Adhesive interactions regulate transcriptional diversity in malignant B cells.
The genetic profiling of B-cell malignancies is rapidly expanding, providing important information on the tumorigenic potential, response to treatment, and clinical outcome of these diseases. However, the relative contributions of inherent gene expression versus microenvironmental effects are poorly understood. The regulation of gene expression programs by means of adhesive interactions was studied here in ARH-77 human malignant B-cell variants, derived from the same cell line by selective adhesion to a fibronectin matrix. The populations included cells that adhere to fibronectin and are highly tumorigenic (designated "type A" cells) and cells that fail to adhere to fibronectin and fail to develop tumors in vivo ("type F" cells). To identify genes directly affected by cell adhesion to fibronectin, type A cells deprived of an adhesive substrate (designated "AF cells") were also examined. Bioinformatic analyses revealed a remarkable correlation between cell adhesion and both B-cell differentiation state and the expression of multiple myeloma (MM)-associated genes. The highly adherent type A cells expressed higher levels of NFkappaB-regulated genes, many of them associated with MM. Moreover, we found that the transcription of several MM-related proto-oncogenes is stimulated by adhesion to fibronectin. In contrast, type F cells, which display poor adhesive and tumorigenic properties, expressed genes associated with higher levels of B-cell differentiation. Our findings indicate that B-cell differentiation, as manifested by gene expression profiles, is attenuated by cell adhesion to fibronectin, leading to upregulation of specific genes known to be associated with the pathogenesis of MM.


Benefits, challenges, and needs of people living with cancer and their companion dogs: An exploratory study.
The study examined whether the bond with a companion dog is associated with well-being among people with cancer, and described the perceived benefits, challenges, and needs accompanying the relationship with the dog. The design was cross-sectional. Participants were 140 people recently diagnosed with cancer with at least one dog in their household. The online survey included measures of the human-pet bond, depressive symptoms, positive affect, and health-related quality of life, as well as open-ended questions about the experience of having a dog since being diagnosed with cancer. Although the bond with a companion dog was not directly linked with well-being, the association between the human-pet bond and depressive symptoms depended in part on treatment status. Companion dogs may play an important role in the lives of people recently diagnosed with cancer. Implications for psychosocial providers: Health care providers can help to support the bond with a companion dog.


Failure to thrive: the importance of measuring the electrolytes.
Diabetes insipidus (DI) is characterized by hypoosmotic polyuria related to deficiency of arginine-vasopressin (AVP) secretion (centraldiabetesinsipidus, CDI) or renalinsensitivity to AVP (nephrogenicdiabetesinsipidus, NDI). We report a case of a child with congenital NDI.


History dependent effects on phenotypic expression of a newly emerged gene.
In this study, we investigate the history dependence of the penetrance of a newly emerged gene. Penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that particular genotype. Here, we used the glutamine synthetase gene and its mutants with lower fitness as model genes. They were introduced into host cells of Escherichia coli deprived of the gene, and their penetrance was measured using the host having a different history: either with or without glutamine starvation. Results show that for all genes tested, the value of penetrance was higher when they were introduced into the host cell without starvation than that when introduced into the starved cell, demonstrating the history dependence of the penetrance of a newly emerged gene. In addition, genes with lower fitness showed lower penetrance, and the effect of the difference in fitness on gene penetrance also depended on the history of the host cell.


Danshensu is the major marker for the antioxidant and vasorelaxation effects of Danshen (Salvia miltiorrhiza) water-extracts produced by different heat water-extractions.
Some of the major components of Danshen (Salvia miltiorrhiza), a widely used Chinese herbal medicine rich in phenolic acids, are thermosensitive and may degrade to other phenolic acids during extractions with heating. The chemical profiles of Danshen water-extract may vary with different heat water extraction at different temperatures, affecting the composition and bioactivity of the extracts. In this study, six water-extracts of Danshen obtained from heat reflux water extraction and microwave-assisted extraction with water (MAE-W) at different temperatures were tested for their composition and pharmacological effects. Among these extracts, the third-round MAE-W (100°C) extract had the highest phenolic acids and tanshinones contents, with the strongest antioxidant activity in 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay and ferric reducing/antioxidant potential (FRAP) assay. This extract also showed the strongest inhibitory effects on 2,2'-azobis-2-amidinopropane (AAPH)-induced hemolysis in human red blood cells, hydrogen peroxide-induced apoptosis in rat heart H9c2 cells and the highest relaxation effects on rat basilar artery. The antioxidant effects of Danshen water-extracts linearly correlated to their relaxation effects (r=0.895-0.977). Through multiple linear regression analysis, danshensu was found to be the most significant marker in the antioxidant and vasodilation effects of Danshen water-extract, while tanshinone IIA as the marker on hydrogen peroxide-induced apoptosis in rat heart H9c2 cells. Danshensu is, therefore, a useful marker for the quality control of Danshen water-extracts in antioxidant and vasodilation, while tanshinone IIA for anti-apoptotic potential of different extracts.


Fear of innovation: public's perception of robotic surgery.
Robotic surgery is used in several surgical procedures with limited evidence of clinical benefit. In some jurisdictions, the demand for robotic surgery may have been fueled by public perception of this novel technology. Therefore, we sought to investigate the public's perception of robotic surgery. We conducted a cross-sectional survey using a series of vignette-associated questions designed to examine the public's perception of robotic surgery. Eligible participants were recruited through Amazon Mechanical Turk's system and randomized to one of two pairs of vignettes: laparoscopic surgery compared to (1) robotic surgery, or (2) "novel surgical technology" (without using the term "robotic"). Outcomes of interest were anticipated postoperative outcomes using the surgical fear questionnaire, procedure preference, perception of error, trust, and competency of the surgeon. The survey included 362 respondents; 64.1% were male with median age of 53 years. There were no differences in the distribution of responses of the questionnaire based on use of the term "robotic" or "novel surgical technology"; therefore, the two cohorts were combined to examine perception of robotic compared to laparoscopic surgery. More respondents feared outcomes of robotic surgery than laparoscopic surgery (78.2% vs 14.9%, p < 0.001). Participants preferred laparoscopic to robotic surgery (64.4% vs 35.6%, p < 0.001). The public fears recovery after robotic surgery and prefers laparoscopic surgery. The propagation of robotic surgery is unlikely based on public demand and may be more related to institutional or surgeon perceptions. Surgeons who provide robotic surgery should ensure their patients are comfortable with and understand this technology.


Phycotoxins: chemistry, mechanisms of action and shellfish poisoning.
Phycotoxins are natural metabolites produced by micro-algae. Through accumulation in the food chain, these toxins may concentrate in different marine organisms, including filter-feeding bivalves, burrowing and grazing organisms, herbivorous and predatory fish. Human poisoning due to ingestion of seafood contaminated by phycotoxins has occurred in the past, and harmful algal blooms (HABs) are naturally occurring events. Still, we are witnessing a global increase in HABs and seafood contaminations, whose causative factors are only partially understood. Phycotoxins are small to medium-sized natural products and belong to many different groups of chemical compounds. The molecular mass ranges from approximately 300 to over 3000 Da, and the compound classes represented include amino acids, alkaloids and polyketides. Each compound group typically has several main compounds based on the same or similar structure. However, most groups also have several analogues, which are either produced by the algae or through metabolism in fish or shellfish or other marine organisms. The different phycotoxins have distinct molecular mechanisms of action. Saxitoxins, ciguatoxins, brevetoxins, gambierol, palytoxins, domoic acid, and, perhaps, cyclic imines, alter different ion channels and/or pumps at the level of the cell membrane. The normal functioning of neuronal and other excitable tissues is primarily perturbed by these mechanisms, leading to adverse effects in humans. Okadaic acid and related compounds inhibit serine/threonine phosphoprotein phosphatases, and disrupt major mechanisms controlling cellular functions. Pectenotoxins bind to actin filaments, and alter cellular cytoskeleton. The precise mechanisms of action of yessotoxins and azaspiracids, in turn, are still undetermined. The route of human exposure to phycotoxins is usually oral, although living systems may become exposed to phycotoxins through other routes. Based on recorded symptoms, the major poisonings recognized so far include paralytic, neurotoxic, amnesic, diarrheic shellfish poisonings, ciguatera, as well as palytoxin and azaspiracid poisonings.


Usefulness of administrative databases in identifying the predictive factors of repeated hospitalizations for heart failure.
to investigate heart failure (HF) hospitalizations, the following one-year follow-up, and any possible connection between rehospitalizations due to HF and patients' characteristics derived from administrative databases. retrospective longitudinal design. the study was conducted analyzing public hospital records of a district in Abruzzo Region (Central Italy), which counts more than 300,000 inhabitants. Patients hospitalized for HF from 01.01.2016 to 31.12.2017 (index event) were included in the study and followed-up for one year. frequency of repeated hospital admissions, time intervals from the index HF hospitalizations, and causes of readmissions were investigated. a total of 1,587 patients discharged alive after an index hospitalization for HF were included in the study. The mean age of the patients was 79.6 years and the majority of them were females (53.7%). The mean length of stay (LOS) for the index hospitalizations was 8.8 ±6.8 days. During the follow-up period, 336 (21.2%) patients underwent one to four repeated hospitalizations for HF. The first readmission due to HF occurred after a median time of 106.5 days from the index event discharge, and for 20.0% of all cases it occurred within 31 days; 453 patients (28.6%) were readmitted exclusively for other causes, and 67 (4.2%) died out of hospital without any previous HF re-hospitalization. When the outcome was considered as a composite endpoint (out-of-hospital death/HF re-hospitalization), age >=75 (HR 1.737; 95%CI 1.330-2.267), LOS at the index hospitalization >=8 days (HR 1.302; 95%CI 1.066-1.591), and repeated hospitalizations for other causes (HR 1.789; 95%IC 1.465-2.185) were associated with the risk of repeated hospitalizations for HF. this study shows that about one HF patient out of five experienced at least one re-hospitalization for HF within one year from index hospitalization. In addition to having a longer index hospitalization, these patients were older and frequently suffered from comorbidities which also led to hospitalizations. The results underline the need for a close and careful follow-up after the discharge of old HF patients with multiple pathologies in order to avoid further HF admissions in a short time.


Naturally occurring coumestans from plants, their biological activities and therapeutic effects on human diseases.
Naturally occurring coumestans are known as a collection of plant-derived polycyclic aromatic secondary metabolites which are characterized by the presence of an oxygen heterocyclic four-ring system comprising a coumarin moiety and a benzofuran moiety sharing a C˭C bond. Recently, there is an increasing attention in excavating the medicinal potential of coumestans, particularly coumestrol, wedelolactone, psoralidin and glycyrol, in a variety of diseases. This review is a comprehensive inventory of the chemical structures of coumestans isolated from various plant sources during the period of 1956-2020, together with their reported biological activities. 120 molecules were collected and further classified as coumestans containing core skeleton, dimethylpyranocoumestans, furanocoumestans, O-glycosylated coumestans and others, which showed a wide range of pharmacological activities including estrogenic, anti-cancer, anti-inflammatory, anti-osteoporotic, organ protective, neuroprotective, anti-diabetic and anti-obesity, antimicrobial, immunosuppressive, antioxidant and skin-protective activities. Furthermore, this review focuses on the counteraction of coumestans against bone diseases and organ damages, and the involved molecular mechanisms, which could provide important information to better understand the medicinal values of these compounds. This review is intended to be instructive for the rational design and development of less toxic and more effective drugs with a coumestan scaffold.


The role of eosinophils in the differential diagnosis of inflammatory skin diseases.
Eosinophils are known to be present in inflammatory skin diseases, but their diagnostic utility is not well established. Upon review of the published status of lesional eosinophils, several categories were identified. 1) Lesional eosinophils highly characteristic such that, in their absence, the pathologist may question the diagnosis. These include arthropod bite reactions and scabies, urticarial dermatitis, and other eosinophilic dermatoses. 2) Lesional eosinophils rare or absent, such that, in their presence, the pathologist may question the diagnosis. These include pityriasis lichenoides, graft versus host disease, and connective tissue disorders. 3) Lesional eosinophils variable and, while in some cases expected, are not required for diagnosis. These include drug reactions, atopic dermatitis and allergic contact dermatitis. 4) Lesional eosinophils variable and not expected but may be seen to a limited extent. These include lichen planus and psoriasis.


The Vicodin abuse problem: A mathematical approach.
The prescription drug epidemic in the United States has gained attention in recent years. Vicodin, along with its generic version, is the country's mostly widely prescribed pain reliever, and it contains a narcotic component that can lead to physical and chemical dependency. The majority of Vicodin abusers were first introduced via prescription, unlike other drugs which are often experienced for the first time due to experimentation. Most abusers report obtaining their supply from a prescription, either their own or someone else's. Although the problem with prescription drug abuse is well known, there is no standard method of addressing the problem. To better understand how to do this, we develop and analyze a mathematical model of Vicodin use and abuse, considering only those patients who were initially prescribed the drug. Through global sensitivity analysis, we show that focusing efforts on abuse prevention rather than treatment has greater success at reducing the population of Vicodin abusers. Our results demonstrate that relying solely on rehabilitation and other treatment programs is not enough to combat the prescription drug problem in the United States. We anticipate that implementing preventative measures in both prescribers and patients will reduce the number of Vicodin abusers.


Prevalence of Depression in Pregnant Women with Bariatric Surgery History and Associated Factors.
To analyze the prevalence and factors associated with depressive symptoms among Brazilian pregnant women with history of bariatric surgery (BS). This is a cohort study with 247 women who got pregnant after BS. Based on data collection via Google Form, the recruitment of participants occurred in Facebook groups for 13 months. All of them answered a form with Informed Consent, a general data protocol and the Brazilian version of the Depression, Anxiety and Stress Scale-21. Descriptive and inferential analysis were performed, and a binary logistic regression model was tested to predict the factors associated with depressive symptoms. The prevalence of depressive symptoms was 32.8%, noted as being higher in the first (40.6%) and third (34.3%) gestational trimesters. Significative associations were found between depression and marital status (p = 0.000), planned pregnancy (p = 0.001), desired pregnancy (p = 0.004) and psychiatric history (p = 0.000). Women who were not married (odds ratio, OR = 3,38; p = 0.002) and had a psychiatric history (OR = 2.70; p = 0.102) had higher chances of showing depression symptoms; while planned and desired pregnancy showed as protective factors to the symptoms of depression. These findings highlight the importance of psychological assistance for pregnant women with history of BS, to prevent development of mental disorders and their outcomes for maternal-child health.


Feasibility, safety, and short-term outcome of totally thoracoscopic mitral valve procedure.
The totally thoracoscopic procedure for mitral valve (MV) disease is a minimally invasive method. We investigated the procedure's feasibility, safety and effectiveness when it was performed by an experienced operator. We retrospectively analysed 53 consecutive patients with MV disease treated between December 2014 and April 2017 by minimally invasive procedures. The procedures were performed on femoral artery-vein bypass through three 2-4 cm incisions, with one additional penetrating point on the right chest wall under totally thoracoscopic visual guidance and surveillance of transoesophageal echocardiography. Two patients who underwent intraoperative conversion to sternotomy were excluded due to indivisible pleural cavity adhesion. Of the others (38 female patients, average age, 49 ± 14 years, left ventricular ejection fraction, 59 ± 7%), 34 received MV replacement for rheumatic mitral lesions, which was redone for one patient after the discovery of serious paravalvular leakage, 17 received MV repair for mitral regurgitation (with 4 secondary to atrial septum defect, 2 diagnosed with left atrial myxoma, and 2 redone for mitral valve replacement due to repair failure), 28 received additional tricuspid valvuloplasty, and one patient received a Warden procedure. The cardiopulmonary bypass and aortic cross clamp times were 144 ± 39 min and 80 ± 22 min, respectively. Postoperational chest tube drainage in the first 48 h was 346 ± 316 ml. The ventilation time and intensive care unit stay length were 11 ± 11 h and 23 ± 2 h, respectively. One patient died of disseminated intravascular coagulation and prosthesis thrombosis with fear of anticoagulation-related bleeding. The totally thoracoscopic procedure on mitral valves by an experienced surgeon is technically feasible, safe, effective and worthy of widespread adoption in clinical practice.


Dedifferentiated fat cells differentiate into osteoblasts in titanium fiber mesh.
Mature adipocyte-derived dedifferentiated fat (DFAT) cells rapidly differentiate into osteoblasts under three-dimensional culture conditions. However, it has not been demonstrated that DFAT cells can differentiate into osteoblasts in a rigid scaffold consisting of titanium fiber mesh (TFM). We examined the proliferation and osteogenic differentiation ability of DFAT cells using TFM as a scaffold. DFAT cells derived from rabbit subcutaneous fat were seeded into TFM and cultured in osteogenic medium containing dexamethasone, L-ascorbic acid 2-phosphate and β-glycerophosphate for 14 days. In scanning electron microscopy (SEM) analysis, well-spread cells covered the titanium fibers on day 3, and appeared to increase in number from day 3 to 7. Numerous globular accretions were found and almost completely covered the fibers on day 14. Cell proliferation, as measured by DNA content in the TFM, was significantly higher on day 7 compared with that of day 1. Osteocalcin and calcium content in the TFM were significantly higher on day 14 compared to those of days 1, 3, and 7, indicating DFAT cells differentiated into osteoblasts. We theorize that globular accretions observed in SEM analysis may be calcified matrix resulting from osteocalcin secreted by osteoblasts binding calcium contained in fetal bovine serum. In this study, we demonstrated that DFAT cells differentiate into osteoblasts and deposit mineralized matrices in TFM. Therefore, the combination of DFAT cells and TFM may be an attractive option for bone tissue engineering.


EasyCloneYALI: Toolbox for CRISPR-Mediated Integrations and Deletions in Yarrowia lipolytica.
In order to unlock the full potential of Yarrowia lipolytica, as model organism and production host, simple and reliable tools for genome engineering are essential. In this chapter, the practical details of working with the EasyCloneYALI Toolbox are described.Highlights of the EasyCloneYALI Toolbox are high genome editing efficiencies, multiplexed Cas9-mediated knockouts, targeted genomic integrations into characterized intergenic loci, as well as streamlined and convenient cloning for both marker-based and marker-free integrative expression vectors.


Effects of the non-peptide inhibitor OPC-21268 on oxytocin and vasopressin stimulation of rat and human myometrium.
OPC-21268 (1-[-1-[4-(3-acetylaminopropoxy)benzoyl]-piperidyl]-3,4- dihydro-2(1H)-quinolinone), a non-peptide vasopressin V1 receptor antagonist, inhibited oxytocin- and vasopressin-induced contractions of myometrial strips from rats and from full-term pregnant women. Administered intravenously in rats the drug also inhibited uterine contractions caused by infusion of oxytocin. When incubated with purified plasma membranes from rat or human myometrial tissue, OPC-21268 inhibited the specific receptor binding of tritiated oxytocin and vasopressin in a dose-dependent and reversible way.


Molecular Mechanisms of Pyroptosis.
Pyroptosis is a regulated form of cell death that leads to inflammation and plays a role in many different diseases. Pyroptosis was initially defined by the dependence on caspase-1, a protease which is activated by innate immune signaling complexes called inflammasomes. Caspase-1 cleaves the protein gasdermin D, releasing the N-terminal pore-forming domain, which inserts into the plasma membrane. Recent studies have revealed that other gasdermin family members form plasma membrane pores, leading to lytic cell death, and the definition of pyroptosis was revised to gasdermin-dependent cell death. In this review, we discuss how the use of the term pyroptosis has changed over time, as well as currently understood molecular mechanisms leading to pyroptosis and functional consequences of this form of regulated cell death.


The ANGPTL8 rs2278426 (C/T) Polymorphism Is Associated with Prediabetes and Type 2 Diabetes in a Han Chinese Population in Hebei Province.
Our aim was to investigate the association between the genetics of the angiopoietin protein-like 8 (ANGPTL8) rs2278426 (C/T) polymorphism with prediabetes (pre-DM) and type 2 diabetes (T2DM) in a Han Chinese population in Hebei Province, China. We enrolled 1,460 participants into this case-control study: healthy controls, n = 524; pre-DM, n = 460; and T2DM: n = 460. Ligase assays on blood samples from all participants were used to identify polymorphisms. Differences in genotype and allele distributions were compared by the chi-square test and one-way analysis of variance, and a post hoc pairwise analysis was performed using the Bonferroni test. The logistic regression technique was adjusted for age, sex, and body mass index. The frequency of the TT (10.9%) genotype was significantly higher in pre-DM patients than in controls (odds ratio [OR] = 1.696, 95% confidence interval [CI] = 1.026-2.802, P=0.039). In the T2DM group, the CT (48%) and TT (15%) genotypes were significantly higher compared with those in the control group (CT : OR = 1.384, 95% CI = 1.013-1.890, P=0.041; TT : OR = 2.530, 95% CI = 1.476-4.334, P=0.001). The frequency of the T allele was significantly higher in the pre-DM (32.8%) and T2DM (39%) groups compared with the control group (26.9%) and was significantly associated with an increased risk of pre-DM (OR = 1.253, 95% CI = 1.017-1.544, P=0.034) and T2DM (OR = 1.518, 95% CI = 1.214-1.897, P=0.001). Furthermore, insulin levels in the pre-DM and T2DM groups were significantly decreased in those with the TT genotype compared with the CC and CT genotypes. ANGPTL8 rs2278426 may be involved in the mechanism of insulin secretion and could lead to an increased risk of pre-DM and T2DM.


Label-free imaging flow cytometry for analysis and sorting of enzymatically dissociated tissues.
Biomedical research relies on identification and isolation of specific cell types using molecular biomarkers and sorting methods such as fluorescence or magnetic activated cell sorting. Labelling processes potentially alter the cells' properties and should be avoided, especially when purifying cells for clinical applications. A promising alternative is the label-free identification of cells based on physical properties. Sorting real-time deformability cytometry (soRT-DC) is a microfluidic technique for label-free analysis and sorting of single cells. In soRT-FDC, bright-field images of cells are analyzed by a deep neural net (DNN) to obtain a sorting decision, but sorting was so far only demonstrated for blood cells which show clear morphological differences and are naturally in suspension. Most cells, however, grow in tissues, requiring dissociation before cell sorting which is associated with challenges including changes in morphology, or presence of aggregates. Here, we introduce methods to improve robustness of analysis and sorting of single cells from nervous tissue and provide DNNs which can distinguish visually similar cells. We employ the DNN for image-based sorting to enrich photoreceptor cells from dissociated retina for transplantation into the mouse eye.


A dynamical stochastic model of yeast translation across the cell cycle.
Translation is a central step in gene expression, however its quantitative and time-resolved regulation is poorly understood. We developed a discrete, stochastic model for protein translation in S. cerevisiae in a whole-transcriptome, single-cell context. A "base case" scenario representing an average cell highlights translation initiation rates as the main co-translational regulatory parameters. Codon usage bias emerges as a secondary regulatory mechanism through ribosome stalling. Demand for anticodons with low abundancy is shown to cause above-average ribosome dwelling times. Codon usage bias correlates strongly both with protein synthesis rates and elongation rates. Applying the model to a time-resolved transcriptome estimated by combining data from FISH and RNA-Seq experiments, it could be shown that increased total transcript abundance during the cell cycle decreases translation efficiency at single transcript level. Translation efficiency grouped by gene function shows highest values for ribosomal and glycolytic genes. Ribosomal proteins peak in S phase while glycolytic proteins rank highest in later cell cycle phases.


Ectopic pregnancy: Review of 80 cases.
Ectopic pregnancy or extrauterine pregnancy will invariably result in abortion or rupture. Though there are risk factors for ectopic pregnancy, but at times the condition can occur without any apparent predisposing factor. Cases admitted with provisional diagnosis of ectopic pregnancy were included in this prospective study. Eighty suspected cases of ectopic pregnancy were incorporated in the study. The management was done based on standard practice. All the cases underwent urine pregnancy test, routine blood investigations including blood group, and transvaginal ultrasound. Serial βhCG was measured in cases where the diagnosis was not clear initially. Incidence of ectopic was 2.46 per 100 deliveries; there was no apparent risk factor in 28.7% and many cases had more than one risk factor. 'Triad' of ectopic was present in only 21 cases. Sixteen cases were asymptomatic and two were admitted as emergency. Ultrasound findings were inconsistent and wide ranging. In 37 doubtful cases, βhCG was measured serially.There was one case of suspected interstitial pregnancy confirmed on laparoscopy. Twenty-seven cases were managed medically, and 9 were managed expectantly. Forty-six cases were managed surgically either by laparoscopy or by laparotomy. Salpingectomy was performed in 37 cases, and salpingostomy in 7 cases either laparoscopically or by laparotomy. Ectopic pregnancy can be managed by laparotomy, operative laparoscopy, and medically and occasionally by observation alone. Management must be customized to the clinical condition and needs of future fertility of the patient.


Impact of dedicated brain PET on intended patient management in participants of the national oncologic PET Registry.
This study seeks to assess the impact of dedicated brain positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose on intended management of patients with primary and metastatic brain tumors. We analyzed demographic characteristics and evaluated change in intended management after PET, using previously described metrics, for patients in the National Oncologic PET Registry (NOPR) undergoing dedicated brain PET. For cases of primary brain tumors, comparisons to the overall NOPR cohort were made. PATIENT PROFILE: Between December 2006 and April 2009, 509 dedicated brain PET scans were done on 479 patients--367 (72.1%) for suspected or proven primary brain tumors and 142 (27.9%) for brain metastases. Compared with the overall NOPR cohort, subjects in the dedicated brain cohort were younger (41.3% less than 65 years vs. 10.5% overall, p < 0.0001) and more frequently had functional limitations from their cancers (78.6% vs. 62.3% overall; odds ratio (OR) 2.2, 95% CI 1.8-2.8). The pre-PET patient management plans in the primary brain tumor and metastasis subgroups were similar. A pre-PET plan of tissue biopsy was slightly more frequent than one of the treatments (31.3% vs. 28.6%) in the primary brain tumor subgroup and was more common than in the overall NOPR cohort (14.2%; OR 2.8, 95% CI 2.2-3.5). Changes from treatment to non-treatment also were more frequent than in the overall NOPR cohort (13.4% vs. 7.7%; OR 1.9, 95% CI 1.3-2.5). Among NOPR patients, dedicated brain PET was associated with similar net changes in intended management as in the overall NOPR cohort. However, brain PET patients were younger, more likely to be symptomatic, and less likely to have a change in management from non-treatment to treatment as a post-PET plan.


Time-dependent changes in the seroprevalence of COVID-19 in asymptomatic liver disease outpatients in an area in Japan undergoing a second wave of COVID-19.
Coronavirus disease 2019 (COVID-19) is a serious public health concern, with unclarified prevalence in Japan. Concomitant liver disease could increase the severity of COVID-19 disease, and chronic liver disease patients sometimes require frequent admission and gastrointestinal endoscopy. Thus, clarifying the prevalence of asymptomatic COVID-19 in outpatients with liver disease is essential for preventing nosocomial infections. We aimed to clarify the time-dependent changes in COVID-19 seroprevalence in liver disease outpatients, who were asymptomatic for COVID-19, in an area of Japan experiencing a second wave of COVID-19. We included the preserved sera of 100, 300, and 300 consecutive liver disease outpatients, who were asymptomatic for COVID-19, from May 2019, March 2020, and May 2020, respectively. The sera were analyzed immunochromatographically to detect immunoglobulin G against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (KURABO) and by Elecsys Anti-SARS-CoV-2-assay (Roche Diagnostics). Analysis of 100 cases from May 2019, before COVID-19 became pandemic, revealed that the specificity of immunochromatographic tests and Elecsys were 98% (95% confidence interval [CI], 93-99.8%) and 100% (95% CI, 97-100%), respectively. Analysis of 300 cases from March 2020 revealed a seroprevalence of 0.3% (1/300; 95% CI, 0-1.8%) for COVID-19 by Elecsys Anti-SARS-CoV-2 assay. Analysis of 300 cases from May 2020 revealed a seroprevalence of 0% (0/300; 95% CI, 0-1.0%). The Elecsys Anti-SARS-CoV-2 assay has high specificity. The cumulative seroprevalence of COVID-19 by the Elecsys Anti-SARS-CoV-2 assay in outpatients with liver disease in Sapporo, who were asymptomatic for COVID-19, was 0.17% (1/600; 95% CI, 0.0-0.9%) until May 2020.


Neurobiological Considerations of the mode of action of lithium carbonate in the treatment of affective disorders?
The effects of lithium on membrane function and cellular processes are considered in relation to lithium's physiochemical properties. Several cellular regulatory functions, including cyclic AMP formation and metabolism and biogenic amine neurotransmitter metabolism, are examined as possible mechanisms whereby lithium might exert its mood stabilizing actions. The necessity for understanding lithium's interactions with "receptors" - the molecular sites affected by lithium - in considering its pre-and post-synapatic effects in stressed.


Using game theory and decision decomposition to effectively discern and characterise bi-locus diseases.
In order to gain insight into oligogenic disorders, understanding those involving bi-locus variant combinations appears to be key. In prior work, we showed that features at multiple biological scales can already be used to discriminate among two types, i.e. disorders involving true digenic and modifier combinations. The current study expands this machine learning work towards dual molecular diagnosis cases, providing a classifier able to effectively distinguish between these three types. To reach this goal and gain an in-depth understanding of the decision process, game theory and tree decomposition techniques are applied to random forest predictors to investigate the relevance of feature combinations in the prediction. A machine learning model with high discrimination capabilities was developed, effectively differentiating the three classes in a biologically meaningful manner. Combining prediction interpretation and statistical analysis, we propose a biologically meaningful characterization of each class relying on specific feature strengths. Figuring out how biological characteristics shift samples towards one of three classes provides clinically relevant insight into the underlying biological processes as well as the disease itself.


Once daily ganciclovir as initial pre-emptive therapy delayed until threshold CMV load > or =10000 copies/ml: a safe and effective strategy for allogeneic stem cell transplant patients.
Quantitative polymerase chain reaction (QPCR) for cytomegalovirus (CMV) is emerging as the preferred screening method for detection of CMV viremia in patients following allogeneic bone marrow and peripheral blood stem cell transplant. However, there are currently no universally accepted QPCR treatment thresholds at which to start pre-emptive therapy. We report here results of a pre-emptive therapy strategy using ganciclovir (GCV) 5 mg/kg initiated once daily (ODG) delayed till a threshold CMV load of > or =10 000 copies/ml whole blood in clinically stable patients. Sixty-nine at risk patients underwent allogeneic stem cell transplant. 48/69 (70%) patients had an initial episode of CMV viremia. 5/48 (10%) cleared viremia without requiring treatment. 28/43 (65%) patients requiring treatment initiated treatment with ODG. 17/28 (61%) patients successfully cleared CMV viremia on ODG, 10/28 (36%) patients required dose escalation to twice daily GCV for increasing viral loads. There were two cases of CMV disease (colitis) and no deaths due to CMV disease in patients initiating treatment with ODG. We conclude delaying pre-emptive therapy with ODG until whole blood QPCR> or =10 000 copies/ml is a safe and effective strategy for CMV viremia after allogeneic stem cell transplant in clinically stable patients.


Susceptibility of Ochlerotatus taeniorhynchus (Diptera: Culicidae) to infection with epizootic (subtype IC) and enzootic (subtype ID) Venezuelan equine encephalitis viruses: evidence for epizootic strain adaptation.
To test the hypothesis that adaptation to epizootic mosquito vectors mediates emergence of Venezuelan equine encephalitis virus (VEEV) from enzootic progenitors, experimental infection studies were conducted to determine the susceptibility of Ochlerotatus taeniorhynchus (Wiedemann) to epizootic and enzootic strains. Artificial blood meals containing epizootic subtype IC strains isolated during the 1962-1964, 1992-1993, and 1995 Venezuelan/Colombian epizootics and closely related Venezuelan enzootic subtype ID strains were used to compare infectivity and transmission potential. Their greater infectivity and replication suggested that adaptation of epizootic strains to Oc. taeniorhynchus may have enhanced epizootic transmission during the 1962-1964 and 1995 IC coastal epizootics. However, strains from the small 1992-1993 Venezuelan outbreak that did not extend to coastal regions do not seem to infect this species better than closely related subtype ID strains. Adaptation of VEEV to epizootic vectors such as Oc. taeniorhynchus mosquitoes may be a determinant of some but not all VEE emergence events and may influence spread into coastal regions.


Evolutionary and functional perspectives of the major histocompatibility complex class I antigen-processing machinery.
Major histocompatibility complex (MHC) class I molecules present antigenic peptides to CD8+ T cells, providing the basis for immune recognition of pathogen-infected cells. Peptides generated mainly by proteasomes in the cytosol are transported into the lumen of the endoplasmic reticulum by transporters associated with antigen processing (TAP). The maturation of MHC class I molecules is controlled by a number of accessory proteins and chaperones that are to a varying degree dedicated to the assembly of MHC class I. Several newly characterised proteins have been demonstrated to play important roles in this process. This review focuses on the functional relationship and evolutionary history of the antigen-processing machinery (APM) components and MHC class I itself. These are of great interest for further elucidating the origin of the immune system and understanding the mechanisms of antigen presentation and immunology in general.


[Continuous-flow determination of delta-aminolevulinic acid in urine (author's transl)].
The automatic determination of urinary ALA using a continuous flow methodology, is described. The amplification of the measured signal, with an adjusted range expander, allows to reduce the sample volume and to decrease drastically the effects of interfering substances. The results are compared with the reference method of Davis and Andelman [11].


Anionic nanoparticle and microplastic non-exponential distributions from source scale with grain size in environmental granular media.
Nanoparticle and microplastic (colloid) transport behaviors impact strategies for groundwater protection and remediation. Complex colloid transport behaviors of anionic nano- and micro-sized colloids have been previously elucidated via independent experiments in chemically-cleaned and amended granular media with grain sizes in the range of fine to coarse sand (e.g., 200-1000 μm). Such experiments show that under conditions where a repulsive barrier was present in colloid-collector interactions (unfavorable conditions), the distribution of retained colloids down-gradient from their source deviates from the exponential decrease expected from compounded loss across a series of collectors (grains). Previous experiments have not examined the impact of colloid size or granular media grain size on colloid distribution down-gradient from their source, particularly in streambed-equilibrated granular media. To address this gap, a field transport experiment in constructed wetland stream beds to distances up to 20 m were conducted for colloids ranging in size from micro to nano (60 nm-7 μm) in streambed-equilibrated pea gravel and sand (4200 and 420 μm mean grain sizes, respectively). All colloid sizes showed non-exponential (hyper-exponential) distributions from source, over meter scales in pea gravel versus cm scales reported for fine sand. Colloids in the ca. 1 μm size range were most mobile, as expected from mass transfer to surfaces and interaction with nanoscale heterogeneity. The distance over which non-exponential colloid distribution occurred increased with media grain size, which carries implications for the potential mechanism driving non-exponential colloid distribution from source, and for strategies to predict transport.


[Adipose-derived stromal cells: history, isolation, immunomodulatory properties and clinical perspectives].
Over the last decade, the clinical use of adipose-derived stromal/stem cells (ASC) in regenerative medicine is rapidly increasing. ASC belong to the mesenchymal stromal cells initially obtained from the bone marrow. Their limited differentiation capacity in vivo into functional mature cells has led to a reassessment of their mechanisms of action. One of the major clinical interests appears related to paracrine effects through a temporary production of trophic and immunomodulatory factors. Our purpose is to provide a review on the latest knowledge in the field of ASC, mechanisms of action, mainly immunomodulatory/immunosuppressive properties, methods of obtention, with a focus on clinical perspectives particularly in the field of cellular therapy and fat grafting technique in plastic surgery.


Identification of entomopathogenic bacteria associated with the invasive pest Drosophila suzukii in infested areas of Germany.
The invasive insect pest Drosophila suzukii causes extensive damage to soft-skinned fruit crops as they ripen. Current control methods involve the application of chemical pesticides, but this approach is ineffective and environmentally hazardous. To investigate the potential of bacterial pathogens carried by D. suzukii as biocontrol agents, we characterized bacteria associated with D. suzukii larvae in two parts of Hesse, Germany, by collecting infested fruits and culturing individual bacteria from moribund specimens for taxonomic classification by 16S rDNA sequencing. Among the bacteria we detected, some had a detrimental effect on the host whereas others were neutral or beneficial. When the detrimental and beneficial bacteria were presented simultaneously, we observed complex tripartite interactions that modulated the insect's innate immune response. Our study provides insight into the complex relationships within the microbiome and pathobiome of D. suzukii and may lead to the isolation of bacteria that can be used as biological control agents.


Western Blotting of Membrane-Bound Proteins in Yarrowia lipolytica.
With the discovery of Western blotting as first described by Towbin et al. in 1979, the transfer and visualization of electrophoretically separated proteins on membranes has become the de facto method for the qualitative and quantitative detection of proteins of interest. In this method, proteins are resolved by electrophoresis on a polyacrylamide gel, followed by a transfer of the separated proteins onto a nitrocellulose or polyvinyl difluoride (PVDF) membrane. Once immobilized on these membranes, the protein of interest can be detected and visualized by exploiting antigen-antibody interactions. However, not all proteins are amenable to easy detection by Western blotting. Integral membrane proteins are a class of proteins that are attached to a biological membrane through a series of transmembrane segments that span the width of the membrane. Due to the inherent hydrophobicity of these proteins and their tendency to aggregate, the characterization and detection of these proteins can be challenging. In this methods chapter, we present a protocol for the easy detection and quantification of these proteins in the industrially important oleaginous yeast Yarrowia lipolytica. The first protocol describes a Western blotting procedure to quantify soluble cytosolic proteins of interest in Yarrowia lipolytica from its total cell lysate. The second protocol describes modifications to the first that are done to enhance detection and quantification of membrane-bound proteins in Yarrowia lipolytica from its total cell lysate, without the need for isolating the membrane-bound proteins, for use in Western blotting. The immunoblotting strategies described here should serve as an efficient and simple guide to quantify both cytosolic and the intractable membrane-bound proteins in Yarrowia lipolytica.


The Chriz-Z4 complex recruits JIL-1 to polytene chromosomes, a requirement for interband-specific phosphorylation of H3S10.
The conserved band-interband pattern is thought to reflect the looped-domain organization of insect polytene chromosomes. Previously, we have shown that the chromodomain protein Chriz and the zinc-finger protein Z4 are essentially required for the maintenance of polytene chromosome structure. Here we show that both proteins form a complex that recruits the JIL-1 kinase to polytene chromosomes, enabling local H3S10 phosphorylation of interband nucleosomal histones. Interband targeting domains were identified at the N-terminal regions of Chriz and Z4, and our data suggest partial cooperation of the complex with the BEAF boundary element protein in polytene and diploid cells. Reducing the core component Chriz by RNAi results in destabilization of the complex and a strong reduction of interband-specific histone H3S10 phosphorylation.


Delivery of maternal thyroid hormones to the fetus.
Thyroid hormones (THs) play an essential role in ensuring normal fetal development, particularly that of the central nervous system. Before 16 weeks gestation, the fetus relies solely on transplacental delivery of maternal T(4), and clinical studies suggest that even mild maternal thyroid hormone deficiency adversely affects the intellectual function of offspring. Maternofetal TH transfer is regulated by trophoblast cell membrane transporters, which mediate influx and efflux of THs, placental deiodinases D3 and D2, which control intraplacental TH levels, and TH-binding proteins (transthyretin), which provide transport roles in the placenta. This review discusses new information about mechanisms of transplacental delivery of T(4) to the fetus, providing insight into complex processes that are vitally important for normal fetal development.


Reliability and Validity of Digital Images to Assess Child Dietary Intake in a Quick-Service Restaurant Setting.
Development of methods to accurately measure dietary intake in free-living situations-restaurants or otherwise-is critically needed to understand overall dietary patterns. This study aimed to develop and test reliability and validity of digital images (DI) for measuring children's dietary intake in quick-service restaurants (QSRs), validating against weighed plate waste (PW) and bomb calorimetry (BC). In 2016, cross-sectional data were collected at two time points within a randomized controlled trial assessing children's leftovers in QSRs from parents of 4- to 12-year-old children. Parents (n = 640; mean age = 35.9 y; 70.8% female) consented and agreed to provide their child's PW for digital imaging, across 11 QSRs in Massachusetts in areas with low socioeconomic status and ethnically diverse populations. Outcome measures were interrater reliability for DIs, correspondence between methods for energy consumed and left over, and correspondence between methods across varying quantities of PW. Intraclass correlations, percent agreement, Spearman correlations, Wilcoxon signed rank tests, and Bland-Altman plots were used. Interrater reliability ratings for DIs had substantial intraclass correlations (ICC = 0.94) but not acceptable exact percent agreement (80.2%); DI and PW energy consumed were significantly correlated (r = 0.96, P < 0.001); DI slightly underestimated energy consumed compared with PW (Mdiff = -1.61 kcals, P < 0.001). Bland-Altman plots showed high DI-PW correspondence across various energy amounts and revealed few outliers. Energy left over by BC was highly correlated with DI (r = 0.87, P < 0.001) and PW (r = 0.90, P < 0.001); and mean differences were not significantly different from DI (Mdiff = 9.77 kcal, P = 0.06) or PW (Mdiff = -2.84 kcal, P = 0.20). Correspondence was high between PW and DI assessments of energy consumed, and high with BC energy left over. Results demonstrate reliability and practical validity of digital images for assessing child meal consumption in QSR settings.


Challenges nurse educators experience with development of student nurses' clinical reasoning skills.
Traditional teacher-centred teaching strategies do not always facilitate the development of desired clinical reasoning skills required for nursing practice. A multiphase study was conducted to facilitate a process of change towards improving educational practices in order to promote the development of undergraduate student nurses' clinical reasoning skills. The study was conducted at a military nursing education institution. This paper reflects on Phase 1, where a descriptive, qualitative study was conducted to explore the challenges nurse educators experienced in utilizing teaching and learning strategies that could promote the development of clinical reasoning skills in undergraduate student nurses. Unstructured interviews were conducted with 16 nurse educators who were selected purposively. Interviews were recorded, transcribed and data were analysed for content. The findings indicate that the clinical learning environment, the military environment, and various role players in the environment are instrumental in nurse educators not utilizing educational practices that promote the development of clinical reasoning skills in undergraduate student nurses. Addressing nurse educator challenges and empowering them with the means, opportunity and skills to utilize student-centred teaching and learning strategies may contribute to the development of undergraduate student nurses' clinical reasoning skills. Raising awareness of challenges nurse educators experience in implementing student-centred facilitation of learning can assist in developing strategies to ensure nurse educators become more student-centred in their teaching.


Primary disorder of vigilance: a novel explanation of inattentiveness, daydreaming, boredom, restlessness, and sleepiness.
We present a novel condition, designated as a primary disorder of vigilance, that has symptoms which overlap those of attention deficit-hyperactivity disorder. Vigilance is the state of being watchful, awake, and alert. When vigilance is lost, the individual has difficulty sustaining attention. The most obvious evidence of lowered vigilance is motor restlessness (fidgeting and moving about, yawning and stretching, talkativeness, or a combination of these) to improve alertness when sitting or standing still or when involved in tasks requiring continuous mental performance. When prevented from being active to stay awake, persons with lowered vigilance will stare off, daydream, show minor hyperactivity, and finally may fall asleep. They will also have decreasing attention to current activities and usually avoid or lose interest in structured or repetitive activities (complaining of boredom and monotony). The primary disorder of vigilance (for which criteria have been established) is a dominantly inherited condition with onset in early childhood and worsening symptoms with age. Persons with the primary disorder of vigilance have a remarkably kind and caring temperament. When untreated this disorder can cause chronic failure at school and work, but when properly recognized it responds well to treatment with stimulant medication and schedules that avoid sameness and repetition.


Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice.
Fas is an apoptosis-signalling cell surface antigen that has been shown to trigger cell death upon specific ligand or antibody binding. Treatment of mice with an anti-Fas antibody causes fulminant hepatic failure due to massive apoptosis. To test a putative protective effect of the anti-apoptotic Bcl-2 protein, transgenic mice were generated to express the human bcl-2 gene product in hepatocytes. Early onset of massive hepatic apoptosis leading to death was observed in all nontransgenic mice treated with an anti-Fas antibody. By contrast, hepatic apoptosis was delayed and dramatically reduced in transgenic animals, yielding a 93% survival rate. These results demonstrate that Bcl-2 is able to protect from in vivo Fas-mediated cytotoxicity, and could be of significance for preventing fulminant hepatic failure due to viral hepatitis in humans.


Decline Is Not Inevitable: Exercise Capacity Trajectory in an Australian and New Zealand Fontan Cohort.
In people with a Fontan circulation, serial cardiopulmonary exercise testing (CPET) to evaluate change in peak exercise capacity has been increasingly recognised as a useful prognostic tool; a decline is associated with adverse clinical outcomes. The aim of this study is to describe the "natural" history of exercise capacity in the Australian and New Zealand (ANZ) Fontan cohort and to identify factors associated with a decline. The ANZ Fontan registry was retrospectively reviewed for adolescent and adult patients (≥16 years) with serial CPET results performed on a cycle ergometer ≥6 months apart. Patients were excluded if they underwent a surgical procedure or fenestration closure in-between tests or if the tests were considered as submaximal effort. Exercise capacity trajectory was defined as the change in percentage of predicted peak oxygen uptake (% pred VO2peak) points per year. Thirty-seven (37) patients (59.5% male, mean age 24±7 years) were eligible. Average duration between CPET was 5.3±3.9 years. At baseline, % pred VO2peak was 61.3±14.5%. Thirteen (13) (35%) had a systemic right ventricle, and 14 (38%) had an atriopulmonary type Fontan circulation. Average change in % pred VO2peak overall was +1.3±6.4 percentage points per year. Sixteen (16) had a negative exercise capacity trajectory, and the average decline in that group was -2.7±3.4 percentage points per year. There was no association between exercise capacity trajectory and clinical characteristics. Of the 18 patients with physical activity levels recorded, 12 (67%) were physically active and % pred VO2peak in that group increased by 2.7±4.0 percentage points per year compared with the physically inactive group who fell by 0.5±0.8 percentage points per year. In this ANZ series of Fontan patients, over half of our cohort had stable, or an increase, in peak exercise capacity. Regular participation in physical activity was common in patients with a positive exercise capacity trajectory. Clinical characteristics were not associated with exercise capacity trajectory.


Ethical perspectives of sustaining residents' autonomy: a cultural transformation best practice.
Baby boomers are demanding changes in care delivery models that reflect patient autonomy, individuality, and dignity. To meet this challenge, the Veterans Administration has adopted a cultural transformation model of patient-centered care. Veterans Administration nursing homes are now community living centers; the staff's mission is to deliver patient-centered care in a homelike environment. How the challenge was met and how the ethics committee helps to sustain the changes, are discussed in this article.


New highly-percolating alginate-PEI membranes for efficient recovery of chromium from aqueous solutions.
Highly percolating membranes are prepared by the interaction of polyethylenimine and alginate (with glutaraldehyde crosslinking). SEM illustrates the macroporous structure of the material. The material is characterized by FTIR before and after chromate anions sorption. Batch-simulated continuous sorption experiments revealed that the maximum sorption occurred at pH 2 and the flow rate has limited effect on sorption efficiency. Uptake kinetics and sorption isotherms are well fitted by the pseudo-second-order rate and Sips equations, respectively. Maximum sorption is found close to 314 mg g-1. Competition effects from Ca(II), Cu(II), Cl-, NO3-, and SO42- are investigated to evaluate sorbent selectivity. The membranes are applied to remediate a simulate of Cr(VI) contaminated electroplating wastewater. Successive cycles of sorption and desorption show that the membranes maintain sorption capacity higher than 200 mg Cr g-1 for both Cr(VI) and total chromium for the first two cycles. These new highly percolating membranes have promising performances for Cr(VI) removal.


Interaction between arginase and L-ornithine carbamoyltransferase in Saccharomyces cerevisiae. The regulatory sites of arginase.
The inhibition of ornithine carbamoyltransferase by arginase in Saccharomyces cerevisiae, which is under the control or arginine and ornithine, involves a regulatory site for arginine on the arginase distinct from its catalytic site. This regulatory site is responsible for the reinforcement effect of arginine on the inhibition of ornithine carbamoyltransferase by arginase. The binding site of ornithine carbamoyltransferase on arginase is also shown by our analysis.


Silica-assisted cross-linked polymer electrolyte membrane with high electrochemical stability for lithium-ion batteries.
This study aims to prepare an organic-inorganic reticular polymer electrolyte. Isocyanate acts as a bridge that connects fumed silica and PEO molecular chains. The PEO-TDI-SiO2 solid polymer electrolytes developed can significantly have improved ionic conductivity of 0.12 mS cm-1 at ambient temperature. This is because the TDI-SiO2 nanoparticles inhibits polymer crystallization which provides more continuous Li-ion transport pathways. Tests at 60 °C indicate that the cross-linked structure of covalent TSI bonded to PEO effectively enlarges the electrochemical window of the polymer electrolyte to 5.6 V. Also, the PTSI electrolyte membrane has a higher Li+ transference number of 0.33 compared to the PEO-LiTFSI electrolytes. It is worth noting that the assembled LiFePO4|PTSI8%|Li cells deliver outstanding rate performance and stable cycling performance. All these considerable merits of PTSI membrane demonstrate that PTSI is a promising candidate that can be used as solid polymer electrolytes for the next-generation Li-ion batteries.


Vancomycin-aminoglycoside combinations in therapy of endocarditis caused by Enterococcus species and Streptococcus bovis.
Between 1974 and 1986, five patients with enterococcal endocarditis (three of whom had a prosthetic valve) and three patients with Streptococcus bovis endocarditis were treated with a combination of vancomycin and an aminoglycoside for a mean duration of 40 days. This regimen was prescribed because of allergy to beta-lactam (n = 7) and/or failure of previous treatment (n = 4). Three of the eight patients underwent valve replacement. In the six evaluable patients cure was achieved with the vancomycin-aminoglycoside combination. An increase of the creatinine serum levels was observed in all cases but it was never necessary to discontinue treatment, adjustment of the vancomycin and aminoglycoside dosage according to the serum and/or serum creatinine levels allowing continuation of therapy.


Reduction of seizures and normalization of the EEG in a severe epileptic following sensorimotor biofeedback training: preliminary study.
Sensorimotor rhythm (SMR) biofeedback training was attempted in a 13-year-old male with frequent epileptic seizures. Prior to training the subject was averaging almost eight clinical seizures an hour. The SMR filter was tuned sharply to 12 plus or minus 1 Hz. Feedback was conducted over approximately six months and continues to the present. In that time the subject's percentage of SMR increased from about 10%, prior to training, to 65% after the 34th training session. Correspondingly, his rate of clinical seizures decreased by a factor of 10 and a significant reduction in percentage of epileptiform discharges was noted. Beginning with trial 35, the subject was provided feedback of epileptiform activity in combination with 12 Hz activity. The combined effect of these two treatment variables was to reduce the trial-to-trial variance in the dependent variables of interest.


Changes in the type II and type I collagen messenger RNA population during growth of chondrocytes in 5-bromo-2-deoxyuridine.
The collagen mRNA population of cultured chick chondrocytes was examined during a 5-bromo-2-deoxyuridine-induced shift in the type of collagen synthesized. When a cell-free protein-synthesizing system was used, it was found that an increase in the translatable mRNA for type I collagen [alpha 1 (I)]2 alpha 2 was correlated with the onset of the synthesis of this collagen type by intact cells. It was also found, both in vivo and in vitro, that a normal 2:1 ratio of type I subunits is not synthesized at early times in the type II to type I shift but that the alpha 1 (I) subunit is found in excess. It would appear, therefore, that the expression of these complementary subunits is not tightly coordinated.


Clinical importance and therapeutic implication of E-cadherin gene methylation in human ovarian cancer.
E-cadherin (E-cad) is widely expressed in epithelial cells and acts as a pivotal tumor suppressor. The promoter methylation of E-cad has been reported to closely relate to its downregulation in many kinds of cancers. E-cad expression and methylation status were detected by immunohistochemistry (IHC) and methylation-specific polymerase chain reaction (MS-PCR) in 50 ovarian cancer tissues. 5-Aza-2'-deoxycytidine (5-Aza-dC) was used to demethylate E-cad in SKOV3 and ES2 ovarian cancer cell lines, of which the effect was verified by Western blot and MS-PCR. Then MTT and transwell experiments were conducted to detect the capacity of cell proliferation and migration for these cells. Downregulation of E-cad expression was observed in 60 % of ovarian cancer tissues (30/50) by IHC, whereas MS-PCR result indicated that E-cad was methylated in 64 % of (32/50) ovarian cancer specimens. And E-cad expression was significantly correlated with E-cad methylation (P = 0.004). 5-Aza-dC was used to process SKOV3 and ES2 ovarian cancer cell lines. By MTT experiment, we found that the proliferation of 5-Aza-dC-treated SKOV3 and ES2 was significantly suppressed by 28.0 % (P < 0.05) and 32.3 % (P < 0.05). By transwell experiment, the motility of SKOV3 and ES2 was found to be significantly suppressed by 38.2 and 27.4 % (P < 0.05), respectively, after treated with 5-Aza-dC. E-cad methylation is one of the main reasons for the expression reduction in ovarian cancer. 5-Aza-dC treatment could significantly restore the expression of E-cad and suppress growth and invasion of SKOV3 and ES2 cells. These results suggest E-cad methylation may be a promising target for ovarian cancer therapy.


A comparative study of stage characteristics and factorial decomposition of CO2 emissions between China and the USA.
CO2 contributes a lot to the greenhouse effect. The total CO2 emissions of the two countries, China and the USA, as the world's top two economies, have exceeded 40% of the total global carbon emissions. In this context, the exploration of the evolution of carbon emissions from energy consumption in China and the USA and the comparison of the characteristics of carbon emission drivers in different periods play a significant role in the policy formulation and climate change cooperation between China and the USA. In this study, the BP structural breakpoint test was used to divide the carbon emission stages of China and the USA from 1970 to 2019. The generalized Divisia index model (GDIM) was developed to decompose the growth of carbon emissions in China and the USA into eight items, GDP, carbon intensity of GDP, energy use, carbon intensity of energy, population, carbon emissions per capita, GDP per capita, and energy intensity, and to analyze the characteristics and cumulative contribution of carbon emission drivers at each stage. Based on the stage and cumulative characteristics of carbon emissions between China and the USA, the USA should take the initiative to assume the legal responsibility of carbon emissions and further deepen the cooperation with other countries in the field of climate change. China should transform the economic growth mode, optimize the energy structure, and improve the efficiency of resource utilization to help achieve the peaking carbon emissions and the carbon neutrality smoothly.


Quantification of proteins using data-independent analysis (MSE) in simple andcomplex samples: a systematic evaluation.
A MS-based method for the quantification of proteins termed data-independent analysis (or MS(E)) has been introduced recently. Although this method has been applied to the analysis of various types of biological samples, a thorough evaluation to assess the performance of this approach has yet to be conducted. Presented here is the first systematic and comprehensive study investigating the MS(E) approach for quantitative analysis of low-, medium-, and high-complexity samples. We demonstrate that this method has a linear dynamic range spanning three orders of magnitude with a limit of quantification of 61 amol/uL in low-complexity samples and 488 amol/uL in high-complexity samples. In addition, comprehensive sequence coverage was obtained and accurate quantification achieved for expression ratios ranging from 1:1.5 to 1:6. However, underestimation of ratios was detected independent of sample type, consistent with other quantitative proteomic methods. The present study provides validation of the MS(E) approach for accurate quantitative proteomic analysis of biological samples while, at the same time, proving high sequence coverage of target proteins.


Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome.
An invasive treatment strategy improves outcome in patients with non-ST-elevation acute coronary syndrome at moderate to high risk. We hypothesized that the circulating level of growth differentiation factor 15 (GDF-15) may improve risk stratification. The Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial randomized patients with non-ST-elevation acute coronary syndrome to an invasive or conservative strategy with a follow-up for 2 years. GDF-15 and other biomarkers were determined on admission in 2079 patients. GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (>1800 ng/L) in 493 patients (23.7%). Elevated levels of GDF-15 independently predicted the risk of the composite end point of death or recurrent myocardial infarction in the conservative group (P=0.016) but not in the invasive group. A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point. The occurrence of the composite end point was reduced by the invasive strategy at GDF-15 levels >1800 ng/L (hazard ratio, 0.49; 95% confidence interval, 0.33 to 0.73; P=0.001), between 1200 and 1800 ng/L (hazard ratio, 0.68; 95% confidence interval, 0.46 to 1.00; P=0.048), but not <1200 ng/L (hazard ratio, 1.06; 95% confidence interval, 0.68 to 1.65; P=0.81). Patients with ST-segment depression or a troponin T level >0.01 microg/L with a GDF-15 level <1200 ng/L did not benefit from the invasive strategy. GDF-15 is a potential tool for risk stratification and therapeutic decision making in patients with non-ST-elevation acute coronary syndrome as initially diagnosed by ECG and troponin levels. A prospective randomized trial is needed to validate these findings.


Structural insights into Rcs phosphotransfer: the newly identified RcsD-ABL domain enhances interaction with the response regulator RcsB.
The Rcs-signaling system is one of the most remarkable phosphorelay pathways in Enterobacteriaceae, comprising several membrane-bound and soluble proteins. Within the complex phosphotransfer pathway, the histidine phosphotransferase (HPt) domain of the RcsD membrane-bound component serves as a crucial factor in modulating the phosphorylation state of the transcription factor RcsB. We have identified a new domain, RcsD-ABL, located N terminally to RcsD-HPt that interacts with RcsB as well. We have determined its structure, characterized its interaction interface with RcsB, and built a structural model of the complex of the RcsD-ABL domain with RcsB. Our results indicate that the effector domain of RcsB, which normally binds to DNA, is recognized by RcsD-ABL, whereas the HPt domain interacts with the phosphoreceiver domain of RcsB.


Economic evaluation of three two-drug chemotherapy regimens in advanced non-small-cell lung cancer.
During the 1990s, a number of new cytotoxic agents with clinically relevant activity in non-small-cell lung cancer (NSCLC), and with a more favourable therapeutic index than drugs already in use, became available. Given the high prices of these new drugs and the large number of patients affected, it is important to compare the relative benefits and costs of these treatments with the existing regimens before treatment policy decisions are changed. An economic evaluation of three different regimens of chemotherapy in patients with advanced NSCLC was performed from the perspective of the Dutch health insurance system using tariffs valid for 2002. The economic evaluation was integrated into a phase III clinical trial in which the reference regimen cisplatin-paclitaxel was compared with two experimental regimens: cisplatin-gemcitabine and gemcitabine-paclitaxel. Unit costs were applied to resource use data collected prospectively on case report forms during the trial. The average total (uncensored) cost per patient was determined for each of the treatment groups. The principal outcome measure for the economic evaluation was the estimated mean survival time per treatment group. This outcome was then incorporated into incremental cost-effectiveness ratios based on costs corrected for censoring. The impact of uncertainty was assessed by bootstrap techniques, and the analysis and interpretation of the data focused on the bivariate density of differences in outcomes and costs in the incremental cost-effectiveness plane. The final results were summarised by the derivation of cost-effectiveness acceptability curves. The estimated mean survival time was equivalent in the two cisplatin-based regimens with largely overlapping confidence intervals. There was a 99% probability that cisplatin-gemcitabine is the least costly regimen of the two and a 72% probability that this regimen reduces costs while at the same time improving survival. Compared with cisplatin-paclitaxel, the gemcitabine-paclitaxel regimen engendered a borderline significant reduction in mean survival time combined with an almost 90% probability of an increase in costs. The two cisplatin-based regimens are equivalent in terms of survival, but cisplatin-gemcitabine may reduce costs by approximately 2000 Euros patient compared with cisplatin-paclitaxel. Gemcitabine-paclitaxel is a dominated option with higher costs and a reduction in mean survival time compared with cisplatin-paclitaxel.


A short scale for evaluation of neuropsychiatric disorders in Parkinson's disease: first psychometric approach.
The neuropsychiatric symptoms and behavioral disorders affecting Parkinson's disease (PD) patients are common and disabling. A PD-specific interview-based 12-item scale, the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's Disease (SEND-PD), has been developed to assess the severity of neuropsychiatric manifestations. The present study is aimed at testing some basic psychometric attributes of this scale. A total of 633 consecutive patients and their caregivers were included in this cross-sectional, multicenter, observational study. In addition to the tested scale, the following assessments were applied: Hoehn and Yahr staging, Scales for Outcomes in Parkinson's Disease Motor and Psychiatric complications, MiniMental State Examination, Clinical Impression of Severity Index, and the Zarit Caregiver Burden Inventory. Patients in all stages of disease were included and 18.38 % were demented. The SEND-PD was responded by patients (86.16 %), caregivers (13.15 %), or both (0.69 %). Three factors (accounting for 66.63 % of the variance) were identified and considered as subscales: Psychotic symptoms, Mood/Apathy, and Impulse control disorders. The subscales showed satisfactory scaling assumptions (multitrait-item success rate 100 %) and internal consistency (alpha indices >0.70). The convergent validity with other measures of psychiatric symptoms and the discriminant validity to distinguish between categories of patients' age, duration and severity of disease, and dopaminergic treatment were satisfactory. The precision of the scale dimensions was acceptable. The SEND-PD performed as an acceptable, consistent, valid, and precise scale for evaluation of neuropsychiatric symptoms in Parkinson's disease.


Callosal alien hand sign following a right parietal lobe infarction.
Callosal alien hand syndrome is characterized primarily by intermanual conflict and is associated with an anterior callosal lesion. We report a patient who presented with topographical disorientation and the callosal type alien hand sign. An MRI of the brain showed a right parietal lobe infarction. This is a rare example of callosal alien hand sign associated with a right parietal lesion. The right parietal lobe appeared to be responsible for the callosal hand sign in this patient, possibly due to interference with peristriate outflow pathways toward the parietal zones, where visual somatosensory interactions are likely to occur.


Structural mechanism for modulation of functional amyloid and biofilm formation by Staphylococcal Bap protein switch.
The Staphylococcal Bap proteins sense environmental signals (such as pH, [Ca2+ ]) to build amyloid scaffold biofilm matrices via unknown mechanisms. We here report the crystal structure of the aggregation-prone region of Staphylococcus aureus Bap which adopts a dumbbell-shaped fold. The middle module (MM) connecting the N-terminal and C-terminal lobes consists of a tandem of novel double-Ca2+ -binding motifs involved in cooperative interaction networks, which undergoes Ca2+ -dependent order-disorder conformational switches. The N-terminal lobe is sufficient to mediate amyloid aggregation through liquid-liquid phase separation and maturation, and subsequent biofilm formation under acidic conditions. Such processes are promoted by disordered MM at low [Ca2+ ] but inhibited by ordered MM stabilized by Ca2+ binding, with inhibition efficiency depending on structural integrity of the interaction networks. These studies illustrate a novel protein switch in pathogenic bacteria and provide insights into the mechanistic understanding of Bap proteins in modulation of functional amyloid and biofilm formation, which could be implemented in the anti-biofilm drug design.


Dose-related effect of statins in patients with endovascular coiling or microsurgical clipping for aneurysmal subarachnoid hemorrhage: updated study-level meta-analysis.
We aimed to quantitatively assess the effects of short-term statin use on delayed ischemic neurologic deficits (DINDs) and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH) through a meta-analysis of the available evidence. We searched the electronic databases up to April 8, 2016 to retrieve relevant studies comparing the outcomes between immediate statin-treated in statin-naïve patients and untreated patients following aneurysmal SAH. Meta-analysis was performed using Review Manager 5.3. Eight randomized controlled clinical trials (RCTs) and 5 observational studies involving 2148 patients met the eligibility criteria. In the RCTs, statins were found to significantly reduce the occurrence of DINDs (relative risk (RR), 0.76; 95% confidence interval (CI), 0.61-0.94; P = 0.01), but did not significantly reduce poor functional outcomes (RR, 1.01; 95% CI, 0.87-1.16; P = 0.93) or mortality (RR, 0.80; 95% CI, 0.58-1.11; P = 0.18). In observational studies, statin use was not associated with any reduction in DINDs, poor outcome, or mortality. Meta-analysis of RCTs indicated a significant reduction in DINDs and mortality in patients with high-dose statin use (RR, 0.63; 95% CI, 0.42-0.95; P = 0.03; I 2 = 0%; and RR, 0.36; 95% CI, 0.15-0.86; P = 0.02; I 2 = 0%, respectively). The present meta-analysis suggests that statin use may prevent DINDs in patients with aneurysmal SAH. Based on our findings, the role of statins in improving neurological outcome was limited. However, the risk of DINDs and mortality decreased with higher statin doses in a dose-dependent manner. Hence, further well-designed RCTs with modified protocols in specific patients are required.


[Radiochromatographic study of the distribution of sidnocarb-14C and its metabolites in inbred mice].
The title study permitted detecting genetic differences in sydnocarb metabolism. It was established that the rate of sydnocarb oxidation in BALB/c mice was higher than in C57B1/6 mice.


Identification of subpopulations of cells with differing telomere lengths in mouse and human cell lines by flow FISH.
Telomeres are specialized nucleoprotein structures at chromosome ends that undergo dynamic changes after each cell cycle. Understanding the mechanisms of telomere dynamics is critically dependent on the ability to accurately measure telomere length in a cell population of interest. Techniques such as Southern blot, which measures average telomere length, and quantitative fluorescence in situ hybridization (Q-FISH), which can estimate telomere length in individual chromosomes, are limited in their capacity to determine the distribution of cells with differing telomere lengths in a given cell population. We employed flow-FISH to determine whether mouse and human cell lines exhibit subpopulations of cells with differing telomere lengths. Our analysis showed that at least one of four analyzed mouse cell lines had two subpopulations of cells with differing telomere lengths. Differences in telomere length between subpopulations of cells were significant, and we term this phenomenon TELEFLUCS (TElomere LEngth FLUctuations in Cell Subpopulations). We also observed TELEFLUCS in 1 of 19 analyzed human nonalternative lengthening of telomere cell lines and in 1 of 2 analyzed human alternative lengthening of telomere cell lines. The existence of cell subpopulations with differing telomere lengths was confirmed by Q-FISH. Our results underscore the importance of flow-FISH in telomere length analysis.


The cognitive science of COVID-19: Acceptance, denial, and belief change.
Because the spread of pandemics depends heavily on human choices and behaviors, dealing with COVID-19 requires insights from cognitive science which integrates psychology, neuroscience, computer modeling, philosophy, anthropology, and linguistics. Cognitive models can explain why scientists adopt hypotheses about the causes and treatments of disease based on explanatory coherence. Irrational deviations from good reasoning are explained by motivated inference in which conclusions are influenced by personal goals that contribute to emotional coherence. Decisions about COVID-19 can also be distorted by well-known psychological and neural mechanisms. Cognitive science provides advice about how to improve human behavior in pandemics by changing beliefs and by improving behaviors that result from intention-action gaps.


Free tissue transfers in the first 2 years of life--a successful cost effective and humane option.
Experience shows that young children are favourable candidates for microsurgical reconstruction, having few of the established risk factors for flap failure. In children's reconstructive surgery free tissue transfer (FTT) permits reconstruction whilst retaining growth potential, and reduces the overall number and duration of care episodes, and their related distress to the child and family. We present one centre's experience of free tissue transfer in children less than 2 years of age, over a 15-year period, demonstrating that free tissue transfer can be successfully employed in children under 2 years old. Salient aspects of patient selection, pre-operative counselling, and per-operative management are presented. Data from all free flaps in children under 2 years of age at the time of surgery were collected prospectively. Forty-seven flaps were performed as 37 separate procedures, in 32 children under 2 years of age. In ten patients, double transfers were performed in single procedures. Free tissue transfers were performed for reconstruction of congenital defects, following trauma and meningococcal septicaemia. All but one flap survived. In our series operative and ischaemia times, re-exploration, complication and flap failure rates were not higher than in comparable adult or older paediatric series from this unit, suggesting that there is no microvascular, or other, factor inherent to the infant that should preclude the use of free tissue transfer. Individual microsurgeons with appropriate facilities should not be inhibited from performing free tissue transfers which are humane and cost effective when compared with alternatives for very young children.


Generic anion-exchange chromatography method for analytical and preparative separation of nucleotides in the development and manufacture of drug substances.
Nucleotides are among the most frequently used chemical building blocks in the research, development and manufacture of drug substances. They are composed of three highly polar subunit molecules (a nucleobase, a sugar, and at least one phosphate group), which makes their separation and analysis very challenging by conventional liquid chromatography techniques. Herein, we describe a simple, efficient, and cost-effective ion-exchange chromatography (IEC) method for the separation and purification of over 20 nucleotides. This method combines the use of a Tosoh TSKgel SuperQ-5P W resin in conjunction with a fully aqueous eluent profile (ammonium bicarbonate-based) that allows for a straightforward scale-up transition and convenient drying process with minimal environmental impact. This generic method was optimized using chromatography simulation software (ACD Labs/LC Simulator) and successfully applied to the preparative purification of multicomponent nucleotide mixtures using readily available Fast Protein Liquid Chromatography (FPLC) instrumentation. These IEC method conditions can be effectively applied as the starting point for method development and isolation of other highly polar nucleotide species beyond those investigated in this study.


Antibody Immobilization.
In the ELISA format(s), the capture antibody is usually affixed to a solid phase, commonly referred to as the immunosorbent. How to tether the antibody most effectively will depend upon the physical properties of the support (plate well, latex bead, flow cell, etc.) as well as its chemical nature (hydrophobic, hydrophilic, the presence of reactive groups such as epoxide, etc.). Of course, it is ultimately the suitability of the antibody to withstand the linking process while preserving its antigen-binding efficiency that must be determined. In this chapter, the antibody immobilization processes and their consequences are described.


F₄-neuroprostanes mediate neurological severity in Rett syndrome.
Rett syndrome (RTT) is a pervasive development disorder, mainly caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. No reliable biochemical markers of the disease are available. Here we assess F₄-neuroprostanes (F₄-NeuroPs), lipid peroxidation products of the docosahexaenoic acid, as a novel disease marker in RTT and correlate it with clinical presentation, MeCP2 mutation type, and disease progression. In addition, we investigate on the impact of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) supplementation on F₄-NeuroPs levels. A case-control study design was used. A cohort of RTT patients (n=144) exhibiting different clinical presentations, disease stages, and MeCP2 gene mutations were evaluated. F₄-NeuroPs were measured in free form using a GC/NICI-MS/MS technique. Plasma F₄-NeuroPs levels in patients were compared to healthy controls and related to RTT forms, disease progression, and response to ω-3 PUFAs supplementation. Plasma F₄-NeuroPs levels were i) higher in RTT than in controls; ii) increased with the severity of neurological symptoms; iii) significantly elevated during the typical disease progression; iv) higher in MeCP2-nonsense as compared to missense mutation carriers; v) higher in typical RTT as compared to RTT variants; and vi) decreased in response to 12 months ω-3 PUFAs oral supplementation. Quantification of plasma F₄-NeuroPs provides a novel RTT marker, related to neurological symptoms severity, mutation type and clinical presentation.


Echo machine-imposed limit on transmitral spectral Doppler velocity-profile analysis.
We have previously developed a kinematic model of ventricular filling. Its application to in vivo transmitral Doppler velocity profiles provides a quantitative characterization of filling. However, the model parameters computed by solving the "inverse problem" may depend on ultrasound machine type and setting (e.g., gain, baseline filter, dynamic range). To determine machine-based effects on the computed model parameters, we performed a flow phantom study using Acuson and HP echocardiography machines at various settings. We compared maximum velocity envelopes (MVEs), as well as the model fit to these MVEs, for 3 simulated waveforms imaged by both machines. For all 3 waveforms, the machines generated comparable MVEs, fit by the model within a mean-square difference of 5E-5 (m/s)2. The associated variations in model parameters for the 3 waveforms were not uniform. Two waveforms showed slight variation between machines, with model parameters varying by less than 6%. The shortest duration waveform showed model parameter variations of 10-15%. Analysis of the parameter space for this waveform showed a constant mean-square error contour that was larger than that for the other two, causing similar small variations in measured MVEs to result in larger differences in the parameter estimates for this waveform. Because this method completely eliminates inter- and intraobserver variability, we conclude that, within the limits established, the slight contour variations due to machine type and setting should not affect this method's applicability in clinical Doppler-flow analysis.


Modified Radical Scavenging and Antioxidant Activity Measurement of β-Carotene with β-Cyclodextrins Complexation in Aqueous Medium.
In order to evaluate the antioxidant capacity/activity of β-carotene (BC) in aqueous media, we investigated the inclusion complexes of BC with methyl-β-cyclodextrin (Me-β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and 2-hydroxyethyl-β-cyclodextrin (HE-β-CD) that enhance water solubility and chemical stability. The inclusion complexes (monitored by FTIR) exhibited higher solubility than free BC, and phase solubility studies showed a linear increase in the solubility with the Me-β-CD concentration. Cupric ion-reducing antioxidant capacity (CUPRAC), ABTS-persulfate, peroxyl and hydroxyl radical scavenging assays were applied. CD-complexed β-carotene exhibited less effective antioxidative and radical scavenging than free BC dissolved in acetone. β-Carotene showed the highest antioxidant capacity in the presence of HE-β-CD, and the lowest with Me-β-CD, probably due to the deeper and more hydrophobic cavity of the latter. We believe that this is the first report on devising simple spectrophotometric methods for the wholistic assessment of antioxidant activity/capacity, hydroxyl and peroxyl radical scavenging activity of β-carotene in aqueous solution with CDs.


Cerebral vasodilation and vasoconstriction associated with acute anxiety.
A randomized, between-groups, repeated measures design was used to evaluate changes in cerebral blood flow (CBF), rating scales, and physiologic indices under resting conditions, during 5% CO2 inhalation in combination with epinephrine or saline infusions, in generalized anxiety disorder patients and controls. Subjects were divided into those with decreased anxiety and mild and more severe anxiety increase. The first group was found to have most pronounced CBF increase during CO2 inhalation, with the second group showing less marked increase, and the last group the least increase. In animals, sympathetic activation limits hypercapnic cerebral vasodilation. Thus, the restricted hypercapnic cerebral vasodilation during severe anxiety may be mediated through cervical sympathetic fibers, which innervate cerebral vessels.


Interleukin-6 involvement in brain arteriovenous malformations.
We recently reported that the GG genotype of the interleukin-6 (IL-6)-174G>C promoter polymorphism is associated with clinical presentation of intracranial hemorrhage in brain arteriovenous malformation (AVM) patients. In this study, we investigated whether tissue IL-6 expression was associated with IL-6-174G>C genotype, and whether IL-6 was linked to downstream targets involved in angiogenesis and vascular instability. Our results showed that the highest IL-6 protein levels in brain AVM tissue were associated with IL-6-174GG genotype (GG: 57.7 +/- 20.2; GC: 35.6 +/- 26.6; CC: 13.9 +/- 10.2pg/mg; p = 0.001). IL-6 protein levels were increased in AVM tissue from patients with hemorrhagic presentation compared with patients without hemorrhage (55 +/- 22 vs 40 +/- 27pg/mg; p = 0.038). IL-6 messenger RNA expression strongly correlated with messenger RNA levels of IL-1beta, tumor necrosis factor-alpha, IL-8, matrix metalloproteinase-3 (MMP-3), MMP-9, and MMP-12. We further investigated the plausibility of IL-6 being an upstream cytokine responsible for initiating the angiogenic cascade by cell culture and animal experiments. IL-6 induced MMP-3 and MMP-9 expression and activity in mouse brain and increased proliferation and migration of cerebral endothelial cells. Together, our results suggest that the IL-6 genotype associated with intracranial hemorrhage modulates IL-6 expression in brain AVM tissue, which is consistent with the hypothesis that inflammatory processes induce angiogenic activity possibly contributory to brain AVM intracranial hemorrhage.


Al-free Sn-Beta zeolite as a catalyst for the selective reduction of carbonyl compounds (Meerwein-Ponndorf-Verley reaction).
The catalytic activity of Sn-Beta zeolite in the Meerwein-Ponndorf-Verley (MPV) reduction of carbonyl compounds with secondary alcohols was performed with quantitative yields to the corresponding alcohol. This heterogeneous catalyst exhibits activities and selectivities not observed before with other Me-zeolites.


Therapeutic potential of melatonin and melatonergic drugs on K18-hACE2 mice infected with SARS-CoV-2.
As the COVID-19 pandemic grows, several therapeutic candidates are being tested or undergoing clinical trials. Although prophylactic vaccination against SARS-CoV-2 infection has been shown to be effective, no definitive treatment exists to date in the event of infection. The rapid spread of infection by SARS-CoV-2 and its variants fully warrants the continued evaluation of drug treatments for COVID-19, especially in the context of repurposing of already available and safe drugs. Here, we explored the therapeutic potential of melatonin and melatonergic compounds in attenuating COVID-19 pathogenesis in mice expressing human ACE2 receptor (K18-hACE2), strongly susceptible to SARS-CoV-2 infection. Daily administration of melatonin, agomelatine, or ramelteon delays the occurrence of severe clinical outcome with improvement of survival, especially with high melatonin dose. Although no changes in most lung inflammatory cytokines are observed, treatment with melatonergic compounds limits the exacerbated local lung production of type I and type III interferons, which is likely associated with the observed improved symptoms in treated mice. The promising results from this preclinical study should encourage studies examining the benefits of repurposing melatonergic drugs to treat COVID-19 and related diseases in humans.


BRCA2 deficiency reveals that oxidative stress impairs RNaseH1 function to cripple mitochondrial DNA maintenance.
Oxidative stress is a ubiquitous cellular challenge implicated in aging, neurodegeneration, and cancer. By studying pathogenic mutations in the tumor suppressor BRCA2, we identify a general mechanism by which oxidative stress restricts mitochondrial (mt)DNA replication. BRCA2 inactivation induces R-loop accumulation in the mtDNA regulatory region and diminishes mtDNA replication initiation. In BRCA2-deficient cells, intracellular reactive oxygen species (ROS) are elevated, and ROS scavengers suppress the mtDNA defects. Conversely, wild-type cells exposed to oxidative stress by pharmacologic or genetic manipulation phenocopy these defects. Mechanistically, we find that 8-oxoguanine accumulation in mtDNA caused by oxidative stress suffices to impair recruitment of the mitochondrial enzyme RNaseH1 to sites of R-loop accrual, restricting mtDNA replication initiation. Thus, oxidative stress impairs RNaseH1 function to cripple mtDNA maintenance. Our findings highlight a molecular mechanism that links oxidative stress to mitochondrial dysfunction and is elicited by the inactivation of genes implicated in neurodegeneration and cancer.


Daily sperm production and testicular morphometry in goats according to external scrotal conformation.
The present study aimed to compare testicular histology and the testicular cell population as well as spermatogenic efficiency in goats with different scrotal conformations. Eighteen goats were divided into 3 groups: Group I - goats without bipartition of the scrotum, Group II - animals with bipartition of the scrotum up to 50% of the testicular length, Group III - goats with scrotal bipartition more than 50% of the testicular length. In goats in Groups I, II and III, the values for the volume density of seminiferous epithelium were 68.9 ± 0.6%, 71.5 ± 2.8% and 73.4 ± 4.7% (P<0.05), the height of the seminiferous epithelium were 60.2 ± 4.9 μm, 61.0 ± 5.0 μm and 73.1 ± 6.6 μm (P<0.05), total length of seminiferous tubules found for Groups I, II and III were 2091.9 ± 27 m, 2172.5 ± 24.1 m, and 2340.1 ± 14 m (P<0.05), number of Sertoli and Leydig cells were 1.8 ± 0.4×10(9) and 1.4 ± 0.1×10(9), 2.2 ± 0.4 and 2.2 ± 0.7×10(9), and 2.5 ± 0.1 10(9) and 2.3 ± 0.5 10(9) (P<0.05) and daily sperm production observed were 2.1 ± 0.3×10(9), 2.8 ± 0.4×10(9), and 3.1 ± 0.7×10(9) (P<0.05). In conclusion, goats with greater scrotal bipartition have a greater capacity to produce reproductive cells that is reflected in a greater reproductive potential.


Rubber hand illusion induced by touching the face ipsilaterally to a deprived hand: evidence for plastic "somatotopic" remapping in tetraplegics.
Studies in animals and humans indicate that the interruption of body-brain connections following spinal cord injury (SCI) leads to plastic cerebral reorganization. To explore whether inducing the Rubber Hand Illusion (RHI) via synchronous multisensory visuo-tactile bodily stimulation may reveal any perceptual correlates of plastic remapping in SCI. In 16 paraplegic, 16 tetraplegic and 16 healthy participants we explored whether RHI may be induced by tactile stimuli involving not only the left hand but also the left hemi-face. Touching the participants actual hand or face was either synchronous or asynchronous with tactile stimuli seen on a rubber hand. We assessed two components of the illusion, namely perceived changes in the real hand in space (indexed by proprioceptive drift) and ownership of the rubber hand (indexed by subjective responses to an ad-hoc questionnaire). Proprioceptive drift and ownership were found in the healthy group only in the condition where the left real and fake hand were touched simultaneously. In contrast, no drift was found in the SCI patients who, however, showed ownership after both synchronous and asynchronous hand stroking. Importantly, only tetraplegics showed the effect also after synchronous face stroking. RHI may reveal plastic phenomena in SCI. In hand representation-deprived tetraplegics, stimuli on the face (represented contiguously in the somatic and motor systems), drive the sense of hand ownership. This hand-face remapping phenomenon may be useful for restoring a sense of self in massively deprived individuals.