Methods of Random Mutagenesis of Aspergillus Strain for Increasing Kojic Acid Production.
Kojic acid is an organic acid that is commonly used in the pharmaceutical and cosmetic industries. This acid compound is a secondary metabolite produced by various microorganisms, one of which is Aspergillus oryzae. Typically, improving the strain can enhance kojic acid production. A mutation is one of the tools to perform strain improvement because the change in kojic acidproducing genes effectively increases kojic acid yield. A random mutagenesis is a classic approach for inducing and producing mutants with random mutations. The mutagenesis can be generated by the individual physical and chemical mutagen, combined physical and chemical mutagens, or initiate by protoplast preparation. Aspergillus strains that are exposed to physical mutagens (e.g., UV) or chemical mutagens (e.g., N-methyl-N-nitro-N-nitrosoguanidine (NTG)) showed their abilities in increasing kojic acid production. Several new mutation methods, such as Ion Beam Implantation and Atmospheric and room temperature plasma (ARTP), also showed good responses in enhancing the production of biological products such as kojic acid. This review compared different random mutagenesis methods of Aspergillus strain with various mutagen types to provide better insight for researchers in choosing the most suitable method to increase kojic acid production.


Factors associated with polypharmacy in primary care: a cross-sectional analysis of data from The English Longitudinal Study of Ageing (ELSA).
While older age and ill health are known to be associated with polypharmacy, this paper aims to identify whether wealth, body mass index (BMI), smoking and alcohol consumption are also associated with polypharmacy (5-9 prescribed medications) and hyperpolypharmacy prevalence (≥10 prescribed medications), among older people living in England. Cross-sectional study. The English Longitudinal Study of Ageing Wave 6 (2012-2013). 7730 participants aged over 50 years. Two multivariate models were created. HR with corresponding 95% CI, for polypharmacy and hyperpolypharmacy, were calculated after adjusting for gender, age, wealth, smoking, alcohol consumption, BMI, self-rated health and the presence of a chronic health condition. Lower wealth (lowest wealth quintile vs highest wealth quintile, adjusted HR 1.28; 95% CI 1.04 to 1.69, P=0.02) and obesity (adjusted HR 1.81; 95% CI 1.53 to 2.15, p<0.01) were significantly associated with polypharmacy. Increasing age (50-59 years vs 70-79 years, adjusted HR 3.42; 95% CI 2.81 to 4.77, p<0.01) and the presence of a chronic health condition (adjusted HR 2.94; 95% CI 2.55 to 3.39, p<0.01) were also associated with polypharmacy. No statistically significant association between smoking and polypharmacy (adjusted HR 1.06; 95% CI 0.86 to 1.29, P=0.56) was established; while, very frequent alcohol consumption (consuming alcohol >5 times per week) was inversely associated with polypharmacy (never drank alcohol vs very frequently, adjusted HR 0.64; 95% CI 0.52 to 0.78, p<0.01). The adjusted HR for hyperpolypharmacy was accentuated, compared with polypharmacy. This study has identified that lower wealth, obesity, increasing age and chronic health conditions are significantly associated with polypharmacy and hyperpolypharmacy prevalence. The effect of these factors, on polypharmacy and especially hyperpolypharmacy prevalence, is likely to become more pronounced with the widening gap in UK wealth inequalities, the current obesity epidemic and the growing population of older people. The alcohol findings contribute to the debate on the relationship between alcohol consumption and health.


Nitrosamines and their precursors in some Kazakh foodstuffs.
Numerous samples of various foods, such as salt-dried and smoke-dried meats, fermented sausages, sour-milk products, fermented mare's and camel's milk, raw vegetables, rice, rock and table salts, local bread and daily food rations were analysed by GC-TEA and HPLC-TEA for the presence of volatile nitrosamines. Apart from the observation of NDMA (up to 0.7 microgram/kg) in three samples of Kazakh cheeses, the volatile nitrosamines were detected only in some meat and meat products. Salted air-dried meat contained NDMA in amounts up to 54 micrograms/kg. NPYR (12 micrograms/kg) was found in one sample of nitrite-cured sausage. The highest content of NPIP (7 micrograms/kg) was detected in fermented, home-made sausage. It is clear that the only significant contribution of these dialkyl and heterocyclic nitrosamines to the diet is from stored, salt-dried meat and nitrite-cured meat products. Analyses of nitrate and nitrite in various local products are reported. The validity of our assumption that the high incidence of oesophageal cancer can be lowered by realistic improvements in the processing and storage of meat and meat products requires further evaluation.


Cam morphology is associated with MRI-defined cartilage defects and labral tears: a case-control study of 237 young adult football players with and without hip and groin pain.
Football players are at risk of developing hip osteoarthritis (OA). Cam morphology (present in almost two of every three football players) may explain this heightened risk, but there is limited research on its role in hip OA development in younger athletes. Knowledge of this relationship will advance our understanding of the aetiology of hip OA in football players. We aimed to study the relationship between cam morphology size and MRI-defined cartilage defects and labral tears, and if this relationship differs by symptomatic state in young adult football players. For this case-control study, 182 (288 hips) symptomatic (hip and/or groin pain >6 months and positive flexion-adduction-internal-rotation (FADIR) test) and 55 (110 hips) pain-free football players (soccer or Australian football) underwent anteroposterior and Dunn 45° radiographs, and 3-Tesla MRI. Cam morphology size was defined using alpha angle, and cartilage defects and labral tears were scored semiquantitatively. Presence, location and score (severity) of cartilage defects and labral tears were determined. Each participant completed the International Hip Outcome Tool 33 and Copenhagen Hip and Groin Outcome Score. Greater alpha angle was associated with cartilage defects (OR 1.03, 95% CI 1.01 to 1.04) and labral tears (OR 1.02, 95% CI 1.01 to 1.04). Greater alpha angle was associated with superolateral cartilage defects (OR 1.03, 95% CI 1.02 to 1.05) and superior labral tears (OR 1.03, 95% CI 1.02 to 1.05). The association of alpha angle with MRI-defined cartilage defects and labral tears was no greater in football players with symptoms than in those without (p=0.189-0.937). Cam morphology size was associated with cartilage defects and labral tears in young adult football players with and without pain. This study provides evidence that cam morphology may contribute to the high prevalence of hip OA in football players. Prospective studies of football players are now needed to establish if cam morphology causes progression of cartilage defects and labral tears and development of hip OA.


Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure.
Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification. Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks. Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation. Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.


A bootstrap-aggregated hybrid semi-parametric modeling framework for bioprocess development.
Hybrid semi-parametric modeling, combining mechanistic and machine-learning methods, has proven to be a powerful method for process development. This paper proposes bootstrap aggregation to increase the predictive power of hybrid semi-parametric models when the process data are obtained by statistical design of experiments. A fed-batch Escherichia coli optimization problem is addressed, in which three factors (biomass growth setpoint, temperature, and biomass concentration at induction) were designed statistically to identify optimal cell growth and recombinant protein expression conditions. Synthetic data sets were generated applying three distinct design methods, namely, Box-Behnken, central composite, and Doehlert design. Bootstrap-aggregated hybrid models were developed for the three designs and compared against the respective non-aggregated versions. It is shown that bootstrap aggregation significantly decreases the prediction mean squared error of new batch experiments for all three designs. The number of (best) models to aggregate is a key calibration parameter that needs to be fine-tuned in each problem. The Doehlert design was slightly better than the other designs in the identification of the process optimum. Finally, the availability of several predictions allowed computing error bounds for the different parts of the model, which provides an additional insight into the variation of predictions within the model components.


Acute bronchiolitis during the COVID-19 pandemic.
The autumn and winter bronchiolitis epidemics have virtually disappeared in the first year of the COVID-19 pandemic. Our objectives were characterised bronchiolitis during fourth quarter of 2020 and the role played by SARS-CoV-2. Prospective multi-centre study performed in Madrid (Spain) between October and December 2020 including all children admitted with acute bronchiolitis. Clinical data were collected and multiplex PCR for respiratory viruses were performed. Thirty-three patients were hospitalised with bronchiolitis during the study period: 28 corresponded to rhinovirus (RV), 4 to SARS-CoV-2, and 1 had both types of infection. SAR-CoV-2 bronchiolitis were comparable to RV bronchiolitis except for a shorter hospital stay. A significant decrease in the admission rate for bronchiolitis was found and no RSV was isolated. SARS-CoV-2 infection rarely causes acute bronchiolitis and it is not associated with a severe clinical course. During COVID-19 pandemic period there was a marked decrease in bronchiolitis cases.


The rhinolith-a possible differential diagnosis of a unilateral nasal obstruction.
Rhinoliths are mineralised foreign bodies in the nasal cavity that are a chance finding at anterior rhinoscopy. Undiscovered, they grow appreciably in size and can cause a foul-smelling nasal discharge and breathing problems. Giant nasal stones are now a very rare occurrence, since improved diagnostic techniques, such as endoscopic/microscopic rhinoscopy, now make it possible to identify foreign bodies at an early stage of development. We report the case of a 37-year-old patient who, at the age of 5-6 years, introduced a foreign body, probably a stone, into his right nasal cavity. On presentation, he complained of difficulty in breathing through the right nostril that had persisted for the last 10 years. For the past four years a strong fetid smell from the nose had been apparent to those in his vicinity. Under general anaesthesia, the stone was removed in toto from the right nasal cavity. The possible genesis of the rhinolith is discussed, our case compared with those described in the literature, and possible differential diagnoses are considered.


PREVALENCE AND RISK FACTORS OF GERD IN ADOLESCENTS IN NOVOSIBIRSK: TEN-YEAR TRENDS.
The aim of the study was the study of ten-year trends (1999-2009) of GERD symptoms and risk factors in schoolchildren in Novosibirsk from 14 to 17 years. The comparison of the results of the screenings performed at 1999 and 2009 was analyzed. Anthropometry, the survey to identify the symptoms of GERD and eating habits, smoking and alcohol consumption, determination of lgG and CagA antibodies to Helicobacterpylori were included at the program of screenings. No significant dynamics of GER symptoms in adolescents, except weekly heartburn among boys. Among the factors associated with dyspepsia and GER, there have been some mixed changes: the frequency of smoking significantly reduced, but the proportion adolescents with excess body weight have increased. Violations of the regime and diet, and Helicobocrerpylori-infection has not changed significantly. The frequency of GERD in adolescents remains high but does not reach the prevalence of GERD in adults.


The pharmacokinetics of salicylate in the pregnant Wistar rat.
Sodium salicylate, in a single dose of 50 mg/kg, was administered by iv injection to nonpregnant female and 20-day pregnant Wistar rats. Blood samples (for serum) and urine were collected and analyzed for salicylate, gentisic acid, salicyluric acid, and salicyl glucuronides by HPLC. Pregnant rats showed a significant decrease in body weight-normalized total clearance but no change in absolute total clearance of salicylate. On a body weight-adjusted basis there was a slight increase in the apparent volume of salicylate distribution in pregnancy but this increase becomes highly significant if expressed in absolute terms. The biological half-life of salicylate was significantly increased in late pregnancy. Serum protein binding of salicylate is decreased in pregnancy relative to nonpregnant females but in both groups binding shows a concentration dependence. The partial clearances of both salicyluric and gentisic acids were reduced by pregnancy in the rat whereas that of the salicyl glucuronides appeared unchanged. This latter result in intact pregnant animals contrasts with previously reported decreases in glucuronyltransferase activity in isolated liver preparations from pregnant rats.


Incidence of fractures among children and adolescents in rural and urban communities - analysis based on 9,965 fracture events.
Previous work has explored the significance of residence on injuries. A number of articles reported higher rates of injury in rural as compared to urban settings. This study aimed to evaluate the importance of residency on the occurrence of fractures among children and adolescents within a region in northern Sweden. In a population based study with data from an injury surveillance registry at a regional hospital, we have investigated the importance of sex, age and place of residency for the incidence of fractures among children and adolescents 0-19 years of age using a Poisson logistic regression analysis. Data was collected between 1998 and 2011. The dataset included 9,965 cases. Children and adolescents growing up in the most rural communities appeared to sustain fewer fractures than their peers in an urban municipality, risk ratio 0.81 (0.76-0.86). Further comparisons of fracture rates in the urban and rural municipalities revealed that differences were most pronounced for sports related fractures and activities in school in the second decade of life. Results indicate that fracture incidence among children and adolescents is affected by place of residency. Differences were associated with activity at injury and therefore we have discussed the possibility that this effect was due to the influence of place on activity patterns. The results suggest it is of interest to explore how geographic and demographic variables affect the injury pattern further.


Focal transmural necrotic tracheitis in commercial meat turkeys.
This report describes an unusual presentation of severe focal necrotic tracheitis in a flock of 8-wk-old commercial turkeys. The flock was kept on a range that is located near a cotton field. The cotton field had been chemically defoliated 2 wk before the birds were submitted for necropsy. At necropsy, most of the birds had a 1-cm, yellow-white constricture in the upper third of the trachea at which the lumen was partially occluded by necrotic tissue. Microscopically, there was severe, transmural necrosis with an accumulation of inflammatory exudate in the tracheal lumen and numerous bacteria within the necrotic debris, mucosa, and lamina propria. Mixed bacteria were isolated from the trachea. No viruses were detected. Neither abnormal heavy metal concentrations in the liver nor paraquat in the respiratory tract were detected. The exact cause of this severe, necrotic tracheitis was not determined. Based on the clinical history and laboratory findings, it was concluded that a combination of a toxic irritant, possibly an aerosolized cotton defoliant, and bacterial infections were likely the cause of this lesion.


The Dual Roles of Clusterin in Extracellular and Intracellular Proteostasis.
Clusterin (CLU) was the first reported secreted mammalian chaperone and impacts on serious diseases associated with inappropriate extracellular protein aggregation. Many studies have described intracellular CLU in locations outside the secretory system and recent work has shown that CLU can be released into the cytosol during cell stress. In this article, we critically evaluate evidence relevant to the proposed origins of cellular CLU found outside the secretory system, and advance the hypothesis that the cytosolic release of CLU induced by stress serves to facilitate the trafficking of misfolded proteins to the proteasome and autophagy for degradation. We also propose future research directions that could help establish CLU as a unique chaperone performing critical and synergic roles in both intracellular and extracellular proteostasis.


Mucinous adenocarcinoma arising in ovarian mature cystic teratoma in pregnancy.
We report a case of mucinous adenocarcinoma arising from mature cystic teratoma (MCT) of the ovary ascertained incidentally during pregnancy. An ovarian adnexal mass was seen in a 38-year-old pregnant woman during cesarean section. Oophorectomy revealed a mucinous adenocarcinoma arising from MCT with additional capsule invasion. Following this, staging procedures were applied. The patient was staged as IC and adjuvant chemotherapy was applied. She has remained disease-free for over 24 months. To our knowledge, this is a case of mucinous adenocarcinoma arising from MCT and the third case of malignant transformation from MCT in pregnancy in English literature.


Correlation of second virial coefficient with solubility for proteins in salt solutions.
In this work, osmotic second virial coefficients (B(22)) were determined and correlated with the measured solubilities for the proteins, α-amylase, ovalbumin, and lysozyme. The B(22) values and solubilities were determined in similar solution conditions using two salts, sodium chloride and ammonium sulfate in an acidic pH range. An overall decrease in the solubility of the proteins (salting out) was observed at high concentrations of ammonium sulfate and sodium chloride solutions. However, for α-amylase, salting-in behavior was also observed in low concentration sodium chloride solutions. In ammonium sulfate solutions, the B(22) are small and close to zero below 2.4 M. As the ammonium sulfate concentrations were further increased, B(22) values decreased for all systems studied. The effect of sodium chloride on B(22) varies with concentration, solution pH, and the type of protein studied. Theoretical models show a reasonable fit to the experimental derived data of B(22) and solubility. B(22) is also directly proportional to the logarithm of the solubility values for individual proteins in salt solutions, so the log-linear empirical models developed in this work can also be used to rapidly predict solubility and B(22) values for given protein-salt systems.


[Determination of L-dopa and dopamine in rat brain microdialysate by ultra high performance liquid chromatography-tandem mass spectrometry using stable isotope-coded derivatization coupled with dispersive liquid-liquid microextraction].
The sensitive detection method of levodopa (L-DOPA) and dopamine (DA) in rat brain microdialysate of Parkinson's disease (PD) is an essential tool for the clinical study and attenuated synergistic drug screening for L-DOPA from traditional Chinese medicines. Using d0/d3-10-methyl-acridone-2-sulfonyl chloride (d0/d3-MASC) as stable isotope derivatization reagent, a novel ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for L-DOPA and DA by stable isotope- coded derivatization coupled with ultrasonic-assisted dispersive liquid-liquid microextraction (UA-DLLME). d3-MASC (light) and d3-MASC (heavy) were used as derivatization reagents for microdialysate samples and standards, respectively. Mixtures of the two solutions were prepared by UA-DLLME for UHPLC-MS/MS analysis with multiple reaction monitoring (MRM) mode. With d3-MASC heavy derivatives as internal standards for corresponding light derivatives from samples, the stable isotope internal standard quantification for L-DOPA and DA was carried out. The stable derivatives were obtained in aqueous acetonitrile (pH 10.8 sodium carbonate-sodium bicarbonate buffer) at 37 °C for 3.0 min, and then were separated within 2.0 min using gradient elution. Linear range was 0.20-1500.0 nmol/L (R > 0.994). LODs were 0.005 and 0.009 nmol/L for DA and L-DOPA (S/N = 3), respectively. This method was validated, and it showed obvious advantages in comparing with the reported methods in terms of sensitivity, analysis speed and anti-matrix interference. This method has been successfully applied to the study of effect of Shouwu Fang on L-DOPA and DA concentration fluctuations in PD rat brain microdialysate.


In vivo antiviral activity: defective interfering virus protects better against virulent Influenza A virus than avirulent virus.
A defective interfering (DI) virus differs from the infectious virus from which it originated in having at least one major deletion in its genome. Such DI genomes are replicated only in cells infected in trans with homologous infectious virus and, as their name implies, they interfere with infectious virus replication and reduce the yield of progeny virus. This potent antiviral activity has been abundantly demonstrated in cell culture with many different DI animal viruses, but few in vivo examples have been reported, with the notable exception of DI Influenza A virus. A clue to this general lack of success arose recently when an anomaly was discovered in which DI Influenza A virus solidly protected mice from lethal disease caused by A/PR/8/34 (H1N1) and A/WSN/40 (H1N1) viruses, but protected only marginally from disease caused by A/Japan/305/57 (A/Jap, H2N2). The problem was not any incompatibility between the DI and infectious genomes, as A/Jap replicated the DI RNA in vivo. However, A/Jap required 300-fold more mouse infectious units to cause clinical disease than A/PR8 and it was hypothesized that it was this excess of infectivity that abrogated the protective activity of the DI virus. This conclusion was verified by varying the proportions of DI and challenge virus and showing that increasing the DI virus : infectious virus ratio in infected mice resulted in interference. Thus, counter-intuitively, DI virus is most effective against viruses that cause disease with low numbers of particles, i.e. virulent viruses.


mTOR inhibitors: an overview.
Inhibitors of the mammalian target of rapamycin are a new class of immunosuppressants. In contrast to other macrolides, such as tacrolimus and cyclosporine A, they do not inhibit calcineurin and thus signal I of T-cell activation. By inhibiting signal III, the mechanism of action and side effects of sirolimus (rapamycin) and its derivative RAD are distinct from other immunosuppressants. Reports of synergism with cyclosporine A and tacrolimus in preclinical and clinical studies, avoidance of nephrotoxicity, and possible treatment or prevention of chronic allograft rejection are leading to high expectations for this new class of immunosuppressants. Furthermore, studies evaluating tolerance induction are being conducted. This review summarizes preclinical and clinical results published to date and exploits the future value of sirolimus and RAD for clinical transplantation.


A METHOD OF PROLONGING THE ACTION OF PENICILLIN.
(1) Single injections of penicillin in beeswax-peanut oil mixture will produce and maintain levels of penicillin in the blood for 7 or more hours. (2) These mixtures have maintained their potency at room, incubator and refrigerator temperatures for 30 to 62 days and show no signs of deterioration to date. (3) Eleven of twelve patients with gonorrhoea have been cured by a single injection of penicillin beeswaxpeanut oil mixture.


Isolation, nucleotide sequence, and preliminary characterization of the Escherichia coli K-12 hemA gene.
The Escherichia coli hemA gene, essential for the synthesis of 5-aminolevulinic acid (ALA), was isolated and sequenced. The following criteria identified the cloned gene as hemA. (i) The gene complemented a hemA mutation of E. coli. (ii) The gene was localized to approximately 26.7 min on the E. coli chromosomal linkage map, consistent with the location of the mapped hemA locus. Furthermore, DNA sequence analysis established that the cloned gene lay directly upstream of prfA, which encodes polypeptide chain release factor 1. (iii) Deletion of the gene resulted in a concomitant requirement for ALA. The hemA gene directed the synthesis of a 46-kilodalton polypeptide in maxicell experiments, as predicted by the coding sequence. The DNA and deduced amino acid sequences of the E. coli hemA gene displayed no detectable similarity to the ALA synthase sequences which have been characterized from a variety of organisms, but are very similar to the cloned Salmonella typhimurium hemA sequences (T. Elliott, personal communication). Results of S1 nuclease protection experiments showed that the hemA mRNA appeared to have two different 5' ends and that a nonoverlapping divergent transcript was present upstream of the putative distal hemA transcriptional start site.


Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer.
Array-based comparative genomic hybridization (CGH) uses multiple genomic clones arrayed on a slide to detect relative copy number of tumor DNA sequences. Application of array CGH to tumor specimens makes genetic diagnosis of cancers possible and may help to differentiate relevant subsets of tumors, biologically and clinically, which would allow better prognostic and therapeutic decision making. In this study, we have used array-based CGH to detect DNA copy number alterations in distinct types of renal cell carcinomas for diagnostic purposes. We were able to correctly diagnose 33 of 34 malignant tumors by automated computational means and to group together eight benign neoplasms and normal kidney samples. These results indicate that array-based CGH is capable of diagnosing the vast majority of renal cell carcinomas based on their genetic profiles.


Abnormal returns and the regulation of nonprofit hospital sales and conversions.
During the 1990s, concerns that nonprofit (NP) hospitals were being sold at below-market prices to investor-owned (IO) chains helped to prompt the widespread adoption of state laws regulating the sale and conversion of nonprofits. In this paper, we provide a simple test of under-pricing using the IO acquirer's abnormal stock market returns at the time of the acquisition. Prior to regulation, we find that IO chains did not earn abnormal returns from their acquisitions of NPs and earned greater returns from purchasing other IO and privately owned hospitals. In states that subsequently adopted regulations, acquisition activity slowed significantly and acquirer returns became negative. Efficient markets theory suggests that, absent regulation, expected merger synergies were already being transferred to the NP target and that regulation may have reduced expected synergies or increased the costs of acquiring NP hospitals.


Hippocampal transcriptome analysis following maternal separation implicates altered RNA processing in a mouse model of fetal alcohol spectrum disorder.
Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the USA and Canada. Children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. We model FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We use RNA-seq followed by clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) to analyze transcriptomic changes that result from the treatments. We use reverse transcription qPCR to validate these changes in the mouse hippocampus. We report an association between adult hippocampal gene expression and prenatal ethanol exposure followed by postnatal separation stress that is related to behavioral changes. Expression profile clustering using WGCNA identifies a set of transcripts, module 19, associated with anxiety-like behavior (r = 0.79, p = 0.002) as well as treatment group (r = 0.68, p = 0.015). Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation (q = 2e-12, p = 0.004, respectively). Together, transcriptional control in the hippocampus is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.


Jugular foramen and mylohyoid bridging in an Asian Indian population.
The incidence of jugular foramen and mylohyoid groove bridging was studied in a population of East Asian Indian skulls (125 males and 109 females). The criteria of Dodo (J. Anat. 144:153-165, 1986) was used in the identification of a jugular bridge. There was an overall incidence of 8.1% in jugular foramen bridging, with males showing a higher rate, though the difference did not reach statistical significance. The right side showed a statistically significant greater occurrence than the left, and the trait tended to be associated between sides. The overall incidence of mylohyoid bridging was found to be 2.6%, with no difference observed between the sexes. This frequency is less than the values reported for other Asian Indian studies. Studies concerned with the incidences of nonmetric traits such as bony bridging may be useful in population studies especially when utilized in combination, thereby enhancing the value of each trait as an anthropological tool.


Improving outcomes in advanced DLBCL: systemic approaches and radiotherapy.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately half of patients will present with advanced (stage III/IV) disease. The cornerstone of treatment is a combination of chemotherapy and immunotherapy, most commonly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Efforts to improve upon R-CHOP-including more chemotherapy cycles, dose-dense chemotherapy, alternative drug combinations, high-dose chemotherapy with autologous stem cell transplant, and maintenance rituximab-have generally proved unsuccessful. There is a growing body of retrospective and prospective data, however, suggesting a benefit for consolidation radiation therapy (RT) in select patients with advanced DLBCL. Consolidation RT has been shown to improve outcomes for patients with advanced DLBCL generally, and in specific instances including initially bulky disease, bone involvement, or in the setting of a partial response to systemic therapy. In these settings consolidation RT is highly efficacious at achieving local disease control and improving overall outcomes.


Are dietary strategies to mitigate enteric methane emission equally effective across dairy cattle, beef cattle, and sheep?
The digestive physiology of ruminants is sufficiently different (e.g., with respect to mean retention time of digesta, digestibility of the feed offered, digestion, and fermentation characteristics) that caution is needed before extrapolating results from one type of ruminant to another. The objectives of the present study were (1) to provide an overview of some essential differences in rumen physiology between dairy cattle, beef cattle, and sheep that are related to methane (CH4) emission; and (2) to evaluate whether dietary strategies to mitigate CH4 emission with various modes of action are equally effective in dairy cattle, beef cattle, and sheep. A literature search was performed using Web of Science and Scopus, and 94 studies were selected from the literature. Per study, the effect size of the dietary strategies was expressed as a proportion (%) of the control level of CH4 emission, as this enabled a comparison across ruminant types. Evaluation of the literature indicated that the effectiveness of forage-related CH4 mitigation strategies, including feeding more highly digestible grass (herbage or silage) or replacing different forage types with corn silage, differs across ruminant types. These strategies are most effective for dairy cattle, are effective for beef cattle to a certain extent, but seem to have minor or no effects in sheep. In general, the effectiveness of other dietary mitigation strategies, including increased concentrate feeding and feed additives (e.g., nitrate), appeared to be similar for dairy cattle, beef cattle, and sheep. We concluded that if the mode of action of a dietary CH4 mitigation strategy is related to ruminant-specific factors, such as feed intake or rumen physiology, the effectiveness of the strategy differs across ruminant types, whereas if the mode of action is associated with methanogenesis-related fermentation pathways, the strategy is effective across ruminant types. Hence, caution is needed when translating effectiveness of dietary CH4 mitigation strategies across different ruminant types or production systems.


Exon-intron structure of the human PTK6 gene demonstrates that PTK6 constitutes a distinct family of non-receptor tyrosine kinase.
Partial PTK6 (also known as Brk) cDNA was initially isolated by reverse transcription-PCR of normal human melanocyte mRNAs and the full-length cDNA encodes a non-receptor protein tyrosine kinase with an SH3 domain, an SH2 domain, and a kinase catalytic domain. We have cloned the human PTK6 gene by screening human genomic lambda libraries using the full-length PTK6 cDNA as probe. The human PTK6 gene consists of 8 exons encompassing 8.8 kb and all the splicing junctions followed the conserved GT/AG rule. Coding sequence of the PTK6 gene was identical to that of the cDNA cloned from T-47D, human breast tumor cell line. Although the amino acid sequence of the PTK6 polypeptide showed the strongest homology to those of the Src family members of protein tyrosine kinases, exon-intron boundaries of the PTK6 gene were quite different from those of the Src family genes, which are evolutionarily conserved. The 813-bp 5'-flanking sequence of the PTK6 gene upstream of a luciferase reporter gene conferred significant promoter activity, at approximately 60% level of the SV40 promoter, in transient expression assays into MCF-7, human breast tumor cell line. PTK6 mRNA was expressed at very high level in colon and at high levels in small intestine and prostate, and at low levels in some tested fetal tissues. These results suggest that PTK6 constitutes an evolutionarily distinct family of non-receptor protein tyrosine kinases and may function as an intracellular signal transducer in specific tissues.


Knowledge and factors influencing long-acting reversible contraceptives use among women of reproductive age in Nigeria.
Background: Approximately 48% of unintended pregnancies occur as a result of contraceptives failure around the world, which is mostly due to incorrect use, poor adherence, and/or technology failure. Long-acting reversible contraceptive (LARC) methods have been developed to close this gap. The main aim of this study is to identify factors associated with the use of LARCs among women of reproductive age and to examine the relationship between knowledge of LARCs and the current use of LARCs in Nigeria. Methods: This study assessed the PMA2020 methodology and secondary dataset using female datasets from PMA 2016 (Round 3) exercise. The survey was conducted out in seven states of Nigeria. The target population for this study was women of reproductive age (15-49 years) currently using contraception prior to the survey. The sample size of women that met the inclusion criteria was 1927. The data were analyzed using frequency distribution, chi-square, and logistic regression at a 5% level of significance. Results: The results showed that 21.0% of women were using traditional methods. 14.8% of the sampled women were using LARCs methods. Findings further showed that at both levels of analyses, there is a significant relationship (P<0.05 and P=0.00 for binary and logistic regression, respectively) between knowledge of LARCs and the use of LARCs. This means that knowledge of LARCs and socio-demographic variables among women of reproductive age in Nigeria can influence the use of LARCs. Conclusions: We concluded in this study that 14.8% of women using contraception were using LARCs. Additionally, the level of education, age of women, household wealth, and the number of living children were significantly associated with using LARCs in Nigeria. Also, when discussing contraception with women, health care practitioners should discuss the risks and benefits of LARCs with women of reproductive age and recommend them as a first-line method.


Molecular phenotyping of lignin-modified tobacco reveals associated changes in cell-wall metabolism, primary metabolism, stress metabolism and photorespiration.
Lignin is an important component of secondarily thickened cell walls. Cinnamoyl CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) are two key enzymes that catalyse the penultimate and last steps in the biosynthesis of the monolignols. Downregulation of CCR in tobacco (Nicotiana tabacum) has been shown to reduce lignin content, whereas lignin in tobacco downregulated for CAD incorporates more aldehydes. We show that altering the expression of either or both genes in tobacco has far-reaching consequences on the transcriptome and metabolome. cDNA-amplified fragment length polymorphism-based transcript profiling, combined with HPLC and GC-MS-based metabolite profiling, revealed differential transcripts and metabolites within monolignol biosynthesis, as well as a substantial network of interactions between monolignol and other metabolic pathways. In general, in all transgenic lines, the phenylpropanoid biosynthetic pathway was downregulated, whereas starch mobilization was upregulated. CCR-downregulated lines were characterized by changes at the level of detoxification and carbohydrate metabolism, whereas the molecular phenotype of CAD-downregulated tobacco was enriched in transcript of light- and cell-wall-related genes. In addition, the transcript and metabolite data suggested photo-oxidative stress and increased photorespiration, mainly in the CCR-downregulated lines. These predicted effects on the photosynthetic apparatus were subsequently confirmed physiologically by fluorescence and gas-exchange measurements. Our data provide a molecular picture of a plant's response to altered monolignol biosynthesis.


Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes.
The E2A-HLF (hepatic leukemia factor) oncoprotein, generated in pro-B lymphocytes by fusion of the trans-activation domain of E2A to the basic region/leucine zipper (bZIP) domain of HLF, functions as an anti-apoptotic transcription factor in leukemic cell transformation. When introduced into interleukin 3 (IL-3)-dependent mouse pro-B lymphocytes, E2A-HLF prevents apoptosis induced by growth factor deprivation, suggesting that IL-3 mediates cell survival through activation of a transcription factor whose activity can be constitutively replaced by the chimeric oncoprotein. We considered four bZIP transcription factors as candidates for this putative IL-3-regulated factor, each of which binds avidly to the DNA consensus sequence recognized by E2A-HLF and is related to the Caenorhabditis elegans CES-2 (cell death specification protein) neuron-specific mediator of cell death. The expression and binding activity of the Nfil3 protein (also called E4bp4), but not of Hlf, Dbp, or Tef, was found to be regulated by IL-3 in mouse pro-B cell lines (Baf-3 and FL5.12). Northern blot analysis showed that Nfil3/E4bp4 is regulated as a "delayed-early" IL-3-responsive gene, requiring de novo protein synthesis. In the absence of IL-3, enforced expression of the human NFIL3/E4BP4 cDNA promoted the survival but not the growth of IL-3-dependent pro-B cells. Our results implicate NFIL3/E4BP4 (nuclear factor regulated by IL-3/adenovirus E4 promoter binding protein) in a distinct growth factor-regulated signaling pathway that is responsible for the survival of early B-cell progenitors, and whose alteration by E2A-HLF leads to childhood B lineage leukemia.


Role of Doppler sonography in fetal/maternal medicine.
Doppler velocimetry of umbilical, fetal, and uteroplacental vessels provides important information on fetal and uterine hemodynamics and has therefore become one of the most dynamic areas of perinatal research. Examinations of umbilical artery velocity waveforms have gained recognition as a valuable clinical method of fetal surveillance in risk pregnancies. Pathological Doppler findings, especially the finding of absent or reverse end-diastolic (ARED) flow velocity, are associated with fetal hypoxia and adverse outcome of pregnancy. The first follow-up studies indicate that abnormal Doppler findings are associated with impaired postnatal neurological development. Velocimetry of the fetal middle cerebral artery provides important information on redistribution of fetal blood flow in hypoxia; its place in clinics remains to be established. Similarly, more studies are needed to evaluate the use of Doppler velocimetry in labor. Possibly, the Doppler method may facilitate the interpretation of equivocal cardiotocography (CTG) tracings. New evidence has been collected on the correlation between hemodynamic findings and the morphology of the placenta and the placental bed. One of the very important applications of Doppler velocimetry is the evaluation of pharmacological effects on fetal circulation of drugs used for treatment in pregnancy and labor.


In vitro evaluation of antibiotic synergy for carbapenem-resistant Klebsiella pneumoniae clinical isolates.
The prevalence of severe infections due to carbapenem-resistant Klebsiella pneumoniae (CRKP) strains has increased worldwide. With rising resistance to polymyxins, the treatment has become challenging. Given the paucity of novel agents and limited data on combination therapy for CRKP, the present study was performed to test antibiotic combinations, for synergy against clinical isolates of CRKP. A total of 50 clinical isolates of CRKP were included. Modified carbapenem inactivation method was performed for the detection of carbapenemases. In vitro synergy testing was done for the following combinations: meropenem+colistin, imipenem+tigecycline and polymyxin B+levofloxacin. It was performed with epsilometric test and microdilution checkerboard method. The time kill assay (TKA) was used to confirm the results. The fractional inhibitory concentration was also calculated. All CRKP isolates (100%) were ESBL producers and were completely resistant to amoxicillin-clavulanic acid, cefepime, cefotaxime, ceftazidime and piperacillin-tazobactam. Resistance to ciprofloxacin, amikacin and tetracycline was 96, 88 and 54 per cent, respectively. Overall, 78 (39/50) and 88 per cent (44/50) of the 50 CRKP isolates exhibited synergy by TKA for meropenem-colistin and imipenem-tigecycline, respectively. No synergy was detected for levofloxacin-polymyxin B combination. The best combination among the three was that of imipenem and tigecycline followed by meropenem-colistin. Of the three combinations tested, imipenem and tigecycline followed by meropenem-colistin were found to be best. No synergy was detected for levofloxacin-polymyxin B combination.


All-fiber laser source for CARS microscopy based on fiber optical parametric frequency conversion.
A novel approach for an all-fiber mono-laser source for CARS microscopy is presented. An Yb-fiber laser generates 100 ps pulses, which later undergo narrowband in-fiber frequency conversion based on degenerate four-wave-mixing. The frequency conversion is optimized to access frequency shifts between 900 and 3200cm-1, relevant for vibrational imaging. Inherently synchronized pump and Stokes pulses are available at one fiber end, readily overlapped in space and time. The source is applied to CARS spectroscopy and microscopy experiments in the CH-stretching region around 3000cm-1. Due to its simplicity and maintenance-free operation, the laser scheme holds great potential for bio-medical applications outside laser laboratories.


Coping with Ethnic-racial Discrimination: Short-term Longitudinal Relations Among Black and Latinx College Students.
Little is known about how Black and Latinx young adults cope with experiences of ethnic-racial discrimination, particularly over short periods of time. A multigroup path model examined the relations between discrimination and five strategies for coping with ethnic-racial discrimination (talking with others, being proud, working hard, being rude, and ignoring) among Black and Latinx young adults (N = 145) at two time points over a six-week period. Experiences of discrimination were positively associated with the coping strategies of being proud of oneself and working hard to prove discriminatory people wrong. There was moderate stability in coping strategy use over time. Models did not vary by race-ethnicity, suggesting discrimination related to coping in similar ways among Black and Latinx young adults.


[Search for new beta-adrenoblockaders among derivatives of (3-amino-2-hydroxypropoxy) phenoxymethyl isoxazole].
In experiments on anesthetized rats it was found that some derivatives of 2-(3-isopropylamino-2-hydroxypropoxy) phenoxymethyl isoxazole possess marked beta-adrenoblocking activity associated with alpha-adrenoblocking properties. The most active compound is 3-methyl-4-chloro-5-(3-isopropylamino-2-hydroxypropoxy) phenoxymethyl isoxazole hydrochloride (compound II) which by its beta-adrenoblocking activity is superior to propranolol, oxprenolol and especially labetalol. By its alpha-adrenoblocking activity the compound does not differ significantly from labetalol but it is inferior to phentolamine. Compound II has partial agonistic activity, exerts nonspecific membrane-stabilizing action and exhibits antifibrillatory and antiarrhythmic activity.


Catalytic Living Ring-Opening Metathesis Polymerization Using Vinyl Ethers as Effective Chain-Transfer Agents.
A catalytic living ring-opening metathesis copolymerization (ROMP) method is described that relies on a degenerative, reversible and regioselective exchange of propagating Fischer-carbenes. All characteristics of a living polymerization such as narrow dispersity, excellent molar mass control and the ability to form block copolymers are achieved by this method. The method allows the use of up to 200 times less ruthenium complex than traditional living ROMP. We demonstrate the synthesis of ROMP-ROMP diblock copolymers, ATRP from a ROMP macro-initiator and living ROMP from a PEG-based macro chain transfer agent. The cost-effective, sustainable and environmentally friendly synthesis of degradable polymers and block copolymers enabled by this strategy will find various applications in biomedicine, materials science, and technology.


Serum matrix metalloproteinase 9 (MMP9) as a biochemical marker for wasting marmoset syndrome.
Use of the common marmoset (Callithrix jacchus) as a non-human primate experimental animal has increased in recent years. Although wasting marmoset syndrome (WMS) is one of the biggest problems in captive marmoset colonies, the molecular mechanisms, biochemical markers for accurate diagnosis and a reliable treatment remain unknown. In this study, as a first step to finding biochemical marker(s) for the accurate diagnosis of WMS, we conducted blood cell counts, including hematocrit, hemoglobin and platelets, and examined serum chemistry values, including albumin, calcium and levels of serum matrix metalloproteinase 9 (MMP9), using a colony of marmosets with and without weight loss. MMP9 is thought to be an enzyme responsible for the degradation of extracellular matrix components and participates in the pathogenesis of inflammatory conditions, such as human and murine inflammatory bowel disease, which, like WMS, are characterized histologically by inflammatory cell infiltrations in the intestines. The values of hematocrit and hemoglobin and levels of serum albumin and calcium in the WMS group were significantly decreased versus the control group. The platelet values and serum MMP9 concentrations were increased significantly in the WMS group compared with the control group. MMP9 could be a new and useful marker for the diagnosis of WMS in addition to hematocrit, hemoglobin, serum albumin and calcium. Our results also indicate that MMP9 could be a useful molecular candidate for treatment.


[Transmissible subacute spongiform encephalopathies in animals].
Transmissible subacute spongiform encephalopathies are a group of neurodegenerative diseases of man and of several species of domestic mammals. Scrapie has been recognised in sheep and goats for more than 250 years. Descriptions in 1986 of the first cases of bovine spongiform encephalopathy (BSE) in United Kingdom, its expansion with an enzootic pattern, and in 1996 of a new variant of Creutzfeldt-Jakob disease, probably related to the same agent, focused the attention of scientists, medias and public on what seems to be a new zoonosis. The biopathological study of BSE and scrapie is useful for evaluating what risk these animal diseases represent for human health.


Impaired glucose homeostasis in Shb-/- mice.
Src homology 2 domain-containing protein B (SHB) is an adapter protein involved in the regulation of beta-cell and endothelial cell function. We have recently obtained the Shb knockout mouse, and consequently, the aim of this study was to assess the effect of Shb deletion upon beta-cell function and blood glucose homeostasis. Shb-/- mice display an elevated basal blood glucose concentration, and this increase is maintained during insulin challenge in insulin sensitivity tests. To assess glucose-induced insulin secretion, pancreata were perfused, and it was observed that Shb-/- first phase insulin secretion was blunted during glucose stimulation. Gene expression of Shb-/- islets shortly after isolation was altered, with increased pancreatic and duodenal homeobox gene-1 (Pdx1) gene expression and reduced expression of Vegf-A. Islet culture normalized Pdx1 gene expression. The microvascular density of the Shb-/- islets was reduced, and islet capillary endothelial cell morphology was changed suggesting an altered microvascular function as a contributing cause to the impaired secretory activity. Capacitance measurements of depolarization-induced exocytosis indicate a direct effect on the exocytotic machinery, in particular a dramatic reduction in readily releasable granules, as responsible for the insulin-secretory defect operating in Shb-/- islets. Shb-/- mice exhibited no alteration of islet volume or beta-cell area. In conclusion, loss of Shb impairs insulin secretion, alters islet microvascular morphology, and increases the basal blood glucose concentration. The impaired insulin secretory response is a plausible underlying cause of the metabolic impairment observed in this mutant mouse.


An investigation into the mechanism of protection by local passive immunization with monoclonal antibodies against Streptococcus mutans.
Local oral passive immunization with Streptococcus mutans-specific monoclonal antibody (MAb) (Guy's 13) prevented recolonization by indigenous S. mutans in human volunteers who had first been treated with a conventional antibacterial agent (chlorhexidine). The F(ab')2 fragment of the MAb was as protective as the intact immunoglobulin G, but the Fab fragment of the molecule failed to prevent recolonization of S. mutans. In subjects receiving the MAb Fab fragment, S. mutans levels in dental plaque and saliva reappeared at a similar rate to that found in sham-immunized subjects who received either saline or a nonprotective MAb. In vitro, MAb had no bacteriostatic or bacteriocidal effect on S. mutans. However, S. mutans grown in the presence of either intact immunoglobulin G MAb or the F(ab')2 fragment formed very long chains, which resulted in clumping of the cells. S. mutans grown with either saline or the MAb Fab fragment formed significantly shorter chains, more characteristic of streptococcal growth in liquid media. The results suggest that the two binding sites of the MAb molecule may be an essential feature for preventing streptococcal colonization but that the ability to bind to phagocytes and activate complement which resides in the Fc fragment is not essential. Protection against colonization by S. mutans lasting up to 2 years was observed in immunized subjects, although MAb was applied over a period of only 3 weeks. Furthermore, functional MAb was detected up to 3 days following application of MAb to the teeth. The long-term protection could not be accounted for by a persistence of MAb on the tooth surface, and we have suggested that it may be due to a shift in the balance of the oral flora which discouraged recolonization by S. mutans. However, examination of the proportions of Streptococcus sanguis and veillonella species in the recolonization experiments failed to reveal a significant change in the proportions of either organism, which returned to approximately the preexperimental levels in both the immunized and control groups. These findings confirm the in vivo functional specificity of the MAb to S. mutans but are not consistent with the suggestion that S. sanguis or veillonella take over the niche vacated by S. mutans, unless the shift in the proportion of these organisms cannot be detected by the method used.


Importance of manual validation for the identification of phosphopeptides using a linear ion trap mass spectrometer.
Accurate determination of protein phosphorylation is challenging, particularly for researchers who lack access to a high-accuracy mass spectrometer. In this study, multiple protocols were used to enrich phosphopeptides, and a rigorous filtering workflow was used to analyze the resulting samples. Phosphopeptides were enriched from cultured rat renal proximal tubule cells using three commonly used protocols and a dual method that combines separate immobilized metal affinity chromatography (IMAC) and titanium dioxide (TiO(2)) chromatography, termed dual IMAC (DIMAC). Phosphopeptides from all four enrichment strategies were analyzed by liquid chromatography-multiple levels of mass spectrometry (LC-MS(n)) neutral-loss scanning using a linear ion trap mass spectrometer. Initially, the resulting MS(2) and MS(3) spectra were analyzed using PeptideProphet and database search engine thresholds that produced a false discovery rate (FDR) of <1.5% when searched against a reverse database. However, only 40% of the potential phosphopeptides were confirmed by manual validation. The combined analyses yielded 110 confidently identified phosphopeptides. Using less-stringent initial filtering thresholds (FDR of 7-9%), followed by rigorous manual validation, 262 unique phosphopeptides, including 111 novel phosphorylation sites, were identified confidently. Thus, traditional methods of data filtering within widely accepted FDRs were inadequate for the analysis of low-resolution phosphopeptide spectra. However, the combination of a streamlined front-end enrichment strategy and rigorous manual spectral validation allowed for confident phosphopeptide identifications from a complex sample using a low-resolution ion trap mass spectrometer.


Can Women Have Children and a Career? IV Evidence from IVF Treatments.
This paper introduces a new IV strategy based on IVF (in vitro fertilization) induced fertility variation among childless women to estimate the causal effect of having children on their career. For this purpose, we use administrative data on IVF treated women in Denmark. Because observed chances of IVF success do not depend on labor market histories, IVF treatment success provides a plausible instrument for childbearing. Our IV estimates indicate that fertility effects on earnings are: (i) negative, large, and long-lasting; (ii) driven by fertility effects on hourly earnings and not so much on labor supply; and (iii) much stronger at the extensive margin than at the intensive margin.


Biomechanical Analysis of Normal Brain Development during the First Year of Life Using Finite Strain Theory.
The first year of life is the most critical time period for structural and functional development of the human brain. Combining longitudinal MR imaging and finite strain theory, this study aimed to provide new insights into normal brain development through a biomechanical framework. Thirty-three normal infants were longitudinally imaged using MRI from 2 weeks to 1 year of age. Voxel-wise Jacobian determinant was estimated to elucidate volumetric changes while Lagrange strains (both normal and shear strains) were measured to reveal directional growth information every 3 months during the first year of life. Directional normal strain maps revealed that, during the first 6 months, the growth pattern of gray matter is anisotropic and spatially inhomogeneous with higher left-right stretch around the temporal lobe and interhemispheric fissure, anterior-posterior stretch in the frontal and occipital lobes, and superior-inferior stretch in right inferior occipital and right inferior temporal gyri. In contrast, anterior lateral ventricles and insula showed an isotropic stretch pattern. Volumetric and directional growth rates were linearly decreased with age for most of the cortical regions. Our results revealed anisotropic and inhomogeneous brain growth patterns of the human brain during the first year of life using longitudinal MRI and a biomechanical framework.


Synthetic capsaicin reversibly impairs vasopressin-mediated blood pressure recovery.
The vasopressin-mediated recovery of arterial pressure observed in adult rats following pharmacological blockade of the sympathetic nervous and renin-angiotensin systems is reduced by neonatal capsaicin treatment. We now demonstrate a similar but reversible effect following treatment of adult Wistar or Sprague-Dawley rats with N-vanillylnonanamide (50 mg/kg sc). One day after treatment, Wistar, but typically not Sprague-Dawley, rats had lost weight and exhibited increased sensitivity to the anesthetic effects of methohexital sodium. In both strains, captopril treatment caused hypotension. After captopril and ganglionic blockade, vasopressin-mediated recovery of arterial pressure was significantly inhibited. Furthermore, treated Wistar rats had reduced sensitivity to the ocular irritancy of N-vanillylnonanamide when examined 2 days postdose. All deficits reversed within 2 wk of dosing. These data suggest that capsaicin-sensitive systems participate in homeostatic mechanisms engaged during acute hypotension. Because the dose of N-vanillylnonanamide employed in the present study has previously been shown to destroy unmyelinated afferent fibers when administered to adult rats, recovery of the functional deficits may reflect regeneration of damaged processes or assumption of their function by undamaged neurons innervating adjacent sites. By extrapolation from other studies of capsaicin, damage to some central neurons may also be involved.


Complement inhibition in cynomolgus monkeys by anti-factor d antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration.
Anti-factor D (AFD; FCFD4514S, lampalizumab) is a humanized IgG Fab fragment directed against factor D (fD), a rate-limiting serine protease in the alternative complement pathway (AP). Evaluation of AFD as a potential intravitreal (IVT) therapeutic for dry age-related macular degeneration patients with geographic atrophy (GA) is ongoing. However, it is unclear whether IVT administration of AFD can affect systemic AP activation and potentially compromise host-immune responses. We characterized the pharmacologic properties of AFD and assessed the effects of AFD administered IVT (2 or 20 mg) or intravenous (0.2, 2, or 20 mg) on systemic complement activity in cynomolgus monkeys. For the IVT groups, serum AP activity was reduced for the 20 mg dose group between 2 and 6 hours postinjection. For the intravenous groups, AFD inhibited systemic AP activity for periods of time ranging from 5 minutes (0.2 mg group) to 3 hours (20 mg group). Interestingly, the concentrations of total serum fD increased up to 10-fold relative to predose levels following administration of AFD. Furthermore, AFD was found to inhibit systemic AP activity only when the molar concentration of AFD exceeded that of fD. This occurred in cynomolgus monkeys at serum AFD levels ≥2 µg/ml, a concentration 8-fold greater than the maximum serum concentration observed following a single 10 mg IVT dose in a clinical investigation in patients with GA. Based on these findings, the low levels of serum AFD resulting from IVT administration of a clinically relevant dose are not expected to appreciably affect systemic AP activity.


Scaffolding kidney organoids on silk.
End stage kidney disease affects hundreds of thousands of patients in the United States. The therapy of choice is kidney replacement, but availability of organs is limited, and alternative sources of tissue are needed. Generation of new kidney tissue in the laboratory has been made possible through pluripotent cell reprogramming and directed differentiation. In current procedures, aggregates of cells known as organoids are grown either submerged or at the air-liquid interface. These studies have demonstrated that kidney tissue can be generated from pluripotent stem cells, but they also identify limitations. The first is that perfusion of cell aggregates is limited, restricting the size to which they can be grown. The second is that aggregates lack the structural integrity required for convenient engraftment and suturing or adhesion to regions of kidney injury. In this study, we evaluated the capacity of silk to serve as a support for the growth and differentiation of kidney tissue from primary cells and from human induced pluripotent stem cells. We find that cells can differentiate to epithelia characteristic of the developing kidney on this material and that these structures are maintained following engraftment under the capsule of the adult kidney. Blood vessel investment can be promoted by the addition of vascular endothelial growth factor to the scaffold, but the proliferation of stromal cells within the graft presents a challenge, which will require some readjustment of cell growth and differentiation conditions. In summary, we find that silk can be used to support growth of stem cell derived kidney tissue.


Evaluation of a screening program on reduction of gastric cancer mortality in Japan: preliminary results from a cohort study.
Systematic population-based screening for gastric cancer is widely spread in Japan. However, the case-control study method has been the main method used to evaluate the effectiveness of the screen ing to reduce gastric cancer mortality in Japan. This article presents a population-based cohort study. A questionnaire about lifestyles and dietary habits was distributed to 36,990 residents in a city of Japan. The response rate to the questionnaire was 92.0%. After ineligible responders had been excluded, 24,134 subjects were classified into screened and un screened groups according to their self-reports of participation in the screening the previous year. We followed them up for 40 months and linked resident death records in the city. We compared mortality from gastric cancer and all other causes between the groups by us ing the Cox proportional hazard model. The follow-up period was 78,156.6 person-years from September 1992 to December 1995. The multivariate relative risks for gastric cancer death of the screened group in comparison with the unscreened group were 0.72 (95% CI 0.31-1.66) among males and 1.46 (95% CI 0.43-4.90) among females. Although our data are preliminary, we were unable to demonstrate a large contribution of the present screening program to decreasing gastric cancer mortality. Further follow-up is needed to in crease the precision.


Process evaluation of Healthy Bodies, Healthy Souls: a church-based health intervention program in Baltimore City.
Soaring obesity rates in the United States demand comprehensive health intervention strategies that simultaneously address dietary patterns, physical activity, psychosocial factors and the food environment. Healthy Bodies, Healthy Souls (HBHS) is a church-based, community-participatory, cluster-randomized health intervention trial conducted in Baltimore City to reduce diabetes risk among urban African Americans by promoting healthy dietary intake, increased physical activity and improvement to the church food environment. HBHS was organized into five 3-8-week phases: Healthy Beverages, Healthy Desserts, Healthy Cooking, Healthy Snacking and Eating Out and Physical Activity. A three-part process evaluation was adopted to evaluate implementation success: an in-church instrument to assess the reach, dose delivered and fidelity of interactive sessions; a post-intervention exposure survey to assess individual-level dose received in a sample of congregants and an evaluation form to assess the church food environment. Print materials were implemented with moderate to high fidelity and high dose. Program reach was low, which may reflect inaccuracies in church attendance rather than study implementation issues. Intervention components with the greatest dose received were giveaways (42.0-61.7%), followed by taste tests (48.7-53.7%) and posters (34.3-65.0%). The dose received of general program information was moderate to high. The results indicate successful implementation of the HBHS program.


Risk factors for SARS-CoV-2 seroprevalence following the first pandemic wave in UK healthcare workers in a large NHS Foundation Trust.
We aimed to measure SARS-CoV-2 seroprevalence in a cohort of healthcare workers (HCWs) during the first UK wave of the COVID-19 pandemic, explore risk factors associated with infection, and investigate the impact of antibody titres on assay sensitivity. HCWs at Sheffield Teaching Hospitals NHS Foundation Trust (STH) were prospectively enrolled and sampled at two time points. SARS-CoV-2 antibodies were tested using an in-house assay for IgG and IgA reactivity against Spike and Nucleoprotein (sensitivity 99·47%, specificity 99·56%). Data were analysed using three statistical models: a seroprevalence model, an antibody kinetics model, and a heterogeneous sensitivity model. As of 12th June 2020, 24·4% (n=311/1275) HCWs were seropositive. Of these, 39·2% (n=122/311) were asymptomatic. The highest adjusted seroprevalence was measured in HCWs on the Acute Medical Unit (41·1%, 95% CrI 30·0-52·9) and in Physiotherapists and Occupational Therapists (39·2%, 95% CrI 24·4-56·5). Older age groups showed overall higher median antibody titres. Further modelling suggests that, for a serological assay with an overall sensitivity of 80%, antibody titres may be markedly affected by differences in age, with sensitivity estimates of 89% in those over 60 years but 61% in those ≤30 years. HCWs in acute medical units working closely with COVID-19 patients were at highest risk of infection, though whether these are infections acquired from patients or other staff is unknown. Current serological assays may underestimate seroprevalence in younger age groups if validated using sera from older and/or more symptomatic individuals. Evidence before this study: We searched PubMed for studies published up to March 6th 2021, using the terms "COVID", "SARS-CoV-2", "seroprevalence", and "healthcare workers", and in addition for articles of antibody titres in different age groups against coronaviruses using "coronavirus", "SARS-CoV-2, "antibody", "antibody tires", "COVID" and "age". We included studies that used serology to estimate prevalence in healthcare workers. SARS-CoV-2 seroprevalence has been shown to be greater in healthcare workers working on acute medical units or within domestic services. Antibody levels against seasonal coronaviruses, SARS-CoV and SARS-CoV-2 were found to be higher in older adults, and patients who were hospitalised.Added value of this study: In this healthcare worker seroprevalence modelling study at a large NHS foundation trust, we confirm that those working on acute medical units, COVID-19 "Red Zones" and within domestic services are most likely to be seropositive. Furthermore, we show that physiotherapists and occupational therapists have an increased risk of COVID-19 infection. We also confirm that antibody titres are greater in older individuals, even in the context of non-hospitalised cases. Importantly, we demonstrate that this can result in age-specific sensitivity in serological assays, where lower antibody titres in younger individuals results in lower assay sensitivity.Implications of all the available evidence: There are distinct occupational roles and locations in hospitals where the risk of COVID-19 infection to healthcare workers is greatest, and this knowledge should be used to prioritise infection prevention control and other measures to protect healthcare workers. Serological assays may have different sensitivity profiles across different age groups, especially if assay validation was undertaken using samples from older and/or hospitalised patients, who tend to have higher antibody titres. Future seroprevalence studies should consider adjusting for age-specific assay sensitivities to estimate true seroprevalence rates.


The uptake of tritiated diethylstilbestrol by the brain, pituitary gland, and genital tract of the fetal macaque: a combined chromatographic and autoradiographic study.
To examine the possible sites of action of the synthetic estrogen diethylstilbestrol (DES) in the developing primate, [3H]DES (250 mu Ci, iv, or 500 mu Ci, sc) was administered directly into two rhesus and nine cynomolgus macaque fetuses at about 122 days gestation (range, 121-124 days). The location of cells accumulating radioactivity 60 min later was examined by autoradiography in two males and two females. In females, labeled neurons were observed in the hypothalamus, preoptic area, and amygdala, but not in the cerebral cortex. In one male a similar pattern of uptake was observed, but percentages of labeled neurons were lower, and in the other male very little labeling was observed in any region. The chemical identity of the radioactivity in cell nuclei was determined by high performance liquid chromatography in three males and four females. Concentrations of radioactivity in nuclear pellets were highest in the hypothalamus and lowest in the cerebral cortex. This regional variation was highly significant (P less than 0.001), but there was no significant difference between nuclear concentrations of radioactivity in males and females. In supernatant fractions, concentrations of radioactivity showed no significant variation between brain regions and after 60 min, 52-67% of the extracted radioactivity was no longer in the form of [3H]DES. Nuclear levels of radioactivity in pituitary glands and genital tracts of both male and female fetuses were 2-5 times higher than those in hypothalamus. The results demonstrated a direct interaction between DES and cell nuclei from specific regions of the brain, pituitary gland, and genital tract at this stage of gestation in a primate.


A revised probability matrix for the identification of gram-negative, aerobic, rod-shaped, fermentative bacteria.
The results of the identification of 933 strains of Gram-negative, aerobic, rod-shaped, fermentative bacteria (Enterobacteriaceae, Pasteurellaceae, Vibrionaceae) by a probabilistic method, in a computer, are given. The identification rate on the matrix was 89.2%. Many of the strains were atypical and had caused difficulty in identification in medical diagnostic laboratories. The results are given for each taxon by genus and species.


"Chaplains for Wellbeing" in Primary Care: A Qualitative Investigation of Their Perceived Impact for Patients' Health and Wellbeing.
Although Health Chaplaincy services are well-established in hospitals in the United Kingdom and across the world, Primary Care Chaplaincy is still in its infancy and much less extensively developed. This study explored the impact the introduction of a Primary Care "Chaplains for Wellbeing" service had upon patients' experience and perceived health and well-being. Sixteen patients participated in one-one interviews. Transcripts were analyzed using interpretative phenomenological analysis (IPA). Patients reported circumstances that had eroded perceived self-efficacy, self-identity, and security manifesting as existential displacement; summarized under the superordinate theme of "loss." "Loss" originated from a number of sources and was expressed as the loss of hope, self-confidence, self-efficacy, and sense of purpose and meaning. Chaplains used a wide range of strategies enabling patients to rebuild self-confidence and self-esteem. Person-centered, dignified, and responsive care offered in a supportive environment enabled patients to adapt and cope with existential displacement.


[Anatomo-pathological diagnosis of pleural mesothelioma].
The problems of the anatomo-pathological diagnosis of pleural mesotheliomas are analysed on the basis of macro- and microscopic findings. It is emphasized that histological diagnosis rests above all on the structural polymorphism of the mesothelioma and presents considerable difficulty. It is considered that systematic examinations with the electroni microscope should pave the way to more accurate diagnoses of this tumour.


Enterocytic gene expression is altered in experimental gastroschisis.
Gastroschisis is a congenital anomaly in which exposure of the intestines to amniotic fluid throughout fetal life results in nutrient malabsorption. To begin to understand the molecular basis underlying epithelial changes in this condition, we investigated enterocytic gene expression during fetal development. Gastroschisis was surgically created at 24 days gestation (term = 31 days) in fetal rabbits; sham-operated and unoperated fetuses served as controls. Bowel was harvested at 28 and 31 days gestation. Cellular lactase expression was detected using immunohistochemistry, and apolipoprotein A-I and cellular retinol binding protein II (CRBPII) mRNA levels were quantitated using Northern blot analysis. Despite absence of gross histological changes in the mucosa, lactase protein expression and apolipoprotein A-I and CRBPII mRNA expression were decreased in intestine from gastroschisis compared to sham-operated animals. Expression of GAPDH (a housekeeping gene) increased over the same period, suggesting that the changes in enterocytic absorptive gene expression associated with gastroschisis were relatively specific. In conclusion, a decrease in expression of a variety of genes involved in nutrient absorption and trafficking within the enterocyte may contribute to the absorptive defects seen in this gastroschisis.


Association of hypernatremia with mortality in patients with COVID-19: A systematic review and meta-analysis.
The COVID-19 pandemic worldwide has caused varying degrees of severity of lung damage in patients, with acute respiratory distress and death in severe cases. However, this is not directly caused by the virus itself, but by the production of inflammasome by monocytes in the body, leading to a systemic inflammatory response, which results in a very poor clinical prognosis for patients with COVID-19. The purpose of this meta-analysis was to look at the relationship between hypernatremia and mortality in COVID-19 patients. We searched the PubMed, Web of Science, Embase, and Cochrane databases for articles published from the inception of the database until August 27, 2022. Three researchers reviewed the literature, retrieved data, and assessed the quality of the literature, respectively. A meta-analysis was performed using State 17 software to assess the value of the effect of hypernatremia on mortality in patients with new coronavirus pneumonia. A total of nine publications was finally included in this study, including a total of 11,801 patients with COVID-19, including 1278 in the hypernatremia group and 10,523 in the normonatremia group. Meta-analysis showed that hypernatremia was associated with mortality in patients with COVID-19 [OR = 4.15, 95% CI (2.95-5.84), p = .002, I² = 66.7%] with a sensitivity of 0.36 [0.26, 0.48] and a specificity of 0.88 [0.83, 0.91]. The posterior probability of mortality was 42% in patients with COVID-19 hypernatremia and 15% in patients who did not have COVID-19 hypernatremia. According to available data, hypernatremia is associated with death in patients with COVID-19.


Beyond dyssynchrony in cardiac resynchronisation therapy.
Cardiac resynchronisation therapy (CRT) in the form of biventricular pacing has emerged as a therapeutic option for patients with refractory heart failure. Patient selection and optimisation for CRT is based on the measurement of electromechanical ventricular dyssynchrony by electrocardiogram and echocardiographic techniques. The final common pathway for raising cardiac output on exertion is to minimise isovolumic time and maximise useful diastolic filling time, but correction of dyssynchrony alone may not lead to global improvement in about one-third of patients. Insights into pressure relations and abnormal timing, as well as clinical management, may hold the key to optimum outcome.


Association of inflammation and tissue damage induced biological processes in masseter muscle with the resolution of chronic myalgia.
Biological processes linked to intramuscular inflammation during myogenous temporomandibular disorder (TMDM) are largely unknown. We mimicked this inflammation by intra-masseteric muscle (MM) injections of complete Freund's adjuvant (CFA) or collagenase type 2 (Col), which emulates tissue damage. CFA triggered mechanical hypersensitivity at 1d post-injection was mainly linked to processes controlling chemotactic activity of monocytes and neutrophils. At 5d post-CFA, when hypersensitivity was resolved, there was minimal inflammation whereas tissue repair processes were pronounced. Low dose Col (0.2U) also produced acute orofacial hypersensitivity that was linked to tissue repair, but not inflammatory processes. High dose Col (10U) triggered prolonged orofacial hypersensitivity with inflammatory processes dominating at 1d post-injection. At pre-resolution time point (6d), tissue repair processes were underway and a significant increase in pro-inflammatory gene expressions compared to 1d post-injection were detected. RNA-seq and flow cytometry showed that immune processes in MM were linked to accumulation of macrophages, natural killer and natural killer T cells, dendritic cells and T-cells. Altogether, CFA and Col treatments induced different immune processes in MM. Importantly, orofacial hypersensitivity resolution was preceded with repairs of muscle cell and extracellular matrix, an elevation in immune system gene expression and accumulation of distinct immune cells in MM.


Human Papillomavirus (HPV) Vaccine Acceptability in Hispanic Males Living on the U.S./Mexico Border.
The human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, and the prevalence rate of infections is approximately 79 million. Research investigating HPV vaccine acceptability has primarily focused on female populations. The current study investigates factors associated with HPV vaccine acceptability in an underrepresented population within the literature, Hispanic males. Ninety-seven male participants (Mage = 21.68 years; SD = 3.97) were recruited from a large urban university along the U.S./Mexico border to complete a 15- to 20-minute survey. More than half of the sample reported to have had a sexual experience within the past 12 months and a fifth of these participants reported that they never use protection such as condoms. Furthermore, about half of the sample reported that they did not receive the HPV vaccine or were unaware if they received the HPV vaccine. A strong correlation emerged between individual vaccine risk perceptions and family vaccine risk perceptions (r = .82; p < .001). The following factors emerged as predictors of vaccine acceptability: having recommendations from health care providers, having a family with positive attitudes toward vaccines, and having a family that perceives less risks associated with vaccines. Implications of the findings are discussed.


Hypothesis-based interventions for tantrum behaviors of persons with developmental disabilities in school settings.
We conducted a functional assessment of problem behaviors of 2 students with developmental disabilities in their classroom environments. Results of the assessments showed that although there were more tantrums in demand than in no-demand conditions, the function of the behavior was to gain attention (positive reinforcement) rather than to avoid or escape demands (negative reinforcement); demand conditions apparently served a discriminative function for the availability of attention. Therefore, intervention was based on the positive reinforcement hypothesis, resulting in a substantial reduction of tantrums for both subjects.


Development of the adaptive music perception test.
Despite vast amounts of research examining the influence of hearing loss on speech perception, comparatively little is known about its influence on music perception. No standardized test exists to quantify music perception of hearing-impaired (HI) persons in a clinically practical manner. This study presents the Adaptive Music Perception (AMP) test as a tool to assess important aspects of music perception with hearing loss. A computer-driven test was developed to determine the discrimination thresholds of 10 low-level physical dimensions (e.g., duration, level) in the context of perceptual judgments about musical dimensions: meter, harmony, melody, and timbre. In the meter test, the listener is asked to judge whether a tone sequence is duple or triple in meter. The harmony test requires that the listener make judgments about the stability of the chord sequences. In the melody test, the listener must judge whether a comparison melody is the same as a standard melody when presented in transposition and in the context of a chordal accompaniment that serves as a mask. The timbre test requires that the listener determines which of two comparison tones is different in timbre from a standard tone (ABX design). Twenty-one HI participants and 19 normal-hearing (NH) participants were recruited to carry out the music tests. Participants were tested twice on separate occasions to evaluate test-retest reliability. The HI group had significantly higher discrimination thresholds than the NH group in 7 of the 10 low-level physical dimensions: frequency discrimination in the meter test, dissonance and intonation perception in the harmony test, melody-to-chord ratio for both melody types in the melody test, and the perception of brightness and spectral irregularity in the timbre test. Small but significant improvement between test and retest was observed in three dimensions: frequency discrimination (meter test), dissonance (harmony test), and attack length (timbre test). All other dimensions did not show a session effect. Test-retest reliability was poor (<0.6) for spectral irregularity (timbre test); acceptable (>0.6) for pitch and duration (meter test), dissonance and intonation (harmony test), and melody-to-chord ratio I and II (melody test); and excellent (>0.8) for level (meter test) and attack (timbre test). The AMP test revealed differences in a wide range of music perceptual abilities between NH and HI listeners. The recognition of meter was more difficult for HI listeners when the listening task was based on frequency discrimination. The HI group was less sensitive to changes in harmony and had more difficulties with distinguishing melodies in a background of music. In addition, the thresholds to discriminate timbre were significantly higher for the HI group in brightness and spectral irregularity dimensions. The AMP test can be used as a research tool to further investigate music perception with hearing aids and compare the benefit of different music processing strategies for the HI listener. Future testing will involve larger samples with the inclusion of hearing aided conditions allowing for the establishment of norms so that the test might be appropriate for use in clinical practice.


[Congenital muscular dystrophy: clinical study of 17 patients].
We concur with the idea that congenital muscular dystrophy (CMD) is a distinct clinical entity, and report 17 patients (2 negroes and 15 whites; 12 M and 5 F; median age 6 years, range 1 to 24 years) with genetic, clinical, laboratorial, electrophysiological and histochemical studies. All our cases have an inheritance compatible with an autosomal recessive pattern. A decrease in fetal movements was reported by 57% of the mothers, generalized hypotonia at birth was present in 82%, limb girdle and neck weakness, absent or decreased deep tendon reflexes, and limb contractures were present in all. Severe muscular wasting was found in 41%. Calf pseudo-hypertrophy was observed in one patient. A patient was severely mentally retarded and another was borderline. During a 30-month follow-up, the muscle weakness of the majority remained essentially unchanged but the degree of motor activity deteriorated and was proportional to the worsening of the limb contractures. Serum CK levels were normal or increased to a maximum of 8 times. The electromyogram was myopathic in 74%, neurogenic in 13% and normal in 13%. CT scans showed a symmetrical white matter hypodensity in the hemispheres in 8 cases. All but 5 patients were operated upon to release the limb contractures and all were submitted to physical therapy. The contractures recurred in 4 patients submitted to surgery and were probably related to the cessation of physical therapy.


Apoptotic activity of genipin in human oral squamous cell carcinoma in vitro by regulating STAT3 signaling.
Genipin, a natural compound derived from the fruit of Gardenia jasminoides Ellis, was reported to have activity against various cancer types. In this study, we determined the underlying mechanism for genipin-induced cell death in human oral squamous cell carcinoma (OSCC). The growth-inhibitory effects of genipin in human OSCC cells was examined by the Cell Counting Kit-8 and soft agar assays. The effects of genipin on apoptosis were assessed by nuclear morphological changes by 4',6-diamidino-2-phenylindole staining, measurement of the sub-G1 population, and Annexin V-fluorescein isothiocyanate/propidium iodide double staining. The underlying mechanism of genipin activity was analyzed by western blot analysis, subcellular fractionation of the nucleus and cytoplasm, immunocytochemistry, and quantitative real-time polymerase chain reaction. Genipin inhibited the growth of OSCC cells and induced apoptosis, which was mediated by a caspase-dependent pathway. Genipin reduced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and its nuclear localization. Furthermore, inhibition of p-STAT3Tyr705 levels following genipin treatment was required for the reduction of survivin and myeloid cell leukemia-1 (Mcl-1) expression, leading to apoptotic cell death. The genipin-mediated reduction in survivin and Mcl-1 expression was caused by transcriptional and/or posttranslational regulatory mechanisms. The results provide insight into the regulatory mechanism by which genipin induces apoptotic cell death through the abrogation of nuclear STAT3 phosphorylation and suggest that genipin may represent a potential therapeutic option for the treatment of human OSCC.


Fine-tuning the effect of π-π interactions on the stability of the NTB phase.
The synthesis and liquid-crystalline properties are reported for novel bent-shaped dimers in which a naphthyl group has been incorporated into the mesogenic cores. In addition to the nematic and twist-bend nematic phase, a new liquid-crystalline phase was observed. The combined experimental and computational study demonstrated how the interplay between the molecular geometry and π-π interactions affects the thermal stability of the twist-bend nematic and nematic phases. Correlation between mesomorphic properties and molecular geometry revealed that a greater conformational diversity leads to a broader distribution of bend-angles and destabilization of the NTB phase. Qualitative correlation between the thermal behaviour and electronic structure of the molecules of a similar geometry suggested that the transition temperatures of both nematic phases depend on the relative contribution of dispersion and electrostatic energies which determines the strength of the π-π interactions. These results provide an insight into how subtle changes in chemical structure can be exploited to tune the intermolecular interactions and influence the thermal stability of the liquid crystalline phase.


Volatilome of Aleppo Pine litter over decomposition process.
Biogenic Volatile Organic Compounds (BVOC) are largely accepted to contribute to both atmospheric chemistry and ecosystem functioning. While the forest canopy is recognized as a major source of BVOC, emissions from plant litter have scarcely been explored with just a couple of studies being focused on emission patterns over litter decomposition process. The aim of this study was to quantitatively and qualitatively characterize BVOC emissions (C1-C15) from Pinus halepensis litter, one of the major Mediterranean conifer species, over a 15-month litter decomposition experiment. Senescent needles of P. halepensis were collected and placed in 42 litterbags where they underwent in situ decomposition. Litterbags were collected every 3 months and litter BVOC emissions were studied in vitro using both online (PTR-ToF-MS) and offline analyses (GC-MS). Results showed a large diversity of BVOC (58 compounds detected), with a strong variation over time. Maximum total BVOC emissions were observed after 3 months of decomposition with 9.18 µg gDM -1 hr-1 mainly composed by terpene emissions (e.g., α-pinene, terpinolene, β-caryophyllene). At this stage, methanol, acetone, and acetic acid were the most important nonterpenic volatiles representing, respectively, up to 26%, 10%, and 26% of total emissions. This study gives an overview of the evolution of BVOC emissions from litter along with decomposition process and will thus contribute to better understand the dynamics and sources of BVOC emission in Mediterranean pine forests.


Blockade of the renin-angiotensin-aldosterone system (RAAS) for primary prevention of non-valvular atrial fibrillation: a systematic review and meta analysis of randomized controlled trials.
The renin-angiotensin-aldosterone system is suggested to play a key role in the development of atrial fibrillation through structural and electrical remodeling. This review aims to assess the effectiveness of blockade of the renin-angiotensin-aldosterone system in the prevention of new onset atrial fibrillation. Electronic databases from 1984 onwards and previous systematic reviews were searched in addition to contacting experts in the field. Two reviewers independently selected eligible randomized controlled trials that reported on new onset atrial fibrillation, and that compared at least one of the following drugs: angiotensin-converting enzyme inhibitors, angiotensin II-receptor blockers, and aldosterone antagonists with conventional therapy or placebo. Fourteen trials including 92,817 randomized patients met the inclusion criteria. RAAS inhibition compared with conventional therapy or placebo reduced new onset atrial fibrillation (RR=0.79; 95% CI; 0.69-0.90, p-value<0.001). ARBs showed a strong effect in the reduction of onset atrial fibrillation (RR=0.78; 95% CI: 0.66-0.92, p-value=0.009), whereas results for ACE inhibitors were not as clear but likely show no effect (RR=0.79, 95% CI: 0.62-1:00, p-value: 0.05). Aldosterone antagonists, did not appear to play a role in the prevention of new onset atrial fibrillation (RR=0.77, 95%CI: 0.55-1.08, p-value: 0.21). Risk reduction was highest among heart failure patients. RAAS inhibition appears to reduce the risk of developing new onset atrial fibrillation in different patient groups with coronary artery disease. Yet these results were considered of low quality evidence and therefore further research with stronger quality trials is required to confirm current results.


Oxalamide-Functionalized Metal Organic Frameworks for CO2 Adsorption.
Metal-organic frameworks (MOFs) have received great attention in recent years as potential adsorbents for CO2 capture due to their unique properties. However, the high cost and their tedious synthesis procedures impede their industrial application. A series of new CO2-philic oxalamide-functionalized MOFs have been solvothermally synthesized: {[Zn3(μ8-OATA)1.5(H2O)2(DMF)]·5/2H2O·5DMF}n (Zn-OATA), {[NH2(CH3)2][Cd(μ4-HOATA)]·H2O·DMF}n (Cd-OATA), and {[Co2(μ7-OATA)(H2O)(DMF)2]·2H2O·3DMF}n (Co-OATA) (H4OATA = N,N'-bis(3,5-dicarboxyphenyl)oxalamide). In Zn-OATA, the [Zn2(CO2)4] SBUs are connected by OATA4- ligands into a 3D framework with 4-connected NbO topology. In Cd-OATA, two anionic frameworks with a dia topology interpenetrated each other to form a porous structure. In Co-OATA, [Co2(CO2)4] units are linked by four OATA4- to form a 3D framework with binodal 4,4-connected 42·84 PtS-type topology. Very interestingly, Cu-OATA can be prepared from Zn-OATA by a facile metal ions exchange procedure without damaging the structure while the CO2 adsorption ability can be largely enhanced when Zn(II) metal ions are exchanged to Cu(II). These new MOFs possess channels decorated by the CO2-philic oxalamide groups and accessible open metal sites, suitable for highly selective CO2 adsorption. Cu-OATA exhibits a significant CO2 adsorption capacity of 25.35 wt % (138.85 cm3/g) at 273 K and 9.84 wt % (50.08 cm3/g) at 298 K under 1 bar with isosteric heat of adsorption (Qst) of about 25 kJ/mol. Cu-OATA presents a very high selectivity of 5.5 for CO2/CH4 and 43.8 for CO2/N2 separation at 0.1 bar, 298 K. Cd-OATA exhibits a CO2 sorption isotherm with hysteresis that can be originated from structural rearrangements. Cd-OATA adsorbs CO2 up to 11.90 wt % (60.58 cm3/g) at 273 K and 2.26 wt % (11.40 cm3/g) at 298 K under 1 bar. Moreover, these new MOFs exhibit high stability in various organic solvents, water, and acidic or basic media. The present work opens a new opportunity in the development of improved and cost-effective MOF adsorbents for highly efficient CO2 capture.


Regulon: An overview of plant abiotic stress transcriptional regulatory system and role in transgenic plants.
Population growth is increasing rapidly around the world, in these consequences we need to produce more foods to full fill the demand of increased population. The world is facing global warming due to urbanizations and industrialization and in this concerns plants exposed continuously to abiotic stresses which is a major cause of crop hammering every year. Abiotic stresses consist of Drought, Salt, Heat, Cold, Oxidative and Metal toxicity which damage the crop yield continuously. Drought and salinity stress severally affected in similar manner to plant and the leading cause of reduction in crop yield. Plants respond to various stimuli under abiotic or biotic stress condition and express certain genes either structural or regulatory genes which maintain the plant integrity. The regulatory genes primarily the transcription factors that exert their activity by binding to certain cis DNA elements and consequently either up regulated or down regulate to target expression. These transcription factors are known as masters regulators because its single transcript regulate more than one gene, in this context the regulon word is fascinating more in compass of transcription factors. Progress has been made to better understand about effect of regulons (AREB/ABF, DREB, MYB, and NAC) under abiotic stresses and a number of regulons reported for stress responsive and used as a better transgenic tool of Arabidopsis and Rice.