] and TGF-β2 (HR = 2.4, 95% CI 1.2-4.7; p = 0.01) were independently associated with a higher risk of recurrent VTE. We propose TGF-β1 and TGF-β2 as potential predictive markers for recurrence in patients with unprovoked VTE.


Topology of diffusion changes in corpus callosum in Alzheimer's disease: An exploratory case-control study.
This study aims to assess the integrity of white matter in various segments of the corpus callosum in Alzheimer's disease (AD) by using metrics derived from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI) and white matter tract integrity model (WMTI) and compare these findings to healthy controls (HC). The study was approved by the institutional ethics board. 12 AD patients and 12 HC formed the study population. All AD patients were recruited from a tertiary neurology memory clinic. A standardized battery of neuropsychological assessments was administered to the study participants by a trained rater. MRI scans were performed with a Philips Ingenia 3.0T scanner equipped with a 32-channel head coil. The protocol included a T1-weighted sequence, FLAIR and a dMRI acquisition. The dMRI scan included a total of 71 volumes, 8 at b = 0 s/mm2, 15 at b = 1,000 s/mm2 and 48 at b = 2,000 s/mm2. Diffusion data fit was performed using DKI REKINDLE and WMTI models. We detected changes suggesting demyelination and axonal degeneration throughout the corpus callosum of patients with AD, most prominent in the mid-anterior and mid-posterior segments of CC. Axial kurtosis was the most significantly altered metric, being reduced in AD patients in almost all segments of corpus callosum. Reduced axial kurtosis in the CC segments correlated with poor cognition scores in AD patients in the visuospatial, language and attention domains.


Efficacy of short course antibiotic prophylaxis in controlling cholera in contacts during epidemic.
During an epidemic of cholera, vaccination has limited applicability in controlling its spread. It has been seen that one out of every five to 10 V. cholerae-infected people develops diarrhoea severe enough to require hospital treatment. Most health authorities are concerned with this severely ill group in whom the majority of deaths occur. During the cholera epidemic of 1975 in Dacca two doses of tetracycline were administered to all family contacts of index cases. The control group of cholera cases did not receive the drug. The families were re-visited after 10-12 days and history of any diarrhoea and hospitalization was obtained. It was found that the subsequent diarrhoea or cholera cases occurring among the cholera contacts within 10-12 days were not different between the treated (13.5%) and the untreated (14.4%) groups. The occurrence of severe cases requiring hospitalization was, however, significantly reduced in the treated group (8.0% to 4.5%). In view of the emergence of V. cholera strains resistant to tetracycline, antibiotic sensitivity testing of epidemic strains would be needed before use of tetracycline for protecting cholera contacts as an immediate control measure.


Using Orem's theory in transcultural settings: a critique.
An overview of the theory describes its component parts and concepts as well as the premises and assumptions upon which the theory is based. The authors explore the compatibility and usefulness of Orem's theory with non-Western or minority Western non-Anglo values and belief systems. A literature review of studies and experiences using Orem's theory in a variety of cultures is presented and discussed. The authors conclude that Orem's theory must be supplemented or replaced by one less culturebound for use with cultures differing from the dominant Western culture.


Utilisation of blood products at a centre in Pakistan. Is donating better than wasting?
The study was designed to investigate the quantity and reasons of wastage of blood products. This was an observational study conducted from February 2018 to February 2019 at the National Institute of Blood Disease and Bone Marrow Transplantation (NIBD and BMT), PECHS campus. The study was approved by the institutional review board. Wastage and reasons of wastage for all the blood products were evaluated. Frequencies were calculated by using SPSS version 23.0. A total of 2,880 bags of blood products were available, including 960 each of platelets, packed red cells and fresh frozen plasma. The overall wastage rate was 3.5%. Packed red cells and platelets were fully consumed, yet shortage of supply was observed. However, highest wastage was observed in fresh frozen plasma i.e. 102 bags. Expiry of unused products 60 (59%) followed by broken bags 30 (29%) were two common modes of wastage. Wastage of blood products is a genuine issue in a hospital setup, strategies and plan of action should be discussed and implemented to ensure that they are available when and where they are needed most.


Exploring the use of resources to support gender equality in Australian workplaces.
Numerous resources exist to support workplaces to undertake gender equality work; however, it is often unclear which existing resources are being utilised by Australian workplaces. One group that can provide insight into the use of existing resources is the professionals who have undertaken gender equality work in their organisation. Purposive sampling was used to identify informants with experience undertaking gender equality work. A sample of 12 informants was recruited from five employment sectors: five informants from the women('s health sector; two from other organisations in the health sector; three from local government; and one each from manufacturing and education. One in-depth semi-structured interview was conducted with each informant. Interview transcripts were analysed using thematic analysis. Four themes emerged from data analysis: "Organisational Context," "Legitimising Gender Equality Work," "Demystifying Gender Equality" and "Embedding Gender Equality into the Workplace." Mechanisms such as drawing on the evidence base, developing internal communications strategies, establishing a working group, undertaking training, conducting an audit, and reviewing policies and procedures were used to embed gender-based considerations into the workplace. A range of resources to underpin most of these approaches was discussed by informants. Informants had a sound understanding of approaches they could use to address existing gender inequality; however, they did not always utilise existing resources to support them to undertake their chosen approach. SO WHAT?: A clearer online database needs to be established to allow workplaces to access a compilation of existing resources and any evaluation on their use.


Ryanodine receptor-operated activation of TRP-like channels can trigger critical Ca2+ signaling events in pancreatic beta-cells.
There is little information available concerning the link between the ryanodine (RY) receptors and the downstream Ca(2+) signaling events in beta-cells. In fura-2 loaded INS-1E cells, activation of RY receptors by 9-methyl 5,7-dibromoeudistomin D (MBED) caused a rapid rise of [Ca(2+)]i followed by a plateau and repetitive [Ca(2+)]i spikes on the plateau. The [Ca(2+)]i plateau was abolished by omission of extracellular Ca(2+) and by SKF 96365. In the presence of SKF 96365, MBED produced a transient increase of [Ca(2+)]i, which was abolished by thapsigargin. Activation of RY receptors caused Ca(2+) entry even when the ER Ca(2+) pool was depleted by thapsigargin. The [Ca(2+)]i plateau was not inhibited by nimodipine or ruthenium red, but was inhibited by membrane depolarization, La(3+), Gd(3+), niflumic acid, and 2-aminoethoxydiphenyl borate, agents that inhibit the transient receptor potential channels. The [Ca(2+)]i spikes were inhibited by nimodipine and ryanodine, indicating that they were due to Ca(2+) influx through the voltage-gated Ca(2+) channels and Ca(2+)-induced Ca(2+) release (CICR). Activation of RY receptors depolarized membrane potential as measured by patch clamp. Thus, activation of RY receptors leads to coherent changes in Ca(2+) signaling, which includes activation of TRP-like channels, membrane depolarization, activation of the voltage-gated Ca(2+) channels and CICR.


Topical urea in dermatology.
For years research has been conducted to find a cutaneous moisturizer that is effective, easily available and relatively inexpensive urea, as a atopical agent, is all of this and is also a mild keratolytic. A trial was conducted over 200 patients suffering from a variety of disorders that were selected and using urea topically as urea 10 (10%), urea-20 lotion (20%), Urea-HC (with hydrocartisanl). The agent was applied twice daily for a maximum period of 8 weeks. Results indicate that urea is an effective moisturizer and in promotes the penetration of hydrocelisone into the skin.


Unoccupied nuclear oestradiol-receptor sites in normal human endometrium.
The existence of unoccupied nuclear oestradiol-receptor sites in normal human endometrium was investigated. Nuclei were prepared from endometrial samples obtained by curettage and exposed to [3H]oestradiol, which became maximmaly bound at 0 degrees C within 1 h. This result contrasted with the binding kinetics of oestradiol--receptor complexes, since the exchange of hormone took at least 3 h at 30 degrees C and no displacement occurred at 0 degrees C. Before concluding that the nuclear sites were unoccupied, the presence of endogenous low-affinity ligands was excluded, because the association rate of oestradiol was unchanged after nuclei were stripped from their putative ligands, and the displacement of oestrone bound to nuclear receptor by oestradiol was very slow at 0 degrees C. The available sites had high affinity for oestradiol (KD 1.3 nM) and binding-specificity characteristics of oestradiol receptors. Similar results were observed with crude and purified nuclear preparations. It was concluded that a significant proportion of nuclear oestradiol receptors in normal human endometrium is unoccupied by endogenous hormones.


Disabling Central Paroxysmal Positioning Upbeat Nystagmus and Vertigo Associated With the Presence of Anti-Glutamic Acid Decarboxylase Antibodies.
An immune attack by anti-glutamic acid decarboxylase (GAD) antibodies is believed to cause a deficiency in gamma-aminobutyric acid-mediated neurotransmission in the cerebellum. This, in turn, leads to several eye movement disorders, including spontaneous downbeat (DBN) and periodic alternating nystagmus. We describe a 68-year-old diabetic woman with disabling paroxysmal positioning upbeat nystagmus (UBN) exclusively in the supine position, associated with asymptomatic spontaneous DBN, alternating skew deviation and hyperactive vestibulo-ocular reflex responses on head impulse testing, in whom high titers of anti-GAD antibodies were detected. After treatment with intravenous immunoglobulin, a complete resolution of positioning UBN and spontaneous DBN occurred, along with a decrease in anti-GAD antibody titers. Positioning UBN in this case may reflect a transient disinhibition of the central vestibular pathways carrying posterior semicircular canal signals, due to lack of normal inhibitory input from the cerebellar nodulus/uvula. Immunoglobulin restored cerebellar inhibitory output, possibly by improving gamma-aminobutyric acid neurotransmission.


The impact of osteoporosis medication beliefs and side-effect experiences on non-adherence to oral bisphosphonates.
Non-adherence to oral bisphosphonate medications is a pervasive problem that blunts their potential to prevent fractures. Using multivariate modeling, we assessed the unique contribution of six classes of variables as drivers of non-adherence to bisphosphonates: (1) beliefs about osteoporosis and its prescription drug treatment, (2) ratings of the affordability of the prescription osteoporosis medications, (3) evaluations of the convenience of the bisphosphonate dosing frequency, (4) reports of troublesome side effects, (5) ratings of aspects of the bisphosphonate dosing regimen, and (6) risk factors for fracture. These categories of predictor variables were selected for investigation because they have been suggested by clinical-trial, survey, and observational studies in osteoporosis as reasons for non-adherence among patients taking prescription osteoporosis therapy. Women aged 45 or older who filled a prescription for an oral bisphosphonate in January or February of 2006 were identified through a dispensing database of 3300 US retail pharmacies. Subjects received a mailed pre-notification letter from the retail pharmacy chain informing them that someone would be calling them to invite them to participate in a telephone survey about osteoporosis medications. Trained interviewers used a standardized telephone script to recruit patients. Our definition of adherence was provisionally based on database records across a 7-month period and then cross-validated using patient self-report during the telephone recruitment. We measured beliefs regarding bisphosphonate effectiveness and safety, osteoporosis health concerns, concerns regarding drug costs, dosing frequency convenience, and experienced side effects using multi-item scales. Data were collected by telephone interview. Bivariate analyses were conducted using chi(2) and t-tests, and multivariate analyses were conducted using logistic regression. Of the 3274 women contacted for study participation, 1092 (33%) completed the interview and 1015 had analyzable data. Multivariate analyses showed that those most symptomatic in terms of side effects and those with the most skeptical beliefs in drug effectiveness and drug safety had odds ratios for non-adherence of 6.78 (95% CI 4.67-9.86), 5.70 (95% CI 3.65-8.92), and 2.26 (95% CI 1.49-3.42), respect ively. In multivariate models, osteoporosis health concerns, dosing frequency convenience, and concerns regarding medication costs were not statistically associated with non-adherence to bisphosphonate therapy. The experience of troublesome side effects and patient beliefs regarding the effectiveness and safety of oral bisphosphonate medications prescribed for them are strongly associated with bisphosphonate non-adherence. Improving adherence to oral bisphosphonates may require providers to solicit and address patients' medication beliefs and to proactively address side effects. Limitations of our study include: (1) the study sample is not likely to be a national random sample of bisphosphonate users, and (2) some evidence of non-response bias was observed.


Explainable artificial intelligence for precision medicine in acute myeloid leukemia.
Artificial intelligence (AI) can unveil novel personalized treatments based on drug screening and whole-exome sequencing experiments (WES). However, the concept of "black box" in AI limits the potential of this approach to be translated into the clinical practice. In contrast, explainable AI (XAI) focuses on making AI results understandable to humans. Here, we present a novel XAI method -called multi-dimensional module optimization (MOM)- that associates drug screening with genetic events, while guaranteeing that predictions are interpretable and robust. We applied MOM to an acute myeloid leukemia (AML) cohort of 319 ex-vivo tumor samples with 122 screened drugs and WES. MOM returned a therapeutic strategy based on the FLT3, CBFβ-MYH11, and NRAS status, which predicted AML patient response to Quizartinib, Trametinib, Selumetinib, and Crizotinib. We successfully validated the results in three different large-scale screening experiments. We believe that XAI will help healthcare providers and drug regulators better understand AI medical decisions.


Cellular immunity to nucleocapsid and pre-S determinants in asymptomatic carriers of hepatitis B virus.
Previous studies of cellular immunity in asymptomatic HBV carriers have been limited to evaluation of responses to plasma-derived HBsAg preparations. We have explored the specificity of cellular immune responses to HBV antigens in these subjects using an indirect T-lymphocyte migration inhibitory factor assay and three antigen preparations (recombinant nucleocapsid antigen (HBcAg), plasma-derived HBsAg with or without pre-S2, and Saccharomyces cerevisiae-synthesized HBsAg without pre-S2 region). T cells from 10 asymptomatic chronic HBV carriers with normal liver function tests were responsive to nucleocapside determinants (mean migration index = 0.55 +/- SD 0.07) and to pre-S2-positive plasma-derived HBsAg (MI = 0.62 +/- 0.05). However, none responded to HBsAg devoid of pre-S2 sequences (MI = 0.98 +/- 0.04). In further experiments, T cells from three HBV carriers, cultured with six different HBsAg preparations, exhibited responsiveness only to those preparations containing significant pre-S2 activities. Our results show that T-cell immunity to nucleocapsid determinants of the virus and HBsAg in present in asymptomatic HBV carriers; the latter is restricted to antigenic preparations containing significant pre-S2 activities. Hence, T-cell immunity to pre-S determinants may not always be associated with HBV clearance.


Evidence of ultra low microwave additive phase noise for an optical RF link based on a class--a semiconductor laser.
The additive RF phase noise of a microwave photonics link is measured using, as the optical source, a semiconductor laser operating in the class-A regime. The relative intensity noise of this laser being below the shot noise relative level, the phase noise floor of the link is shown to be shot noise limited, -152 dBc/Hz in our experimental conditions. As a result, the phase noise floor evolves as the inverse of the detected photocurrent, pushing the limits of performance to the availability of high power photo-detectors. Below 6 kHz from the carrier frequency at 3GHz, some noise, in excess with respect to the shot noise limit, is observed but remains lower than -110 dBc/Hz at 100 Hz offset frequency. This residual noise originates mainly from environmental noise and can be reduced by isolating the laser from acoustic/electromagnetic perturbations.


The effect of fat pad modification during ablation of atrial fibrillation: late gadolinium enhancement MRI analysis.
Magnetic resonance imaging (MRI) can visualize locations of both the ablation scar on the left atrium (LA) after atrial fibrillation (AF) ablation and epicardial fat pads (FPs) containing ganglionated plexi (GP). We investigated 60 patients who underwent pulmonary vein antrum (PVA) isolation along with LA posterior wall and septal debulking for AF. FPs around the LA surface in well-known GP areas (which were considered as the substitution of GP areas around the LA) were segmented from the dark-blood MRI. Then the FP and the ablation scar image visualized by late gadolinium enhancement (LGE)-MRI on the LA were merged together. Overlapping areas of FP and the ablation scar image were considered as the ablated FP areas containing GP. Patients underwent 24-hour Holter monitoring after ablation for the analysis of heart rate variability. Ablated FP area was significantly wider in patients without AF recurrence than those in patients with recurrence (5.6 ± 3.1 cm(2) vs 4.2 ± 2.7 cm(2) , P = 0.03). The mean values of both percentage of differences greater than 50 ms in the RR intervals (pRR > 50) and standard deviation of RR intervals over the entire analyzed period (SDNN), which were obtained from 24-hour Holter monitoring 1-day post-AF ablation, were significantly lower in patients without recurrence than those in patients with recurrence (5.8 ± 6.0% vs 14.0 ± 10.1%; P = 0.0005, 78.7 ± 32.4 ms vs 109.2 ± 43.5 ms; P = 0.005). There was a significant negative correlation between SDNN and the percentage of ablated FP area (Y = -1.3168X + 118.96, R(2) = 0.1576, P = 0.003). Extensively ablating LA covering GP areas along with PVA isolation enhanced the denervation of autonomic nerve system and seemed to improve procedural outcome in patients with AF.


The Effectiveness of Mindfulness-Based Stress Reduction on Psychological Distress and Cognitive Functioning in Patients with Multiple Sclerosis: a Pilot Study.
Patients with multiple sclerosis (MS) often suffer from psychological distress and cognitive dysfunctioning. These factors negatively impact the health-related quality of life. Only recently behavioral therapeutic approaches are being used to treat psychological distress in MS. The aim of the present pilot study was not only to investigate the effectiveness of mindfulness-based stress reduction (MBSR) on psychological distress but also to explore whether it can improve cognitive functioning among patients with MS. Outpatients of the MS Center of the Radboud University Medical Center (Radboudumc) were invited to participate in an MBSR training. Psychological and cognitive measures were administered pre- and post-intervention. Twenty-five MS patients completed the MBSR training and psychological measures, of which 16 patients completed the cognitive tests. Significant improvements were found in depressive symptoms, quality of life, fatigue, mindfulness skills, and self-compassion. Of the cognitive tests, performance on a visual spatial processing test significantly improved after the intervention. Overall, this pilot study showed promising results of the effects of MBSR on reducing psychological distress, and it suggests MBSR might improve cognitive functioning in MS patients. Future randomized controlled trials should be conducted to confirm the possible effectiveness of MBSR-and its long-term effects-on psychological and cognitive functioning in MS patients.


High-throughput and label-free single nanoparticle sizing based on time-resolved on-chip microscopy.
Sizing individual nanoparticles and dispersions of nanoparticles provides invaluable information in applications such as nanomaterial synthesis, air and water quality monitoring, virology, and medical diagnostics. Several conventional nanoparticle sizing approaches exist; however, there remains a lack of high-throughput approaches that are suitable for low-resource and field settings, i.e., methods that are cost-effective, portable, and can measure widely varying particle sizes and concentrations. Here we fill this gap using an unconventional approach that combines holographic on-chip microscopy with vapor-condensed nanolens self-assembly inside a cost-effective hand-held device. By using this approach and capturing time-resolved in situ images of the particles, we optimize the nanolens formation process, resulting in significant signal enhancement for the label-free detection and sizing of individual deeply subwavelength particles (smaller than λ/10) over a 30 mm(2) sample field-of-view, with an accuracy of ±11 nm. These time-resolved measurements are significantly more reliable than a single measurement at a given time, which was previously used only for nanoparticle detection without sizing. We experimentally demonstrate the sizing of individual nanoparticles as well as viruses, monodisperse samples, and complex polydisperse mixtures, where the sample concentrations can span ∼5 orders-of-magnitude and particle sizes can range from 40 nm to millimeter-scale. We believe that this high-throughput and label-free nanoparticle sizing platform, together with its cost-effective and hand-held interface, will make highly advanced nanoscopic measurements readily accessible to researchers in developing countries and even to citizen-scientists, and might especially be valuable for environmental and biomedical applications as well as for higher education and training programs.


Radiosensitizing Pancreatic Cancer Xenografts by an Implantable Micro-Oxygen Generator.
Over the past decades, little progress has been made to improve the extremely low survival rates in pancreatic cancer patients. Extreme hypoxia observed in pancreatic tumors contributes to the aggressive and metastatic characteristics of this tumor and can reduce the effectiveness of conventional radiation therapy and chemotherapy. In an attempt to reduce hypoxia-induced obstacles to effective radiation treatment, we used a novel device, the implantable micro-oxygen generator (IMOG), for in situ tumor oxygenation. After subcutaneous implantation of human pancreatic xenograft tumors in athymic rats, the IMOG was wirelessly powered by ultrasonic waves, producing 30 μA of direct current (at 2.5 V), which was then utilized to electrolyze water and produce oxygen within the tumor. Significant oxygen production by the IMOG was observed and corroborated using the NeoFox oxygen sensor dynamically. To test the radiosensitization effect of the newly generated oxygen, the human pancreatic xenograft tumors were subcutaneously implanted in nude mice with either a functional or inactivated IMOG device. The tumors in the mice were then exposed to ultrasonic power for 10 min, followed by a single fraction of 5 Gy radiation, and tumor growth was monitored thereafter. The 5 Gy irradiated tumors containing the functional IMOG exhibited tumor growth inhibition equivalent to that of 7 Gy irradiated tumors that did not contain an IMOG. Our study confirmed that an activated IMOG is able to produce sufficient oxygen to radiosensitize pancreatic tumors, enhancing response to single-dose radiation therapy.


Transcriptional and post-transcriptional regulation of prolactin during the turkey reproductive cycle.
The present study examined turkey prolactin (PRL) transcription and PRL mRNA stability during different reproductive stages. Nuclear run-on transcription assays were performed using isolated nuclei from pituitaries of turkeys at different reproductive stages. Meanwhile, cytoplasmic PRL mRNA and plasma PRL were measured by slot blot and RIA respectively. The PRL transcription, pituitary cytoplasmic PRL mRNA abundance and plasma PRL levels increased after photostimulation and peaked at the incubating stage (P < 0.05). A decrease in PRL transcription, pituitary cytoplasmic PRL mRNA and plasma PRL (P < 0.05) was observed during the transition from incubation to photorefractoriness. Nest-deprivation reduced circulating PRL (P < 0.05), whereas pituitary cytoplasmic PRL mRNA and PRL transcription were not significantly altered from those in incubating birds (P > 0.05). The half-life of PRL mRNA was determined in pituitaries of non-photostimulated, laying, incubating and photorefractory hens. Primary pituitary cell cultures were treated with the transcription inhibitor actinomycin-D and the decay of the pre-existing PRL mRNA was quantified using Northern blot analysis. The PRL mRNA half-life was 1.5- and 1.4-fold greater in incubating and laying birds respectively than in non-photostimulated turkeys (P < 0.05). The half-life of PRL mRNA in photorefractory and incubating hens was similar in spite of great differences in pituitary PRL mRNA steady-state levels and PRL transcription. Our data suggest that photoinduced changes in pituitary PRL mRNA and plasma PRL are due to changes in both PRL transcription and PRL mRNA stability. Nest-deprivation inhibits the PRL releasing mechanism(s) independently of PRL transcription in turkeys.


Putting policy into practice? Poverty and people with serious mental illness.
This paper addresses the effects of chronic poverty on people with serious mental illness. More specifically, we are concerned with the extent to which welfare restructuring, by deepening the poverty facing people with serious mental illness, undermines the expressed intent of mental health policy to improve the quality of life (QOL) of this population. The province of Ontario in Canada forms the setting for the study. The paper first examines recent trends in mental health care and social assistance policy in Ontario. While income support is consistently recognized as a core element of mental health care, welfare restructuring has led to a significant decline in the real value of income supports received by people with serious mental illness. The paper then examines the implications of this trend for the QOL of residential care facility tenants in Hamilton, Ontario. Here, the case study is explicitly connected to QOL scholarship. In addition, the study is grounded in an analysis of the broader transformation of the welfare state in Ontario. Interview data suggest that tenants experience chronic poverty that has a deleterious impact on multiple life domains including basic needs, family, social relations, leisure and self-esteem. Implications for research and policy are discussed.


Knowledge, attitudes and beliefs about HIV/AIDS in Sana'a, Yemen.
Although HIV prevalence is low in the Republic of Yemen, existing conditions could lead to the rapid spread of HIV/AIDS. Interviewers helped 1033 residents aged 14-49 years from randomly chosen households to complete a survey of knowledge, attitudes and beliefs about HIV/AIDS. General awareness was good, although there were many misconceptions about transmission modes, stigmas and discrimination against HIV positive persons. Knowledge was significantly determined by schooling, residence and sex. Although they recognized the global threat of AIDS, participants underestimated its threat to the Republic of Yemen. Television was the commonest source of information. Fostering public awareness is recommended to facilitate the development of intervention programmes, fight stigmas and ensure delivery of care to those affected.


The very distal part of the basilar papilla in the chicken: a morphological approach.
The very distal part of the chicken basilar papilla was investigated by light and electron (scanning and transmission) microscopy. The rostral tip of the basilar papilla has a lenticular area with atypical sensory hair cells which are more similar to vestibular than to auditory cells. The structure of the lenticular area appears to be suitable for vestibular function or, more likely, for auditory perception at very low frequencies. Several hypotheses can be proposed to explain this very peculiar portion of the avian cochlea. It is difficult to consider it a continuously growing area since it remains stable in adulthood. A better explanation would be that there is an incomplete ontogenetic or phylogenetic process.


Simple and convenient synthesis of esters from carboxylic acids and alkyl halides using tetrabutylammonium fluoride.
A simple and convenient method has been developed for the synthesis of esters from the corresponding carboxylic acids and alkyl halides by using a stoichiometric amount of tetrabutylammonium fluoride (Bu₄NF) as the base. The reaction of carboxylic acids and a Bu₄NF/THF solution in DMF or THF as the solvent generates carboxylate ions in situ. The carboxylate ions thus generated and accumulated are highly reactive. They are then allowed to react with alkyl halides as the electrophiles, and afford the corresponding esters in moderate to good yields. The reaction without Bu₄NF does not afford any product; therefore, Bu₄NF seems to play an important role as the base in these reactions. A bulky countercation such as the tetrabutylammonium cation seems to increase the reactivity of the carboxylate ions in the solution phase.


Functional Polymer Nanocomposites with Increased Anticorrosion Properties and Wear Resistance for Water Transport.
Corrosive destruction and hydroabrasive wear is a serious problem in the operation of machine parts and water transport mechanisms. It is promising to develop new composite materials with improved properties to increase the reliability of transport vehicles. In this regard, the use of new polymer-based materials, which are characterized by improved anticorrosion properties and wear resistance, is promising. In this work, therefore, for the formation of multifunctional protective coatings, epoxy dian oligomer brand ED-20, polyethylene polyamine (PEPA) hardener, a mixture of nanodispersed compounds with a dispersion of 30-90 nm, fillers Agocel S-2000 and Waltrop with a dispersion of 8-12 μm, and particles of iron slag with a dispersion of 60-63 μm are used for the formation of multifunctional protective coatings. Using the method of mathematically planning the experiment, the content of additives of different physico-chemical natures in the epoxy binder is optimized to obtain fireproof coatings with improved operational characteristics. A mathematical model is developed for optimizing the content of components in the formation of protective anticorrosion and wear-resistant coatings for means of transport as a result of the complex effect of a mixture of nanodispersed compounds, iron scale, and Waltrop. Based on the mathematical planning of the experiment, new regularities of increasing the corrosion resistance and resources of the means of transport are established through the formation of four different protective coatings, which are tested for resistance to aggressive environments (technical water-CAS No. 7732-18-5, gasoline-CAS No. 64742-82-1, acetone-CAS No. 67-64-1, I-20A lubricant-CAS No. 64742-62-7, sodium solutions-CAS No. 1310-73-2, and sulfuric acid-CAS No. 7664-93-9) and hydroabrasive wear resistances. A study of the change in the permeability index in aggressive environments is additionally carried out, taking into account the rational ratio of dispersive fillers in the epoxy binder, which made it possible to create an effective barrier to the penetration of aggressive water molecules into the base. A decrease in the permeability of protective coatings by 2.0-3.3 times relative to the epoxy matrix is achieved. In addition, the wear resistance of the developed materials under the action of hydroabrasion is investigated. The relative resistance of the CM to the action of hydroabrasion was found by the method of materials and coatings testing on the gas-abrasive wear with a centrifugal accelerator. This method enables one to model the real process of the wear of mechanism parts under the hydroabrasive action. It is shown that the coefficient of the wear resistance of the developed materials is 1.3 times higher than that of the polymer matrix, which indicates the resistance of the composites to the influence of hydroabrasive environment. As a result, modified epoxy composite protective coatings with improved anticorrosion properties and wear resistance under hydroabrasive conditions are developed. It is established that the protective coating filled with particles of a mixture of nanodispersed compounds (30-90 nm), iron scale (60-63 μm), and Waltrop (8-12 μm) has the lowest permeability indicators. The permeability in natural conditions of such a coating during the time t = 300 days of the study is χ = 0.5%, which is 3.6 times less than the similar indicators of the epoxy matrix. It is substantiated that the protective coating filled with particles of a mixture of nanodispersed compounds (30-90 nm), iron scale (60-63 μm), and Agocel S-2000 (8-12 μm) is characterized by the highest indicators of wear resistance. The coefficient of wear resistance under the action of hydroabrasion of such a coating is K = 1.75, which is 1.3 times higher than the similar indicators of the original epoxy matrix.


Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.


Effect of Repeated Screw Joint Closing and Opening Cycles and Cyclic Loading on Abutment Screw Removal Torque and Screw Thread Morphology: Scanning Electron Microscopy Evaluation.
To evaluate the effect of repeated screw joint closing and opening cycles and cyclic loading on abutment screw removal torque and screw thread morphology using scanning electron microscopy (SEM). Three groups (n = 10 in each group) of implant-abutment-abutment screw assemblies were created. There were also 10 extra abutment screws as new screws in group 3. The abutment screws were tightened to 12 Ncm with an electronic torque meter; then they were removed and removal torque values were recorded. This sequence was repeated 5 times for group 1 and 15 times for groups 2 and 3. The same screws in groups 1 and 2 and the new screws in group 3 were then tightened to 12 Ncm; this was also followed by screw tightening to 30 Ncm and retightening to 30 Ncm 15 minutes later. Removal torque measurements were performed after screws were subjected to cyclic loading (0.5 × 10⁶ cycles; 1 Hz; 75 N). Moreover, the surface topography of one screw from each group before and after cyclic loading was evaluated with SEM and compared with an unused screw. All groups exhibited reduced removal torque values in comparison to insertion torque in each cycle. However, there was a steady trend of torque loss in each group. A comparison of the last cycle of the groups before loading showed significantly greater torque loss value in the 15th cycle of groups 2 and 3 compared with the fifth cycle of group 1 (P < .05). Nonetheless, torque loss values after loading were not shown to be significantly different from each other. Using a new screw could not significantly increase the value of removal torque. It was concluded that restricting the amount of screw tightening is more important than replacing the screw with a new one when an abutment is definitively placed.


Unsafe injecting practices among attendees of syringe exchange programmes in France.
To describe syringe exchange programme attendees and their injection practices. Cross-sectional study (one week in 1998). Data were collected through a standardized questionnaire. 60/74 syringe exchange programmes (SEPs) in France. Clients requesting syringes in 60 SEPs. Self-reports of drug use, injecting behaviour, sexual behaviour, serological status (HIV, HBV, HCV). Prevalence of unsafe injecting practices in the previous month such as: syringe sharing; and sharing other injection paraphernalia. 1004 questionnaires were collected (response rate: 50%). The mean age of respondents was 30 years, and 70% were males. Among individuals tested, HIV reported prevalence was 19.2%, HCV 58.4% and HBV 20.8%. The mean duration of drug use was 11 years. Eighty-five percent were polydrug users and buprenorphine high-dosage was the substance most used (73%). In the previous month, 45% of the participants had re-used a syringe, 93% injected at least daily (mean 3.6 injections per day), 18% shared a syringe and 71% shared injection paraphernalia. In multivariate analyses, unsafe injecting practices were associated with heroin and cocaine use and with living in a couple. The cluster analysis identified five categories of IDUs: users of buprenorphine-HD (45% of the responders), morphine-sulphate (17%), benzodiazepines and other legal drugs (13%), methadone associated with other legal drugs (13%) and crack-cocaine (13%). The buprenorphine-HD group had better social status and safer injection practices. In France, despite an increase in the accessibility to syringes and substitution treatments, unsafe injecting practices persist among SEP attenders. Interventions should stress the importance of using sterile material for each injection, even with a steady sex partner.


Heart rate variability as a measure of autonomic function during weight change in humans.
Changes in autonomic function were studied during experimentally induced weight changes in seven subjects. A spectral analysis of heart rate variability (HRV) was used to evaluate autonomic activity during weight change. With a 10% increase in body weight above the usual or starting weight, there was a decline in parasympathetic power accompanied by a rise in mean heart rate. Heart rate declined during weight reduction, but the power of HRV did not change significantly. Because heart rate power at the frequency of respiratory rate can be affected by respiratory rate, three additional subjects were tested at a constant respiratory rate. Weight increases in this group also led to a decline in the power of HRV at a frequency attributable to the parasympathetic nervous system. Such a parasympathetic effect of weight increase may be one mechanism for the arrhythmias and other cardiac alterations that accompany obesity.


Cutaneous necrosis following peripheral intravenous vasopressin therapy.
Vasopressin infusion through peripheral veins is a commonly used modality for control of bleeding esophageal varices. A cirrhotic patient in whom multiple areas of cutaneous necrosis developed during a course of vasopressin therapy is presented. The involved areas included the infusion sites as well as sites unrelated to infusion but subject to pressure. Patients receiving this form of therapy must be carefully observed for the development of ischemic cutaneous complications.


COTA to OTR: factors influencing professional development.
This pilot study examined factors that influenced the pursuit of a professional educational degree by certified occupational therapy assistants (COTAs) seeking to become registered occupational therapists (OTRs). Questionnaires were distributed to 92 COTAs attending a weekend professional occupational therapy education program. Although the stressors on these students were many, the depth and breadth of motivators, resources, and supports and the availability of weekend classes enabled this group of COTAs to pursue their professional development goal. Enabling the pursuit of professional degrees while working was viewed by the participants as essential to their professional development and career mobility. Strategies for meeting the diverse needs of COTAs and other nontraditional adult students seeking a professional degree in occupational therapy are identified and need to be supported by educators and practitioners. An increased appreciation of the challenges faced by these students and the development of innovative programming to meet their educational needs will strengthen the profession's ability to recruit and retain diverse, competent practitioners.


Purification and characterization of a novel L-2-amino-Delta2-thiazoline-4-carboxylic acid hydrolase from Pseudomonas sp. strain ON-4a expressed in E. coli.
L-2-Amino-Delta2-thiazoline-4-carboxylic acid hydrolase (ATC hydrolase) was purified and characterized from the crude extract of Escherichia coli, in which the gene for ATC hydrolase of Pseudomonas sp. strain ON-4a was expressed. The results of SDS-polyacrylamide gel electrophoresis and gel filtration on Sephacryl S-200 suggested that the ATC hydrolase was a tetrameric enzyme consisted of identical 25-kDa subunits. The optimum pH and temperature of the enzyme activity were pH 7.0 and 30-35 degrees C, respectively. The enzyme did not require divalent cations for the expression of the activity, and Cu2+ and Mn2+ ions strongly inhibited the enzyme activity. An inhibition experiment by diethylpyrocarbonic acid, 2-hydroxy-5-nitrobenzyl bromide, and N-bromosuccinimide suggested that tryptophan, cysteine, or/and histidine residues may be involved in the catalytic site of this enzyme. The enzyme was strictly specific for the L-form of D,L-ATC and exhibited high activity for the hydrolysis of L-ATC with the values of Km (0.35 mM) and Vmax (69.0 U/mg protein). This enzyme could not cleave the ring structure of derivatives of thiazole, thiazoline, and thiazolidine tested, except for D,L- and L-ATC. These results show that the ATC hydrolase is a novel enzyme cleaving the carbon-sulfur bond in a ring structure of L-ATC to produce N-carbamoyl-L-cysteine.


Nephritis and cerebellar ataxia: rare presenting features of enteric fever.
Enteric fever is a common infectious disease of the tropical world, about 80% of these cases occur in Asian countries. Enteric fever presenting with isolated cerebellar ataxia or nephritis is rare. We report three cases of enteric fever that presented with these complications. Isolated cerebellar ataxia usually occurs in the second week, whereas in our cases it presented within first four days of fever. The common complications of enteric fever related to the urinary tract are cystitis, pyelitis, and pyelonephritis. Glomerulonephritis is uncommon. Most patients with enteric glomerulonephritis present with acute renal failure, hypertensive encephalopathy, or nephritic syndrome. In comparison, our case had milder manifestations. All three patients were treated with parenteral ceftriaxone and showed a prompt recovery.


Comparative analysis identifies genetic and molecular factors associated with prognostic clusters of PANoptosis in glioma, kidney and melanoma cancer.
The importance of inflammatory cell death, PANoptosis, in cancer is increasingly being recognized. PANoptosis can promote or inhibit tumorigenesis in context-dependent manners, and a computational approach leveraging transcriptomic profiling of genes involved in PANoptosis has shown that patients can be stratified into PANoptosis High and PANoptosis Low clusters that have significant differences in overall survival for low grade glioma (LGG), kidney renal cell carcinoma (KIRC) and skin cutaneous melanoma (SKCM). However, the molecular mechanisms that contribute to differential prognosis between PANoptosis clusters require further elucidation. Therefore, we performed a comprehensive comparison of genetic, genomic, tumor microenvironment, and pathway characteristics between the PANoptosis High and PANoptosis Low clusters to determine the relevance of each component in driving the differential associations with prognosis for LGG, KIRC and SKCM. Across these cancer types, we found that activation of the proliferation pathway was significantly different between PANoptosis High and Low clusters. In LGG and SKCM, we also found that aneuploidy and immune cell densities and activations contributed to differences in PANoptosis clusters. In individual cancers, we identified important roles for barrier gene pathway activation (in SKCM) and the somatic mutation profiles of driver oncogenes as well as hedgehog signaling pathway activation (in LGG). By identifying these genetic and molecular factors, we can possibly improve the prognosis for at risk-stratified patient populations based on the PANoptosis phenotype in LGG, KIRC and SKCM. This not only advances our mechanistic understanding of cancer but will allow for the selection of optimal treatment strategies.


A physiologically based criterion for muscle force predictions on locomotion.
A quantitative method of muscle activity prediction is presented which uses a criterion of maximum endurance of musculoskeletal function and is based on the inversely nonlinear relationship of muscle force and contraction endurance. The results obtained through the use of this method agree more closely with known patterns of muscle activity, as revealed by electromyography, than do those obtained by most linear optimization techniques.


Effects of hypoxia and ischemia on microRNAs in the brain.
Hypoxia and ischemia play a major role in the pathogenesis of cerebrovascular diseases such as stroke. However, the protective strategies against hypoxic and ischemic insults are very limited in clinical settings. This has reinforced the need to improve our understanding of the hypoxic and ischemic cascades and explore novel solutions of hypoxic/ ischemic injury. Recent research has identified the crucial role of microRNAs in regulation of gene expression under hypoxic/ischemic conditions. These 19-24 ribonucleotide non-coding RNA molecules function as inhibitory modulators of gene expression, by targeting mRNAs and promoting either RNA degradation or translational repression. They are differentially regulated in the brain as well as other organs under hypoxic and ischemic conditions. Targeting microRNA expression/activity offers a potentially effective way to intervene against hypoxic and ischemic injury. In this review, we highlight recent updates with summary of our recent work, which provides an insight into the roles and mechanisms of microRNA-induced regulation of cellular and molecular processes in response to hypoxic and/or ischemic stress.


Spatial insurance in multi-trophic metacommunities.
Metacommunity theory suggests that dispersal is a key driver of diversity and ecosystem functioning in changing environments. The capacity of dispersal to mitigate effects of environmental change might vary among trophic groups, potentially resulting in changes in trophic interactions and food web structure. In a mesocosm experiment, we compared the compositional response of bacteria, phyto- and zooplankton to a factorial manipulation of acidification and dispersal. We found that the buffering capacity of dispersal varied among trophic groups: dispersal alleviated the negative effect of acidification on phytoplankton diversity mid-experiment, but had no effect on the diversity of zooplankton and bacteria. Likewise, trophic groups differed in whether dispersal facilitated compositional change. Dispersal accelerated changes in phytoplankton composition under acidification, possibly mediated by changes in trophic interactions, but had no effect on the composition of zooplankton and bacteria. Overall, our results suggest that the potential for spatial insurance can vary among trophic groups.


Low energy electronic excitations in the layered cuprates studied by copper L3 resonant inelastic x-ray scattering.
We have measured the resonant inelastic x-ray scattering (RIXS) spectra at the Cu L3 edge in a variety of cuprates. Exploiting a considerably improved energy resolution (0.8 eV) we recorded significant dependencies on the sample composition and orientation, on the scattering geometry, and on the incident photon polarization. The RIXS final states correspond to two families of electronic excitations, having local (dd excitations) and nonlocal (charge-transfer) character. The dd energy splitting can be estimated with a simple crystal field model. The RIXS at the L3 edge demonstrates here a great potential, thanks to the resonance strength and to the large 2p spin-orbit splitting.


The absence of IDO upregulates type I IFN production, resulting in suppression of viral replication in the retrovirus-infected mouse.
Indoleamine 2,3-dioxygenase, the L-tryptophan-degrading enzyme, plays a key role in the powerful immunomodulatory effects on several different types of cells. Because modulation of IDO activities after viral infection may have great impact on disease progression, we investigated the role of IDO following infection with LP-BM5 murine leukemia virus. We found suppressed BM5 provirus copies and increased type I IFNs in the spleen from IDO knockout (IDO(-/-)) and 1-methyl-D-L-tryptophan-treated mice compared with those from wild-type (WT) mice. Additionally, the number of plasmacytoid dendritic cells in IDO(-/-) mice was higher in the former than in the WT mice. In addition, neutralization of type I IFNs in IDO(-/-) mice resulted in an increase in LP-BM5 viral replication. Moreover, the survival rate of IDO(-/-) mice or 1-methyl-D-L-tryptophan-treated mice infected with LP-BM5 alone or with both Toxoplasma gondii and LP-BM5 was clearly greater than the survival rate of WT mice. To our knowledge, the present study is the first report to observe suppressed virus replication with upregulated type I IFN in IDO(-/-) mice, suggesting that modulation of the IDO pathway may be an effective strategy for treatment of virus infection.


Dexamethasone-mediated changes in adipose triacylglycerol metabolism are exaggerated, not diminished, in the absence of a functional GR dimerization domain.
The glucocorticoid (GC) receptor (GR) has multiple effector mechanisms, including dimerization-mediated transactivation of target genes via DNA binding and transcriptional repression mediated by protein-protein interactions. Much attention has been focused on developing selective GR modulators that would dissociate adverse effects from therapeutic anti-inflammatory effects. The GR(dim/dim) mouse has a mutation in the dimerization domain of GR and has been shown to have attenuated transactivation with intact repression. To understand the role of GR dimerization-dependent targets in multiple tissues, we measured metabolic fluxes through several disease-relevant GC target pathways using heavy water labeling and mass spectrometry in wild-type and GR(dim/dim) mice administered the potent GC dexamethasone (DEX). Absolute triglyceride synthesis was increased in both wild-type and GR(dim/dim) mice by DEX in the inguinal and epididymal fat depots. GR(dim/dim) mice showed an exaggerated response to DEX in both depots. De novo lipogenesis was also greatly increased in both depots in response to DEX in GR(dim/dim), but not wild-type mice. In contrast, the inhibitory effect of DEX on bone and skin collagen synthesis rates was greater in wild-type compared with GR(dim/dim) mice. Wild-type mice were more sensitive to DEX-dependent decreases in insulin sensitivity than GR(dim/dim) mice. Wild-type and GR(dim/dim) mice were equally sensitive to DEX-dependent decreases in muscle protein synthesis. Chronic elevation of GCs in GR(dim/dim) mice results in severe runting and lethality. In conclusion, some metabolic effects of GC treatment are exaggerated in adipose tissue of GR(dim/dim) mice, suggesting that selective GR modulators based on dissociating GR transactivation from repression should be evaluated carefully.


Antigen removal process preserves function of small diameter venous valved conduits, whereas SDS-decellularization results in significant valvular insufficiency.
Chronic venous disease (CVD) is the most common reported chronic condition in the United States, affecting more than 25 million Americans. Regardless of its high occurrence, current therapeutic options are far from ideal due to their palliative nature. For best treatment outcomes, challenging cases of chronic venous insufficiency (CVI) are treated by repair or replacement of venous valves. Regrettably, the success of venous valve transplant is dependent on the availability of autologous venous valves and hindered by the possibility of donor site complications and increased patient morbidity. Therefore, the use of alternative tissue sources to provide off-the-shelf venous valve replacements has potential to be extremely beneficial to the field of CVI. This manuscript demonstrates the capability of producing off-the-shelf fully functional venous valved extracellular matrix (ECM) scaffold conduits from bovine saphenous vein (SV), using an antigen removal (AR) method. AR ECM scaffolds maintained native SV structure-function relationships and associated venous valves function. Conversely, SDS decellularization caused significant changes to the collagen and elastin macromolecular structures, resulting in collagen fibril merging, elimination of fibril crimp, amalgaming collagen fibers and fragmentation of the inner elastic lamina. ECM changes induced by SDS decellularization resulted in significant venous valve dysfunction. Venous valved conduits generated using the AR approach have potential to serve as off-the-shelf venous valve replacements for CVI. STATEMENT OF SIGNIFICANCE: Retention of the structure and composition of extracellular matrix (ECM) proteins within xenogeneic scaffolds for tissue engineering is of crucial importance, due to the undeniable effect ECM proteins can impose on repopulating cells and function of the resultant biomaterial. This manuscript demonstrates that alteration or elimination of ECM proteins via commonly utilized decellularization approach results in complete disruption of venous valve function. Conversely, retention of the delicate ECM structure and composition of native venous tissue, using an antigen removal tissue processing method, results in preservation of native venous valve function.


Mono- and Difluorinated Saturated Heterocyclic Amines for Drug Discovery: Systematic Study of Their Physicochemical Properties.
A comprehensive study of physicochemical properties (pKa , LogP, and intrinsic microsomal clearance) within the series of mono- and difluorinated azetidine, pyrrolidine, and piperidine derivatives was performed. While the number of fluorine atoms and their distance to the protonation center were the major factors defining the compound's basicity, both pKa and LogP values were affected considerably by the conformational preferences of the corresponding derivatives. For example, features of "Janus face" (facially polarized) cyclic compounds (i. e., unusually high hydrophilicity) were identified for cis-3,5-difluoropiperidine, preferring a diaxial conformation. Intrinsic microsomal clearance measurements demonstrated high metabolic stability of the compounds studied (with a single exception of the 3,3-difluoroazetidine derivative). According to pKa - LogP plots, the title compounds provide a valuable extension of the fluorine-containing (e. g., fluoroalkyl-substituted) saturated heterocyclic amine series as building blocks for rational optimization studies in early drug discovery.


[Transformation Path of Clinical Research Achievements and Its Application in Medical Equipment Management under Background of Multi-agent Collaborative Innovation].
By studying the current situation of multi-agent collaborative innovation and clinical achievements transformation at home and abroad, it is clear that multi-agent collaborative innovation is the only way for clinical research achievements transformation under the current background. This paper proposes a set of transformation path of clinical research achievements based on the multi-agent collaborative innovation platform of "production, teaching, research and medicine", which is supported by policy guidance and innovation management, and explore the role of equipment management department in achievement transformation.