Detection of SARS-CoV-2 RNA in wastewater, river water, and hospital wastewater of Nepal.
The applicability of wastewater-based epidemiology (WBE) has been extensively studied throughout the world with remarkable findings. This study reports the presence and reduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at two wastewater treatment plants (WWTPs) of Nepal, along with river water, hospital wastewater (HWW), and wastewater from sewer lines collected between July 2020 and February 2021. SARS-CoV-2 RNA was detected in 50%, 54%, 100%, and 100% of water samples from WWTPs, river hospitals, and sewer lines, respectively, by at least one of four quantitative PCR assays tested (CDC-N1, CDC-N2, NIID_2019-nCOV_N, and N_Sarbeco). The CDC-N2 assay detected SARS-CoV-2 RNA in the highest number of raw influent samples of both WWTPs. The highest concentration was observed for an influent sample of WWTP A (5.5 ± 1.0 log10 genome copies/L) by the N_Sarbeco assay. SARS-CoV-2 was detected in 47% (16/34) of the total treated effluents of WWTPs, indicating that biological treatments installed at the tested WWTPs are not enough to eliminate SARS-CoV-2 RNA. One influent sample was positive for N501Y mutation using the mutation-specific qPCR, highlighting a need for further typing of water samples to detect Variants of Concern. Furthermore, crAssphage-normalized SARS-CoV-2 RNA concentrations in raw wastewater did not show any significant association with the number of new coronavirus disease 2019 (COVID-19) cases in the whole district where the WWTPs were located, suggesting a need for further studies focusing on suitability of viral as well as biochemical markers as a population normalizing factor. Detection of SARS-CoV-2 RNA before, after, and during the peaking in number of COVID-19 cases suggests that WBE is a useful tool for COVID-19 case estimation in developing countries.


The role of lipoprotein lipase in metabolism of normolipidemic very low density lipoprotein by macrophages.
It was demonstrated by using lipoprotein lipase (LPL) inhibitor benzene boronic acid (BBA) that LPL played a major role in the accumulation of triglycerides (TG) in mouse peritoneal macrophages exposed to rabbit normal very low density lipoproteins (N-VLDL). There wwere less free fatty acids (FFA) and much more N-VLDL-TG left in the media containing BBA than in the controls. TG accumulation in the cells was greatly diminished or even prohibited by BBA. Thus, we obtained direct evidence that LPL played a more important role than the receptor did in the uptake of N-VLDL-TG by mouse macrophages. The mechanisms of LPL action were discussed.


Spontaneous hemopneumothorax: is conservative treatment enough?
Spontaneous hemopneumothorax is a rare disorder, occurring in 1% to 12% of patients with spontaneous pneumothorax. The present review was undertaken to emphasize the potential life-threatening condition of spontaneous hemopneumothorax and reassess the benefit of conservative treatment with chest tube drainage. From 1997 to 2002, 291 cases of spontaneous pneumothorax were treated in our department. Of these, 9 (3.09%) developed hemopneumothorax (> 400 ml). The clinical features of these patients and the results of conservative and surgical management were retrospectively reviewed. Seven patients were treated conservatively and two required VATS and thoracotomy because of worsening clinical condition. The amount of aspirated blood ranged from 400 to 3700 ml (mean, 1533 ml). Six patients received a homologous blood transfusion. In conclusion, hemopneumothorax is a serious condition complicating spontaneous pneumothorax. Conservative treatment is adequate in most cases and should be performed if bleeding persists for less than 24 hours after chest tube placement.


Efficient auditory coding.
The auditory neural code must serve a wide range of auditory tasks that require great sensitivity in time and frequency and be effective over the diverse array of sounds present in natural acoustic environments. It has been suggested that sensory systems might have evolved highly efficient coding strategies to maximize the information conveyed to the brain while minimizing the required energy and neural resources. Here we show that, for natural sounds, the complete acoustic waveform can be represented efficiently with a nonlinear model based on a population spike code. In this model, idealized spikes encode the precise temporal positions and magnitudes of underlying acoustic features. We find that when the features are optimized for coding either natural sounds or speech, they show striking similarities to time-domain cochlear filter estimates, have a frequency-bandwidth dependence similar to that of auditory nerve fibres, and yield significantly greater coding efficiency than conventional signal representations. These results indicate that the auditory code might approach an information theoretic optimum and that the acoustic structure of speech might be adapted to the coding capacity of the mammalian auditory system.


Pathophysiological and parasitological studies on Ostertagia ostertagi infections in calves.
Friesian calves given a low level infection of the abomasal parasite Ostertagia ostertagi over a six week period displayed a mild diarrhoea with high faecal egg counts and elevated plasma pepsinogen values. At necropsy on day 23 abomasal lesions characteristic of ostertagiasis were widespread. At 42 and 84 days oedema and congestion were also prominent. Total worm burdens on days 23 and 42 were similar but a marked decrease had occurred by day 84. Feed digestibility and nitrogen economy were not markedly affected but radioisotopic measurements demonstrated an increase in albumin disappearance and catabolic rates, and plasma faecal clearance during the course of the infection. Prior administration of a morantel sustained release bolus to a group of similarly infected calves reduced the total worm burdens to less than 50 per cent of those recorded in the infected calves on days 23 and 42 and this fell to 3 per cent on day 84. Abomasal damage and the adverse pathophysiological changes associated with infection were prevented in this group.


Spurious DNA blot hybridization resulting from bacterial contamination of primary tissue preparations.
We have observed, by Southern blot hybridization, numerous episomes in DNA prepared from tumors grown as athymic mouse xenografts. These extrachromosomal DNAs were present in multiple copies and existed as relaxed and supercoiled conformational isomers. The episomes were readily detected with pBR322 plasmid probes, but not with purified plasmid inserts. Subsequently, four species of bacteria were isolated from tumor xenografts, suggesting that the pBR322 related episomes which we observed were bacterial DNAs, copurified during the isolation of xenograft DNA. This finding illustrates a potential problem which may be encountered in blot hybridizations utilizing nucleic acids from primary tissue preparations.


Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration.
The hemodynamic effects of dopamine and dobutamine (at doses of 6 micrograms X kg-1 X min-1) were compared during fluid resuscitation from septic shock induced by endotoxin (3 mg/kg) in the dog. In the first part of the study, when a standard amount of saline solution was infused (in 24 dogs), dopamine infusion resulted in higher cardiac filling pressures than did dobutamine infusion, whereas dobutamine infusion resulted in higher cardiac output. In the second part of the study, when fluid infusion was titrated to maintain pulmonary artery balloon-occluded pressure at constant level (in 24 dogs), the total amount of fluids was significantly greater with dobutamine than when dopamine was used (109 +/- 13 vs 71 +/- 10 ml/kg). The combination of dobutamine with fluids resulted in significantly greater stroke volume (39.6 +/- 3.8 vs 21.0 +/- 4.0 ml, P less than 0.05) and oxygen consumption (194 +/- 18 vs 144 +/- 8 ml/min, P less than 0.05). The different effects of dopamine and dobutamine on cardiac filling pressures can be due to differences in effects on myocardial contractility, ventricular afterload, and cardiac compliance. This experimental study indicates that when fluid therapy is combined with adrenergic agents in resuscitation from septic shock, dobutamine can be associated with higher cardiac output and oxygen transport and can result in higher tissue oxygen consumption than dopamine.


Enhanced immunogenicity of Mycobacterium bovis BCG through CRISPRi mediated depletion of AftC.
Mycobacterium tuberculosis causes the disease tuberculosis and affects a third of the world's population. The recent COVID-19 pandemic exacerbated the situation with a projected 27% increase in tuberculosis related deaths. M. tuberculosis has an elaborate cell wall consisting of peptidoglycan, arabinogalactan and mycolic acids which shield the bacilli from the toxic bactericidal milieu within phagocytes. Amongst, the numerous glycosyltransferase enzymes involved in mycobacterial cell wall biosynthesis, arabinofuranosyltransferase C (aftC) is responsible for the branching of the arabinan domain in both arabinogalactan and lipoarabinomannan. Using Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) we have generated aftC knockdowns in Mycobacterium bovis BCG and demonstrated the generation of a truncated, immunogenic lipoarabinomannan within its cell envelope. The aftC depleted BCG mutants were unable to form characteristic mycobacterial pellicular biofilms and elicit a potent immunostimulatory phenotype compared to wild type M. bovis BCG in a THP1 cell line. This study paves the way to further explore novel BCG mutants as promising vaccine boosters in preventing pulmonary tuberculosis.


Trends in breast cancer incidence rates by race/ethnicity: Patterns by stage, socioeconomic position, and geography in the United States, 1999-2017.
The incidence rate of breast cancer has been increasing over time across race/ethnicity in the United States. It is unclear whether these trends differ among stage, poverty, and geography subgroups. Using data from the North American Association of Central Cancer Registries, this study estimated trends in age-adjusted breast cancer incidence rates among women aged 50 to 84 years from 1999 to 2017 by race/ethnicity (non-Hispanic Black, non-Hispanic White, and Hispanic) and across subgroups (stage, county-level poverty, county urban/rural status, and geographic region [West, Midwest, South, and Northeast]). From 2004 to 2017, breast cancer incidence rates increased across race/ethnicity and subgroups, with the greatest average annual percent increases observed for non-Hispanic Black women, overall (0.9%) and those living in lower poverty areas (0.8%), rural areas (1.2%), and all regions except the West (0.8%-1.0%). Stronger increases among non-Hispanic Black women were observed for local-stage disease and for some subgroups of distant-stage disease. Non-Hispanic Black women had the smallest decrease in regional-stage disease across most subgroups. Similarly, Hispanic women had the strongest increases in some subgroups, including areas with higher poverty (0.6%-1.2%) and in the West (0.8%), for local- and distant-stage disease. These trends highlight concerns for an increasing burden of breast cancer among subpopulations, with some already experiencing disparate breast cancer mortality rates, and they highlight the need for targeted breast cancer prevention and efforts to reduce mortality disparities in areas with increasing incidence.


Insights into bone health in Duchenne muscular dystrophy.
Poor bone health is a significant problem for patients with Duchenne muscular dystrophy (DMD), a progressive, disabling disease. Although the primary focus of DMD disease pathogenesis is degeneration of striated muscle, impairment of bone health likely has a role in the disease that has only been superficially examined to date. Deficiency of bone mineral density and increased incidence of bone fractures are well-recognized clinical components of the DMD phenotype. Furthermore, therapy with corticosteroids, an approved treatment for DMD that prolongs ambulation, may have multiple effects on bone health in DMD patients. This review examines the evidence in preclinical models and in human DMD disease that provides insight into the role performed by bone in the disease pathogenesis and phenotype of DMD. The information reviewed here points toward the need for mechanistic and therapeutic studies to optimize bone health in DMD patients.


A Meta-Device for Intelligent Depth Perception.
The optical illusion affects depth-sensing due to the limited and specific light-field information acquired by single-lens imaging. The incomplete depth information or visual deception would cause cognitive errors. To resolve this problem, an intelligent and compact depth-sensing meta-device that is miniaturized, integrated, and applicable for diverse scenes in all light levels is demonstrated. The compact and multifunction stereo vision system adopts an array with 3600 achromatic meta-lenses and a size of 1.2 × 1.2 mm2 to measure the depth over a 30 cm range with deep-learning support. The meta-lens array can act as multiple imaging lenses to collect light field information. It can also work with a light source as an active optical device to project a structured light. The meta-lens array can serve as the core functional component of a light-field imaging system under bright conditions or a structured-light projection system in the dark. The depth information in both ways can be analyzed and extracted by the convolutional neural network. This work provides a new avenue for the applications such as autonomous driving, machine vision, human-computer interaction, augmented reality, biometric identification, etc.


Treatment at Safety-Net Hospitals Is Associated with Delays in Coil Embolization in Patients with Subarachnoid Hemorrhage.
Successful endovascular management of aneurysmal subarachnoid hemorrhage (aSAH) requires timely access to substantial resources. Prior studies suggest an association between time to treatment and patient outcome. Patients treated at safety-net hospitals are thought to be particularly vulnerable to disparities in access to interventions that require substantial technologic resources. We hypothesized that patients with aSAH treated at safety-net hospitals are at greater risk for delayed access to endovascular treatment. Adults undergoing endovascular coiling procedures between 2002 and 2011 in the Nationwide Inpatient Sample were included. Hospitals in the quartile with the highest proportion of Medicaid or uninsured patients were defined as safety-net hospitals. A multivariate model including patient-level and hospital-level factors was constructed to permit analysis of delays in endovascular treatment (defined as time to treatment >3 days). Analysis included 7109 discharges of patients with aSAH undergoing endovascular coil embolization procedures from 2002 to 2011. Median time to coil embolization in all patients was 1 day; 10.1% of patients waited >3 days until treatment. In multivariate analysis, patients treated at safety-net hospitals were more likely to have a prolonged time to coil embolization (odds ratio = 1.32, P < 0.01) compared with patients treated at low-burden hospitals. After controlling for patient and hospital factors, individuals with aSAH treated at safety-net hospitals from 2002 to 2011 were more likely to have a delay to endovascular coil embolization than individuals treated at non-safety-net hospitals. This disparity could affect patient outcomes.


Genetic deviation in geographically close populations of the dengue vector Aedes aegypti (Diptera: Culicidae): influence of environmental barriers in South India.
Mosquitoes are vectors of devastating pathogens and parasites, causing millions of deaths every year. Dengue is a mosquito-borne viral infection found in tropical and subtropical regions around the world. Recently, dengue transmission has strongly increased in urban and semiurban areas, becoming a major international public health concern. Aedes aegypti (Diptera: Culicidae) is a primary vector of dengue. Shedding light on genetic deviation in A. aegypti populations is of crucial importance to fully understand their molecular ecology and evolution. In this research, haplotype and genetic analyses were conducted using individuals of A. aegypti from 31 localities in the north, southeast, northeast and central regions of Tamil Nadu (South India). The mitochondrial DNA region of cytochrome c oxidase 1 (CO1) gene was used as marker for the analyses. Thirty-one haplotypes sequences were submitted to GenBank and authenticated. The complete haplotype set included 64 haplotypes from various geographical regions clustered into three groups (lineages) separated by three fixed mutational steps, suggesting that the South Indian Ae. aegypti populations were pooled and are linked with West Africa, Columbian and Southeast Asian lineages. The genetic and haplotype diversity was low, indicating reduced gene flow among close populations of the vector, due to geographical barriers such as water bodies. Lastly, the negative values for neutrality tests indicated a bottle-neck effect and supported for low frequency of polymorphism among the haplotypes. Overall, our results add basic knowledge to molecular ecology of the dengue vector A. aegypti, providing the first evidence for multiple introductions of Ae. aegypti populations from Columbia and West Africa in South India.


A prospective analysis of risk factors for the discontinuation of second-line antirheumatic drugs.
Clinical and laboratory factors influencing the discontinuation of second-line antirheumatic drugs were prospectively studied using survival analysis in a consecutive series of 245 patients with recently diagnosed rheumatoid arthritis. A statistically significant influence of age, sex, serum IgA and HLA-DR3 on the discontinuation rate of chrysotherapy because of toxicity was observed. The discontinuation of sulfasalazine was increased by advanced age and high rank order of prescription. With respect to efficacy, high initial disease activity appeared to predispose to treatment termination of hydroxychloroquine, sulfasalazine and penicillamine. Furthermore, an influence of the rank order of prescription on discontinuation of sulfasalazine therapy because of lack of efficacy was found. Of interest is that discontinuation of hydroxychloroquine therapy because of lack of efficacy occurred less frequently in HLA-DR3-positive than in HLA-DR3-negative patients. Although these prognostic factors are of secondary importance in clinical practice, they may be of significance in the interpretation and comparison of clinical trials.


Stopping HIV before it begins: issues faced by women in India.
Despite advances in understanding HIV pathogenesis, the economic, social and legal constraints in India continue to make women particularly vulnerable to HIV infection.


The clinicopathological and prognostic implications of tyrosine phosphatase SHP2 and ankyrin Hook1 gene expression in non- small cell lung cancer patients treated with gemcitabine plus platinum as first-line chemotherapy.
SHP2, a widely expressed phosphatase, which has been linked to the initiation, progression and prognosis of various malignancies. We previously identified a new SHP2 anchorage protein Hook1 in the alveolar II epithelial cells, and it is suggested that Hook1 is a novel endogenous suppressor molecule of SHP2 phosphatase activity. Nevertheless, few studies have been mentioned the clinicopathological and prognostic relevance of SHP2 and Hook1 expression in patients with non-small cell lung cancer (NSCLC). A total of 61 patients with NSCLC receiving gemcitabine plus carboplatin chemotherapy were studied. Immunohistochemical staining was conducted to determine the protein expression of SHP2 and Hook1. The relationships between gene expression and clinical and pathological factors, as well as prognosis, were evaluated. A significant correlation was observed between the SHP2 and Hook1 expression, with a total expression rate of 71.4%. The positive expression of Hook1 in adenocarcinoma and in stage IIIb-IV was higher than that in patients with squamous (73.5% vs. 31.2%, P=0.013) and I-IIIa (75% vs. 48.8%, P=0.05), suggesting that Hook1 might act as an indicator of NSCLC status. However, no significant correlation was observed between Hook1 expression and survival time (P>0.05). In contrast, patients with negative SHP2 expression had a higher survival rate (median overall survival 68 vs. 24 months, P=0.003). Cox multivariate regression analysis showed that SHP2 was an independent indicator for overall survival (P=0.009). The present study suggested that NSCLC patients with negative SHP2 expression could benefit from gemcitabine plus carboplatin chemotherapy, and further study is needed to confirm the prognostic value of SHP2 and Hook1.


Leveraging Pathology Informatics Concepts to Achieve Discrete Lab Data for Clinical Use and Translational Research.
Clinical practice is most efficient when physicians have the right information, including pathology and laboratory results, at the point of contact with the patient. In downstream workflows, subsequent groups using lab data want to have it available in a format that is easy to manipulate. With the complexity of electronic medical records, hospital information systems, and the need to accommodate data from outside systems, this is not easy to accomplish. By utilizing a group of concepts from clinical and pathology informatics, system implementations may be improved to achieve relevant laboratory data in a format that is usable by healthcare entities to improve patient care and forward endeavors in precision medicine.


Nuclear lamin antigen and messenger RNA expression in bovine in vitro produced and nuclear transfer embryos.
The nuclear lamina is a complex meshwork of nuclear lamin filaments that lies on the interface of the nuclear envelope and chromatin and is important for cell maintenance, nucleoskeleton support, chromatin remodeling, and protein recruitment to the inner nucleolus. Protein and mRNA patterns for the major nuclear lamins were investigated in bovine in vitro fertilized (IVF) and nuclear transfer embryos. Expression of lamins A/C and B were examined in IVF bovine germinal vesicle (GV) oocytes, metaphase II oocytes, zygotes, 2-cell, 8-cell, 16-32-cell embryos, morulae, and blastocysts (n = 10). Lamin A/C was detected in 9/10 immature oocytes, 10/10 zygotes, 8/10 2-cell embryos, 4/10 morulae, 10/10 blastocysts but absent during the maternal embryonic transition. Lamin B was ubiquitously expressed during IVF preimplantation development but was only detected in 4/10 GV oocytes. Messenger RNA expression confirms that the major lamins, A/C and B1 are expressed throughout preimplantation development and transcribed by the embryo proper. Lamin A/C and B expression were observed (15 min, 30 min, 60 min, 120 min) following somatic cell nuclear transfer using adult fibroblasts and at the 2-cell, 8-cell, 16-32-cell, morula and blastocyst stage (n = 5). Altered expression levels and localization of nuclear lamins A/C and B was determined in nuclear transfer embryos during the first 2 hr post fusion, coincidental with only partial nuclear envelope breakdown as well as during the initial cleavage divisions, but was restored by the morula stage. This mechanical and molecular disruption of the nuclear lamina provides key evidence for incomplete nuclear remodeling and reprogramming following somatic cell nuclear transfer.


[Relation with patients and caregiver in home enteral nutrition (HEN)--from a pharmacist's point of view].
We opened dispensary in August 1997 and started consultation and home care in October of the same year. I learned about the necessity of guidance for caregivers and communication with people, and many other things. From now on, we need to provide our knowledge not only about medicine, but also about care goods, how to care, services to support care, and so on. Also, it is necessary for us to lighten the family's burden, and to cooperate with them in all aspects so they can provide complete care. This report describes the point at issue that I felt when helping two cases involving home enteral nutrition (HEN).


A gamma-ray pulsar timing array constrains the nanohertz gravitational wave background.
After large galaxies merge, their central supermassive black holes are expected to form binary systems. Their orbital motion should generate a gravitational wave background (GWB) at nanohertz frequencies. Searches for this background use pulsar timing arrays, which perform long-term monitoring of millisecond pulsars at radio wavelengths. We used 12.5 years of Fermi Large Area Telescope data to form a gamma-ray pulsar timing array. Results from 35 bright gamma-ray pulsars place a 95% credible limit on the GWB characteristic strain of 1.0 × 10-14 at a frequency of 1 year-1. The sensitivity is expected to scale with tobs, the observing time span, as [Formula: see text]. This direct measurement provides an independent probe of the GWB while offering a check on radio noise models.


Loss of emotional insight in behavioral variant frontotemporal dementia or "frontal anosodiaphoria".
Loss of insight is a prominent clinical manifestation of behavioral variant frontotemporal dementia (bvFTD), but its characteristics are poorly understood. Twelve bvFTD patients were compared with 12 Alzheimer's disease (AD) patients on a structured insight interview of cognitive insight (awareness of having a disorder) and emotional insight (concern over having a disorder). Compared to the AD patients, the bvFTD patients were less aware and less concerned about their disorder, and they had less appreciation of its effects on themselves and on others. After corrective feedback ("updating"), the bvFTD patients were just as aware of their disorder as the AD patients but remained unconcerned and unappreciative of its effects. These findings suggest that lack of insight in bvFTD is not due to "anosognosia," or impaired cognitive and executive awareness of disease, but to "frontal anosodiaphoria," or lack of emotional concern over having bvFTD and its impact on themselves and others.


Social support and job satisfaction in nursing staff: Understanding the link through role ambiguity.
This study aimed to analyse the mediator effect of role ambiguity between social support from supervisor and colleagues and job satisfaction in Portuguese nursing staff. Few studies have analysed the processes through which social support increases job satisfaction in the nursing context. A cross-sectional design using questionnaires. A total of 124 registered nurses and 130 certified nursing assistants participated in the study. Mediation analysis was performed by calculating percentile confidence intervals (10,000 resamples). Mediation analysis revealed a partial mediation between social support and job satisfaction through role ambiguity. The direct effect was greater in the case of supervisor support. Social support is a crucial resource in the nursing work context with a beneficial effect on well-being (e.g. reducing role stress) and job satisfaction. Managers of hospitals and health units can establish the organizational bases to facilitate this process, considering the importance of the role of the supervisors and colleagues in the provision of high levels of instrumental and socio-emotional support.


Antibiotic susceptibility pattern, risk factors, and prediction of carbapenem-resistant Pseudomonas aeruginosa in patients with nosocomial pneumonia.
This study was aimed at describing antibiotic susceptibility patterns and developing a predictive model by assessing risk factors for carbapenem-resistant Pseudomonas aeruginosa (CRPA). A retrospective case-control study was conducted at a teaching hospital in China from May 2019 to July 2021. Patients were divided into the carbapenem-susceptible P. aeruginosa (CSPA) group and the CRPA group. Medical records were reviewed to find an antibiotic susceptibility pattern. Multivariate analysis results were used to identify risk factors and build a predictive model. A total of 61 among 292 patients with nosocomial pneumonia were infected with CRPA. In the CSPA and CRPA groups, amikacin was identified as the most effective antibiotic, with susceptibility of 89.7%. The CRPA group showed considerably higher rates of resistance to the tested antibiotics. Based on the results of mCIM and eCIM, 28 (45.9%) of 61 isolates might be carbapenemase producers. Independent risk factors related to CRPA nosocomial pneumonia were craniocerebral injury, pulmonary fungus infection, prior use of carbapenems, prior use of cefoperazone-sulbactam, and time at risk (≥15 d). In the predictive model, a score >1 point indicated the best predictive ability. CRPA nosocomial pneumonia could be predicted by risk factor assessment particularly based on the underlying disease, antimicrobial exposure, and time at risk, which could help prevent nosocomial pneumonia.


ReDU: a framework to find and reanalyze public mass spectrometry data.
We present ReDU ( https://redu.ucsd.edu/ ), a system for metadata capture of public mass spectrometry-based metabolomics data, with validated controlled vocabularies. Systematic capture of knowledge enables the reanalysis of public data and/or co-analysis of one's own data. ReDU enables multiple types of analyses, including finding chemicals and associated metadata, comparing the shared and different chemicals between groups of samples, and metadata-filtered, repository-scale molecular networking.


Simultaneous right and left heart real-time, free-breathing CMR flow quantification identifies constrictive physiology.
The purpose of this study was to evaluate the ability of a novel cardiac magnetic resonance (CMR) real-time phase contrast (RT-PC) flow measurement technique to reveal the discordant respirophasic changes in mitral and tricuspid valve in flow indicative of the abnormal hemodynamics seen in constrictive pericarditis (CP). Definitive diagnosis of CP requires identification of constrictive hemodynamics with or without pericardial thickening. CMR to date has primarily provided morphological assessment of the pericardium. Sixteen patients (age 57 ± 13 years) undergoing CMR to assess known or suspected CP and 10 controls underwent RT-PC that acquired simultaneous mitral valve and tricuspid valve inflow velocities over 10 s of unrestricted breathing. The diagnosis of CP was confirmed via clinical history, diagnostic imaging, cardiac catheterization, intraoperative findings, and histopathology. Ten patients had CP, all with increased pericardial thickness (6.2 ± 1.0 mm). RT-PC imaging demonstrated discordant respirophasic changes in atrioventricular valve inflow velocities in all CP patients, with mean ± SD mitral valve and tricuspid valve inflow velocity variation of 46 ± 20% and 60 ± 15%, respectively, compared with 16 ± 8% and 24 ± 11% in patients without CP (p < 0.004 vs. patients with CP for both) and 17 ± 5% and 31 ± 13% in controls (p < 0.001 vs. patients with CP for both). There was no difference in atrioventricular valve inflow velocity variation between patients without CP compared with controls (p > 0.3 for both). Respiratory variation exceeding 25% across the mitral valve yielded a sensitivity of 100%, a specificity of 100%, and an area under the receiver-operating characteristic curve of 1.0 to detect CP physiology. Using a cutoff of 45%, variation of transtricuspid valve velocity had a sensitivity of 90%, a specificity of 88%, and an area under the receiver-operating characteristic curve of 0.98. Accentuated and discordant respirophasic changes in mitral valve and tricuspid valve inflow velocities characteristic of CP can be identified noninvasively with RT-PC CMR. When incorporated into existing CMR protocols for imaging pericardial morphology, RT-PC CMR provides important hemodynamic evidence with which to make a definite diagnosis of CP.


Atrial Fibrillation Ablation Strategy: "Ready Made" or "Tailored"?
Atrial fibrillation (AF) is the most common arrhythmia leading to hospital admissions. Catheter ablation has evolved as an effective treatment strategy; however, ablation strategies continue to evolve due to the complex and multifactorial nature of atrial fibrillation. A standardized and primarily anatomical approach may not be sufficient to eliminate all mechanisms of atrial fibrillation. A tailored ablation strategy can target specific triggers and drivers of atrial fibrillation; however, it is limited by the accuracy and sensitivity of the methods used in identifying specific mechanisms of atrial fibrillation.


Diversity of magnetotactic bacteria of the Moskva River.
Diversity of magnetotactic bacteria in the Moskva River at the Strogino area was studied using microscopy and phylogenetic analysis. Magnetotactic cocci were the predominant morphotype. Phylogenetic analysis of the 16S rRNA gene sequences revealed 13 OTUs of the orders Magnetococcales and Rhodospirillales, class Alphaproteobacteria. The shares of the relevant sequences were 90 and 10%, respectively. An axenic culture of magnetotactic spirilla was isolated from the studied community. According to the results of the 16S rRNA gene sequencing, the isolate was identified as a new Magnetospirillum species.


The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion.
Much of the epidemiology of Plasmodium falciparum in Sub-Saharan Africa focuses on the prevalence patterns of asexual parasites in people of different ages, whereas the gametocytes that propagate the disease are often neglected. One expected benefit of the widespread introduction of artemisinin-based combination therapy for malaria is a reduction in gametocyte carriage. However, the factors that affect the transmission of parasites from humans to mosquitoes show complex dynamics in relation to the intensity and seasonality of malaria transmission, and thus such benefits might not be automatic. Here, we review data on gametocyte carriage in the context of the development of naturally acquired immunity and population infectivity.


Development and characterization of membrane surface display system using molecular chaperon, prsA, of Bacillus subtilis.
We report a new membrane surface display system based on molecular chaperon, prsA, of Bacillus subtilis. Clostridium thermocellum cellulase, celA, was fused to C-terminal end of PrsA. Cellulase activity of B. subtilis protoplast, which expressed PrsA-CelA was 15 times higher compared to control strain. More than 85% of total cellulase activity was observed in surface displayed format and less than 15% of total cellulase activity was found in supernatant. Flow cytometric analysis of protoplast of PrsA-CelA fusion expressing bacteria provided another proof of uniform expression of fusion protein onto cytoplasmic membrane of B. subtilis. Without lysozyme treatment, only part of cellulase activity (10%) was observed in whole cell fraction.


Anatomically guided self-adapting deep neural network for clinically significant prostate cancer detection on bi-parametric MRI: a multi-center study.
To evaluate the effectiveness of a self-adapting deep network, trained on large-scale bi-parametric MRI data, in detecting clinically significant prostate cancer (csPCa) in external multi-center data from men of diverse demographics; to investigate the advantages of transfer learning. We used two samples: (i) Publicly available multi-center and multi-vendor Prostate Imaging: Cancer AI (PI-CAI) training data, consisting of 1500 bi-parametric MRI scans, along with its unseen validation and testing samples; (ii) In-house multi-center testing and transfer learning data, comprising 1036 and 200 bi-parametric MRI scans. We trained a self-adapting 3D nnU-Net model using probabilistic prostate masks on the PI-CAI data and evaluated its performance on the hidden validation and testing samples and the in-house data with and without transfer learning. We used the area under the receiver operating characteristic (AUROC) curve to evaluate patient-level performance in detecting csPCa. The PI-CAI training data had 425 scans with csPCa, while the in-house testing and fine-tuning data had 288 and 50 scans with csPCa, respectively. The nnU-Net model achieved an AUROC of 0.888 and 0.889 on the hidden validation and testing data. The model performed with an AUROC of 0.886 on the in-house testing data, with a slight decrease in performance to 0.870 using transfer learning. The state-of-the-art deep learning method using prostate masks trained on large-scale bi-parametric MRI data provides high performance in detecting csPCa in internal and external testing data with different characteristics, demonstrating the robustness and generalizability of deep learning within and across datasets. A self-adapting deep network, utilizing prostate masks and trained on large-scale bi-parametric MRI data, is effective in accurately detecting clinically significant prostate cancer across diverse datasets, highlighting the potential of deep learning methods for improving prostate cancer detection in clinical practice.


Chronic stress effects of high doses of vitamin D3 on Megalobrama amblycephala.
Dietary vitamin D3 plays an important role in the growth of aquatic animals, but long-term excessive feeding has potential hazards. In this study, Megalobrama amblycephala specimens were fed different experimental diets with 2000 IU/kg or 200,000 IU/kg of vitamin D3 for 90 days, in order to evaluate chronic stress effects of high doses of vitamin D3 on growth, immunity, and structural damage to enterohepatic tissues. The results showed that high doses of vitamin D3 did not have a significant influence on the growth performance of M. amblycephala (P > 0.05), but it significantly reduced the survival rate after infection by Aeromonas hydrophila (P < 0.05). Serum albumin, alkaline phosphatase, and insulin levels, as well as hepatic total antioxidant capacity, were also significantly reduced (P < 0.05). Serum cortisol levels and hepatic heat stress protein 70 expression in M. amblycephala showed that high doses of vitamin D3 significantly inhibit the anti-stress ability of M. amblycephala (P < 0.05). Paraffin tissue sections and electron microscopy showed that high doses of vitamin D3 could cause different degrees of structural damage to enterohepatic tissues of M. amblycephala. Our results indicate that, although M. amblycephala can tolerate high doses of dietary vitamin D3 over a long period, its glycolipid metabolism, immune function, anti-stress function, and resistance to pathogenic infections are adversely affected.


Publisher Correction: Targeting chromatin.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


Public health and palliative care in 2015.
Palliative care is a public health concern, because the problems faced by patients and their families represent a substantial burden of illness and cost to the society that is likely to increase markedly in the future as the world's population continues to age. There are also inequities in access to palliative care and continued unmet need. There is evidence to support palliative care services, but not yet enough information on the cost-effectiveness of many specific treatments/interventions.


Macroscopic Evaluation of Colon Cancer Resection Specimens.
Colon cancer is a common disease internationally. Outcomes have not improved to the same degree as in rectal cancer, where the focus on total mesorectal excision and pathological feedback has significantly contributed to improved survival and reduced local recurrence. Colon cancer surgery shows significant variation around the world, with differences in mesocolic integrity, height of the vascular ligation and length of the bowel resected. This leads to variation in well-recognised quality measures like lymph node yield. Pathologists are able to assess all of these variables and are ideally placed to provide feedback to surgeons and the wider multidisciplinary team to improve surgical quality over time. With a move towards complete mesocolic excision with central vascular ligation to remove the primary tumour and all mechanisms of spread within an intact package, pathological feedback will be central to improving outcomes for patients with operable colon cancer. This review focusses on the key quality measures and the evidence that underpins them.


Phosphorylation-dephosphorylation changes in yeast ribosomal proteins S2 and S6 during growth under normal and hyperthermal conditions.
Dynamic changes were observed in the phosphorylation level of a basic ribosomal protein S6 under different growth conditions of yeast culture. The maximum level of S6 phosphorylation occurred within 30 min of 32P-labelling after the transfer of cells into fresh nutrient medium. The elevation of temperature to supraoptimal level (38 degrees C and 41 degrees C) led to extensive dephosphorylation of S6 protein, and the recovery from heat shock was characterized by its rephosphorylation. Contrary to S6, phosphorylation of ribosomal protein S2 remained on unchanged level, irrespective of growth conditions.


Antioxidant and antibacterial compounds from feijoa leaf extracts obtained by pressurized liquid extraction and supercritical fluid extraction.
This work investigated the efficiency of pressurized liquid extraction (PLE) and supercritical fluid extraction with cosolvent (SFE) in obtaining feijoa leaf extracts with high antioxidant and antibacterial activities. PLE was performed in customized equipment with environmentally friendly solvents, at 40/80 °C, in dynamic and static mode, and SFE was carried out for 210 min at 30 MPa, 55 °C and 15% ethanol-water as cosolvent. PLE extract (80 °C/ethanol-water/dynamic) provided the highest yield, total phenolic content, and antioxidant activities, but it was not effective as antibacterial agent. In contrast, SFE extract exhibited effectiveness against S. aureus, E. coli, and S. typhimurium, with minimum inhibitory concentration values from 14,211 to 3,553 µg.mL-1. Finally, gallic acid, catechin and isoquercetin were the major phenolics identified by liquid chromatography. Our findings revealed that feijoa leaf extracts by PLE and SFE have remarkable bioactivity, presenting a great potential to be used as natural food additives.


Pigmented atypical fibroxanthoma.
The purpose of this report is to call attention to a pigmented variant of atypical fibroxanthoma that resembles malignant melanoma, both clinically and histopathologically. Thirty-eight cases of atypical fibroxanthoma were examined for the presence of pigmented areas. Four such cases were found. Neoplastic cells showed erythrophagocytosis and accumulation of haemosiderin pigment in the cytoplasm. In three cases, immunohistochemical studies using a battery of antibodies were performed. Neoplastic cells were strongly positive for vimentin and weakly positive for CD68, whereas they were negative for melanocytic markers, including S100 protein, HMB45, and the monoclonal antibody NK1-C3 to melanoma-associated antigen. Pigmented atypical fibroxanthoma represents a poorly recognized variant of the neoplasm that may be easily misinterpreted as malignant melanoma. To the best of our knowledge, this is the first report of erythrophagocytosis in atypical fibroxanthoma.


Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.
Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.


The value of pre-discharge Duplex scanning in infrainguinal graft surveillance.
Protocols and criteria for Duplex-based graft surveillance programmes (GS) vary widely as to the optimum regimens for maximising detection of "at risk" grafts. Few centres recommend starting GS before discharge. The aim of this study was to audit our experience with respect to early scanning. Vascular Studies Unit, Bristol Royal Infirmary. The records of 123 patients entering GS from January 1992 were reviewed. Patients were scanned at 1 week, 6 weeks and 3, 6, 9 and 12 months post-bypass. Haemodynamic criteria used were a peak mean velocity (PMV) less than 45 cm/s and a focal velocity disturbance with a V2/V1 ratio of 1.5 or more. Forty-six abnormalities (37% detection rate) were identified on scans within one week. In all cases, on-table completion studies with either arteriography and/or flow measurements had failed to identify the anomalies subsequently detected by Duplex. At 1 week, six grafts had occluded, 27 had a focal PMV increase (mean V2/V1 ratio: 2.6; range 1.5-4.3), four had low flow velocities, four had arteriovenous fistulae, one contained mobile thrombus, two had retained cusps and two had hamstring entrapment. Of 40 patent, but compromised grafts, 18 warranted immediate investigation. Of the 27 patients with velocity disturbances on Duplex, 25 were simply observed but, eight have since required intervention for definitive stenoses at these sites which, in retrospect, were evident within the first postoperative week. Pre-discharge scanning is a useful modality for detecting technical problems. Intrinsic graft abnormalities, possibly the sites of future definitive stenoses, have been visualised even at 1 week and once identified, can be more closely scrutinised thereafter. Pre-discharge colour Duplex is recommended as standard practice for quality control after infrainguinal bypass.


Photodegradation of wood at elevated temperature: colour change.
The purpose of this investigation was to evaluate the effect of elevated temperature on the photodegradation of solid wood. The work presented here, dealt with the changes of colour during the degradation process. Wood samples were irradiated by mercury vapour lamp at 80°C and at 30°C to screen out the effect of thermal decomposition during photodegradation. Results demonstrated that the same light irradiation resulted in considerably greater redness increase at 80°C than at 30°C. Pine samples showed 57% higher redness change at 80°C than at 30°C during the 200h light exposure. Corresponding data for spruce, ash and poplar were 33%, 40% and 15%, respectively. Results indicated that the extractive content has an important role in thermal decomposition during photodegradation. The elevated environmental temperature did not affect yellowness.


The vascular nervous skeleton: a disregarded factor of vascular pathology.
The nervous supply of the vascular wall in its organ entirety represents the felt-like 'nervous skeleton'. Its growth is more vulnerable than that of any other tissue component of the developing vessel wall. Selective growth impairment of the vascular nervous skeleton should result in developmental vascular stenosis. Escape of the epithelial or smooth muscle cells from the confines of the nervous skeleton should be taken into account as a possible common denominator of carcinogenesis and atherogenesis.


Comparison of Scheuermann's kyphosis correction by combined anterior-posterior fusion versus posterior-only procedure.
Conventional treatment of rigid deformity in Scheuermann's kyphosis (SK) in young patients includes a preliminary anterior spinal release and fusion (ASF) followed by posterior spinal fusion and instrumentation (PSF). However, recently there are more trends to do posterior-only surgery for correction of this deformity. The aim of our study was to compare clinical and radiological outcomes of ASF/PSF and PSF-only procedures in treatment of SK. In a prospective clinical and radiological review, thirty operated SK patients in two groups were evaluated. Group A: ASF/PSF technique (n: 16) and group B: PSF-only procedure (n: 14) were followed for at least 2 years (average 57.6 months). Two groups were well matched for the following four criteria: average age, flexibility status, posterior fusion levels, and preoperative Cobb's kyphosis angle. Oswestry disability index (ODI) and scoliosis research society questionnaire-30 (SRS-30) and radiological (kyphosis correction, correction loss, sagittal balance) parameters were evaluated before and after surgery and at the final follow-up. In group A, primary thoracic Cobb's kyphosis, immediate post-operative kyphosis, and final follow-up kyphosis angle were 83.6°, 41.4° and 43°, respectively (P < 0.05). Correction rate and correction loss were 50.5 % and 1.6° ± 2.4, respectively. In group B, the corresponding values were 81.9°, 40.1° and 43.2°, respectively (P < 0.05). Correction rate and correction loss were 51 % and 3.1° ± 2.5, respectively. SRS-30 and ODI scores in group A were averaged 68.5 and 21.3 preoperatively and 128.7 and 6.25 at the final follow-up, respectively. In group B, the corresponding values were 64 and 23.2 preoperatively and 133.5 and 5.8 at the final follow-up, respectively. Clinical and radiological parameters were similar in both groups after surgical correction while, complication rates, operation time and blood loss were significantly higher in ASF/PSF procedure.


Isolation and characterization of plant growth-promoting rhizobacteria and their effects on the growth of Medicago sativa L. under salinity conditions.
Plant growth-promoting rhizobacteria are a group of free-living bacteria that colonize plant rhizosphere and benefit plant root growth, thereby increasing host plant to cope with salinity induced stress. The aim of this study was to (1) isolate and characterize auxin-producing bacteria showing a high plant growth-promoting (PGP) potential, and (2) evaluate the PGP effects on the growth of Medicago sativa L under salinity stress (130 mM NaCl). Of thirteen isolates, Bacillus megaterium NRCB001 (NRCB001), B. subtilis subsp. subtilis NRCB002 (NRCB002) and B. subtilis NRCB003 (NRCB003) had the ability to produce auxin, which ranged from 47.53 to 154.38 μg ml-1. The three auxin-producing bacterial strains were shown multiple PGP traits, such as producing siderophore and NH3, showing ACC deaminase activity, solubilize phosphate and potassium. Furthermore, NRCB001, NRCB002, and NRCB003 could survive in LB medium containing 1750 mM NaCl. The three auxin-producing with salinity tolerance strains were selected for further analyses. In greenhouse experiments, when inoculated with NRCB001, NRCB002 and NRCB003, dry weight of alfalfa significantly (P < 0.05) increased by 24.1%, 23.1% and 38.5% respectively, compared with those of non-inoculated control seedlings under normal growth condition. When inoculated with NRCB002 and NRCB003, dry weight of alfalfa significantly (P < 0.05) increased by 96.9 and 71.6% respectively, compared with those of non-inoculated control seedlings under 130 mM NaCl condition. Our results indicated that NRCB002 and NRCB003 having PGP traits are promising candidate strains to develop biofertilizers, especially used under salinity stress conditions.


Aversive stimuli and loss in the mesocorticolimbic dopamine system.
There is mounting evidence that the mesolimbic dopamine system carries valuation signals not only for appetitive or gain-related stimuli, with which it is traditionally associated, but also for aversive and loss-related stimuli. Cellular-level studies demonstrate that the neuronal architecture to support aversive stimuli encoding in this system does exist. Both cellular-level and human neuroimaging research suggest the co-existence of appetitive and aversive prediction-error signals within the mesocorticolimbic system. These findings shift the view of the mesocorticolimbic system as a singular pathway for reward to a system with multiple signals across a wide range of domains that drive value-based decision making.


Thermoascus aurantiacus CBHI/Cel7A production in Trichoderma reesei on alternative carbon sources.
To develop functional enzymes in cellulose hydrolysis at or above 70 degrees C the cellobiohydrolase (CBHI/Cel7A) of Thermoascus aurantiacus was cloned and expressed in Trichoderma reesei Rut-C30 under the strong cbh1 promoter. Cellulase production of the parental strain and the novel strain (RF6026) was examined in submerged fermentation experiments using various carbon sources, which were lactose, Solka Floc 200 cellulose powder, and steam pretreated corn stover. An industrially feasible production medium was used containing only distiller's spent grain, KH(2)PO(4), and (NH(4))(2)SO(4). Enzyme production was followed by measurements of protein concentration, total cellulase enzyme activity (filter paper activity), beta-glucosidase activity, CBHI activity, and endogenase I (EGI) activity. The Thermoascus CBHI/Cel7A activity was taken as an indication of the heterologous gene expression under the cbh1 promoter.


A comparative trial of posttransplant immunosuppression in patients transplanted for thalassemia. Cyclosporine alone versus cyclosporine, cyclophosphamide, and methotrexate.
This study compares the efficacy of 2 posttransplant immunosuppressive regimens for prevention of graft-versus-host disease (GVHD). Forty-four patients, ages 8-15 years, with homozygous beta thalassemia received marrow allografts from HLA-identical siblings following an ablative regimen of busulfan and cyclophosphamide. Twenty-two patients received cyclosporine (CsA) alone and 22 received cyclosporine, cyclophosphamide, and methotrexate for prophylaxis against GVHD. Two who received CsA alone have died (1 of graft rejection and 1 of acute GVHD) as did 4 patients who received 3 drugs (1 of rejection, 1 of acute GVHD, 1 of infection and cardiac failure before engraftment, and 1 of acute respiratory failure before engraftment). One patient in each group rejected the transplant and survives with thalassemia. The probability of developing acute GVHD was 41% for the CsA group and 15% for the 3-drug group (P = less than 0.05). Patients receiving CsA alone had a probability of event-free survival of 86% compared to 77% in the group receiving 3 drugs (P = 0.40) with a followup of 209-706 days. Although the study showed a decrease in the incidence of GVHD in recipients of the more intensive prophylactic regimen, this study was terminated since it was apparent that even if larger numbers of patients were studied it would be difficult to demonstrate a significant survival advantage with the use of this drug regimen.


Juxtamedullary afferent and efferent arterioles constrict to renal nerve stimulation.
Sympathetic neural control of afferent and efferent arterioles of inner cortical (juxtamedullary) glomeruli has not been established, in part, because of difficulty accessing these vessels, normally located deep below the kidney surface. In this study we utilized the rat hydronephrotic kidney model to visualize the renal microcirculation and to quantitate the responses of juxtamedullary arterioles to brief (30 sec) renal nerve stimulated (RNS). Juxtamedullary afferent and efferent arterioles constricted in a frequency-dependent fashion to RNS, achieving a maximal constriction of 35% to 8 Hz stimulation. In these same kidneys, outer cortical afferent arterioles also constricted to RNS but outer cortical efferent arterioles did not. Microinjection of norepinephrine (NE) around single outer cortical efferent arterioles (to avoid the constriction of preglomerular vessels) constricted the efferent arterioles. However, the afferent arterioles of the same glomeruli were considerably more responsive to microinjected NE. Thus, the lack of constriction of outer cortical efferent arterioles to RNS may relate, in part, to their low sensitivity to NE, the primary neurotransmitter. These direct observations indicate that the juxtamedullary efferent arterioles are responsive to renal nerve stimulation whereas the outer cortical efferent vessels are not. These results, which should be cautiously extrapolated to normal filtering kidneys, indicate that glomerular hemodynamic changes evoked by the sympathetic nervous system are different for outer cortical and inner cortical glomeruli.


New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-latanoprost.
Reduction of intraocular pressure is the only proven method to treat glaucoma. Initial treatment of glaucoma commonly involves using anti-glaucoma medications either as monotherapy or combination therapy. Studies on aqueous humour dynamics have contributed to our understanding of aqueous outflow mechanisms that have led to the discovery of new drugs. Three new drugs (latanoprostene bunod 0.24%, netarsudil 0.02%, and fixed combination netarsudil 0.02% -latanoprost 0.005%) have been introduced recently in the market with novel mechanisms of action. Latanoprostene bunod 0.024% is a nitric oxide-donating prostaglandin F2α analogue which increases the aqueous outflow both by uveoscleral and trabecular pathways. Netarsudil 0.02% is a potent Rho kinase/norepinephrine transporter inhibitor acting by increasing the trabecular outflow, decreasing the aqueous production, and possibly decreasing the episcleral venous pressure. This review highlights the role of these drugs in the management of glaucoma, with an overview of the major clinical trials on their efficacy, safety, and tolerability.


Hemodynamic physiology in aortic arch and trigger factors of atherosclerosis.
Magnetic resonance angiography showed that blood flow in the aortic arch during protodiastole is separated into the opposite flows, which are temporarily arrested at the certain sites creating the flat front of the flow. The protodiastolic antegrade peak acceleration 6-fold surpasses the systolic one. Due to adhesion, the high gradient pressure forces can damage the vascular wall.


Can menopausal hormone therapy prevent coronary heart disease?
Observational studies show that women who take menopausal hormone therapy (MHT) have a greatly reduced risk of coronary heart disease (CHD). But in some large randomized controlled trials, MHT failed to decrease CHD and so has been deemed inappropriate for long-term prophylaxis against atherosclerosis or other chronic diseases associated with the menopause. Despite the apparent strength of this conclusion, several recent reports suggest that MHT could be atheroprotective when started close to the menopause, and effects of early discontinuation of MHT have never been studied in randomized trials. Here, we examine these reports and highlight existing uncertainty regarding the effects of long-term continuation versus early discontinuation of early-start MHT on atherosclerosis and CHD risk. We call for new research on this question, and an evidence-based review of existing recommendations for MHT.


Vortex focusing of ions produced in corona discharge.
Completeness of the ion transportation into an analytical path defines the efficiency of ionization analysis techniques. This is of particular importance for atmospheric pressure ionization sources like corona discharge, electrospray, ionization with radioactive ((3)H, (63)Ni) isotopes that produce nonuniform spatial distribution of sample ions. The available methods of sample ion focusing are either efficient at reduced pressure (~1Torr) or feature high sample losses. This paper deals with experimental research into atmospheric pressure focusing of unipolar (positive) ions using a highly swirled air stream with a well-defined vortex core. Effects of electrical fields from corona needle and inlet capillary of mass spectrometer on collection efficiency is considered. We used a corona discharge to produce an ionized unipolar sample. It is shown experimentally that with an electrical field barrier efficient transportation and focusing of an ionized sample are possible only when a metal plate restricting the stream and provided with an opening covered with a grid is used. This gives a five-fold increase of the transportation efficiency. It is shown that the electric field barrier in the vortex sampling region reduces the efficiency of remote ionized sample transportation two times. The difference in the efficiency of light ion focusing observed may be explained by a high mobility and a significant effect of the electric field barrier upon them. It is possible to conclude based on the experimental data that the presence of the field barrier narrows considerably (more than by one and half) the region of the vortex sample ion focusing.


Venetoclax: First Global Approval.
Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.


The new oral adenosine A1 receptor agonist capadenoson in male patients with stable angina.
Anti-ischaemic effect of A1 adenosine receptor agonists was shown in animal and preclinical studies. The present proof-of-concept study aimed at evaluation of the efficacy and safety of a new adenosine A1 receptor agonist capadenoson in patients with stable angina. This was a randomized, double-blind, placebo-controlled, single dose-escalating, multicenter trial comparing the effect of capadenoson at 1, 2.5, 5, 10, and 20 mg versus placebo. For each dose step patients were randomized to receive single doses of either capadenoson or matching placebo in a 5:1 ratio. The primary efficacy variable was the absolute difference in heart rate (HR) at maximum comparable level of workload between baseline and post dose exercise tolerance test at maximum concentration of capadenoson. Capadenoson effect on total exercise time and time to 1-mm ST-segment depression were also measured. Sixty-two male patients with stable angina were enrolled in the study. There was a consistent trend for HR reduction at comparable maximum work load in active treatment groups, with significant differences against placebo for 10 and 20 mg (HR reduction by 12.2 and 6.8 beats per min, p = 0.0002 and p = 0.032, respectively). A statistically significant trend (p = 0.0003) for a reduction in HR with increasing doses of capadenoson was shown. Increases in total exercise time and time to 1-mm ST-segment depression were also observed. In patients with stable angina capadenoson lowers exercise HR at comparable maximum workload, which is associated with improved total exercise time and prolongation of time to ischaemia.


The experience of new graduate nurses in rural practice in New South Wales.
The recruitment and retention of health professionals in rural areas is a long-standing concern in Australia. In the context of an ageing rural nursing workforce, recruitment and retention of new graduate nurses is an important issue. To explore the role transition for new graduate nurses in rural practice in New South Wales (NSW). This study utilised a qualitative hermeneutic-phenomenological framework. A purposive sample was drawn from eight rural health care facilities in NSW where participants were employed as new graduate nurses in the first year of a graduate nurse transition program. The ward culture, workload and level of responsibility within rural healthcare facilities were of concern for new graduates and influenced their retention within the rural nursing workforce. There are specific aspects of the transition experience that are unique to graduate nurses in rural practice settings. The findings have implications for undergraduate curricula in the preparation of graduates for the reality of the rural nursing workforce. Additionally, the expectations that staff have of new graduates as they enter the nursing workforce, and the workplace cultural issues recognised as having a significant impact on the retention of graduates must be addressed locally and at the area health service level if nurses are to be retained in this unique nursing specialty.


Protein flexibility and rigidity predicted from sequence.
Structural flexibility has been associated with various biological processes such as molecular recognition and catalytic activity. In silico studies of protein flexibility have attempted to characterize and predict flexible regions based on simple principles. B-values derived from experimental data are widely used to measure residue flexibility. Here, we present the most comprehensive large-scale analysis of B-values. We used this analysis to develop a neural network-based method that predicts flexible-rigid residues from amino acid sequence. The system uses both global and local information (i.e., features from the entire protein such as secondary structure composition, protein length, and fraction of surface residues, and features from a local window of sequence-consecutive residues). The most important local feature was the evolutionary exchange profile reflecting sequence conservation in a family of related proteins. To illustrate its potential, we applied our method to 4 different case studies, each of which related our predictions to aspects of function. The first 2 were the prediction of regions that undergo conformational switches upon environmental changes (switch II region in Ras) and the prediction of surface regions, the rigidity of which is crucial for their function (tunnel in propeller folds). Both were correctly captured by our method. The third study established that residues in active sites of enzymes are predicted by our method to have unexpectedly low B-values. The final study demonstrated how well our predictions correlated with NMR order parameters to reflect motion. Our method had not been set up to address any of the tasks in those 4 case studies. Therefore, we expect that this method will assist in many attempts at inferring aspects of function.


Coiled-coil domain containing 3 suppresses breast cancer growth by protecting p53 from proteasome-mediated degradation.
Coiled-coil domain containing 3 (CCDC3) was previously shown to regulate liver lipid metabolism as a secretory protein. Here, we report an unexpected intracellular role of CCDC3 as a tumor suppressor in breast cancer (BrC). Bioinformatics datasets analysis showed that CCDC3 is under-expressed in BrCs, while its higher levels are correlated with higher overall survival and lower relapse of cancer patients, and CCDC3 is positively correlated with p53 and its target genes. Ectopic CCDC3 markedly suppressed proliferation, colony formation, and xenograft tumor growth by augmenting p53 activity in BrC cells. Depletion of endogenous CCDC3 by CRISPR-Cas9 increased proliferation and drug resistance of BrC cells by alleviating 5-Fluorouracil (5-FU)-induced p53 level and activity. Mechanistically, CCDC3 bound to the C-termini of p53 and MDM2, consequently stabilizing p53 in the nucleus and impairing MDM2 recruitment of p53 to the 26S proteosome without inhibiting p53 ubiquitination. p53 induced CCDC3 expression by binding to its promoter in BrC cells. Our results unveil a unique mechanism underlying CCDC3 activation of p53 in a positive feedback fashion to suppress BrC growth.


Porokeratosis has neoplastic clones in the epidermis: microfluorometric analysis of DNA content of epidermal cell nuclei.
Clinical evidence of malignant epithelial tumors developing on the lesions of porokeratosis has accumulated. To determine the cytologic basis for the malignant change of porokeratosis, the nuclear DNA content of epidermal cells from porokeratosis lesions was measured using microfluorometry. A total of 42% of 33 porokeratosis skin lesions in eight of the 16 patients showed DNA polyploidization in the epidermis. Most of the porokeratosis skin lesions, with or without DNA polyploidization, increased cell proportions in the S and G2/M phase range. These findings suggest that porokeratosis is undergoing the neoplastic process, and is the precursor skin manifestation of malignant tumors.


Estrogen-like activity of cyclic peptides from Vaccaria segetalis extracts.
Methanol and ethyl acetate extracts of Wang Bu Liu Xing (seeds of Vaccaria segetalis, Caryophyllaceae) and cyclic peptides (named segetalins A and B) obtained from the extracts were shown to have an estrogen-like activity.


Evidence for immunological cross-reaction between sporozoites and blood stages of a human malaria parasite.
Malaria parasites (Plasmodium spp.) show a complex pattern of development in the mammalian host and many studies support the view that the surface of the sporozoite, injected by the mosquito, has no antigens in common with the erythrocytic stage of development. For example, immunization with the erythrocytic parasites generates antisera with negligible titre by indirect immunofluorescence to the sporozoite surface. Although monoclonal antibodies prepared against erythrocytic stages were reported to show cross-reaction to the sporozoite stage, this appeared to be due to cytoplasmic antigens exposed by the method of sporozoite preparation, and in Plasmodium knowlesi, a cDNA clone coding for the circumsporozoite antigen, the major protein of the sporozoite surface, showed no hydridization to mRNA isolated from the erythrocytic stages. Here, however, we present evidence for an antigenic determinant shared by the sporozoite surface and the erythrocytic stages of the human malaria parasite, P. falciparum. Moreover, our studies show that the antigen(s) elicit a strong immune response in man.


LC/MS/MS identification of 20-hydroxyecdysone in a scorpion (Liocheles australasiae) and its binding affinity to in vitro-translated molting hormone receptors.
Recent advances in mass spectrometry (MS) technology have facilitated the detection and quantification of minor components in organisms and the environment. In this study, we successfully identified 20-hydroxyecdysone (20E) in first instar nymphs (7 days after hatching) of the scorpion Liocheles australasiae, using tandem mass spectrometry combined with high-performance liquid chromatography (LC/MS/MS). This substance was not found in adults after the fifth stage. Other possible molting hormone candidates such as makisterone A (MaA) and ponasterone A (PoA), both of which are reported to be the molting hormones of a few arthropod species, were not detected in this scorpion. The ligand-receptor binding of 20E and its analogs was quantitatively evaluated against the in vitro-translated molting hormone receptor, the heterodimer of ecdysone receptor (EcR) and the retinoid X receptor (RXR) of L. australasiae (LaEcR/LaRXR). The concentrations of ecdysone (E), MaA, 20E, and PoA that are required to inhibit 50% of [(3)H]PoA binding to the LaEcR/LaRXR complex were determined to be 1.9, 0.69, 0.05, and 0.017 μM, respectively. The activity profiles of these 4 ecdysteroids are consistent with those obtained for the molting hormone receptors of several insects. The binding of a non-steroidal E agonist, tebufenozide, to EcR was not observed even at high concentrations, indicating that the structure of the ligand-binding pocket of LaEcR is not favorable for interaction with tebufenozide.


Human vitreous distribution of linezolid after a single oral dose.
To evaluate the relationship between vitreous linezolid concentrations versus both time and serum concentrations after a single 600 mg oral dose. Two groups of six subjects undergoing a pars plana vitrectomy indicated by macular pucker or full thickness macular hole were given a single tablet of linezolid before surgery. The early group underwent vitrectomy at random times before the time of maximum serum linezolid concentration (i.e., 77 minutes) and the late group underwent vitrectomy at random times afterward. Each patient had a serum sample drawn shortly before and after vitrectomy and the vitreous specimen was sampled at the initiation of surgery. The early group and late group had mean vitreous linezolid concentrations of 0.06 mcg/mL and 1.25 mcg/mL, respectively. The vitreous linezolid concentration showed a strong correlation to the interpolated serum concentration (R2 = 0.74, P < 0.01) at the time of vitrectomy. The study demonstrates that linezolid penetrates the blood-retina barrier in noninflamed eyes. Because the vitreous concentrations appeared to exponentially trend upward with time and 33% of the late group achieved sufficient MIC90 levels for the common pathogens found in postoperative endophthalmitis, adequate concentrations might be achieved with an altered dosing regimen to achieve higher serum steady state levels. Further study is warranted.


A swollen cheek, an unusual course of acute mastoiditis.
An acute mastoiditis can occasionally present as a swelling in front of the ear. An inflammation of the air cells of the mastoid cavity can spread, via the cells in the root of the zygomatic arch, to the soft tissues of the cheek. Unfamiliarity with this underlying cause of a swollen cheek can lead to delay of proper treatment with potential harm to the patient. This case presents such an uncommon form of mastoiditis in a 3-year-old boy; the failure to recognize the disease initially led to extensive osteomyelitis of the temporal bone. CT scanning was important in establishing the cause of the persistently severe condition of the boy, in spite of bilateral myringotomies and mastoidectomy on the right side. Destruction of bone from the zygomatic arch to the suture between temporal and occipital bone was shown. Extensive removal of diseased bone was achieved neurosurgically, thus leading to uneventful recovery.


Automated Perfusion Calculations vs. Visual Scoring of Collaterals and CBV-ASPECTS : Has the Machine Surpassed the Eye?
Use of automated perfusion software has gained importance for imaging of stroke patients for mechanical thrombectomy (MT). We aim to compare four perfusion software packages: 1) with respect to their association with 3‑month functional outcome after successful reperfusion with MT in comparison to visual Cerebral Blood Volume - Alberta Stroke Program Early CT Score (CBV-ASPECTS) and collateral scoring and 2) with respect to their agreement in estimation of core and penumbra volume. This retrospective, multicenter cohort study (2015-2019) analyzed data from 8 centers. We included patients who were functionally independent before and underwent successful MT of the middle cerebral artery. Primary outcome measurements were the relationship of core and penumbra volume calculated by each software, qualitative assessment of collaterals and CBV-APECTS with 3‑month functional outcome and disability (modified Rankin scale >2). Quantitative differences between perfusion software measurements were also assessed. A total of 215 patients (57% women, median age 77 years) from 8 centers fulfilled the inclusion criteria. Multivariable analyses showed a significant association of RAPID core (common odds ratio, cOR 1.02; p = 0.015), CBV-ASPECTS (cOR 0.78; p = 0.007) and collaterals (cOR 0.78; p = 0.001) with 3‑month functional outcome (shift analysis), while RAPID core (OR 1.02; p = 0.018), CBV-ASPECTS (OR 0.77; p = 0.024), collaterals (OR 0.78; p = 0.007) and OLEA core (OR 1.02; p = 0.029) were significantly associated with 3‑month functional disability. Mean differences on core estimates between VEOcore and RAPID were 13.4 ml, between syngo.via and RAPID 30.0 ml and between OLEA and RAPID -3.2 ml. Collateral scoring, CBV-ASPECTS and RAPID were independently associated with functional outcome at 90 days. Core and Penumbra estimates using automated software packages varied significantly and should therefore be used with caution.


Population density gratings induced by few-cycle optical pulses in a resonant medium.
Creation, erasing and ultrafast control of population density gratings using few-cycle optical pulses coherently interacting with resonant medium is discussed. In contrast to the commonly used schemes, here the pulses do not need to overlap in the medium, interaction between the pulses is mediated by excitation of polarization waves. We investigate the details of the dynamics arising in such ultrashort pulse scheme and develop an analytical theory demonstrating the importance of the phase memory effects in the dynamics.


Abnormal liver function in chronic hypervitaminosis A.
A case of chronic hypervitaminosis A is reported in a 57-year-old woman who took vitamin preparations for alopecia. Liver biopsy of the patient showed both an increase in the number and size of fat-storing cells on light microscopy and rapidly fading green autofluorescence of vitamin A. Electron microscopy confirmed the presence of engorged fat-storing cells in the space of Disse and minor toxic changes in hepatocytes. This case illustrates the early hepatic changes of chronic hypervitaminosis A and indicates a need for restriction of sales of vitamin preparations.


Effect of contralateral disease on duplex measurements of internal carotid artery stenosis.
Duplex ultrasonography is increasingly used as the sole method of imaging before carotid endarterectomy. This study investigated the measured degree of stenosis in the contralateral carotid artery before and after operation. Duplex-derived peak systolic velocity (PSV), end-diastolic velocity (EDV) and internal carotid artery/common carotid artery (ICA/CCA) velocity ratios were measured in the contralateral unoperated ICA before 131 consecutive unilateral endarterectomies and compared with preoperative angiographic findings. Three months later duplex scans were repeated to assess whether there had been any alteration in the severity of the stenosis in the contralateral unoperated artery. Bilateral ICA disease (greater than 50 per cent stenosis) was present in 50 patients (38 per cent). Three months after operation, ultrasonography of the 105 unoperated, patent, contralateral arteries showed a decrease in mean(s.d.) PSV (1.21(0. 83) versus 1.07(0.69) m/s; P < 0.01) and EDV (0.41(0.29) versus 0. 35(0.24) m/s; P < 0.01). This resulted in 14 (42 per cent) of 33 patients with contralateral disease being downgraded to a less severe category of stenosis. Use of the ICA/CCA velocity ratio prevented overestimation in eight of the 14 patients, while preoperative angiography correctly classified 13 of the 14 patients. Bilateral carotid artery disease can cause overestimation of the severity of stenosis by duplex ultrasonography if absolute velocity is used as the main criterion.


A general model of the P2 protein of peripheral nervous system myelin based on secondary structure predictions, tertiary folding principles, and experimental observations.
The amino acid sequence of the P2 protein of peripheral myelin was analyzed with regard to regions of probable alpha-helix, beta-structure, beta-turn, and unordered conformation by means of several algorithms commonly used to predict secondary structure in proteins. Because of the high beta-sheet content and virtual absence of alpha-helix shown by the circular dichroic spectra of the protein, a bias was introduced into the algorithms to favor the beta-structure over the alpha-helical conformation. In order to define those beta-sheet residues that could lie on the external hydrophilic surface of the protein and those that could lie in its hydrophobic interior, the predicted beta-strands were examined for charged and uncharged amino acids located at alternating positions in the sequence. The sequential beta-strands in the predicted secondary structure were then ordered into beta-sheets and aligned according to generally accepted tertiary folding principles and certain chemical properties peculiar to the P2 protein. The general model of the P2 protein that emerged was a "Greek key" beta-barrel, consisting of eight antiparallel beta-strands with a two-stranded ribbon of antiparallel beta-structure emerging from one end. The model has an uncharged, hydrophobic core and a highly hydrophilic surface. The two Cys residues, which form a disulfide, occur in a loop connecting two adjacent antiparallel strands. Two hydrophilic loops, each containing a cluster of acidic residues and a single Phe, protrude from one end of the molecule. The general model is consistent with many of the properties of the actual protein, including the relatively weak nature of its association with myelin lipids and the positions of amino acid substitutions. Alternative beta-strand orderings yield three specific models having different interstrand connections across the barrel ends.


[Characteristics of the enamel mineralization of the intact permanent teeth in children 6 to 14 years old].
The composition of enamel from the first permanent lower molars was studied intravitally in 140 somatically asymptomatic children with intact teeth. The contents of Ca, P and molar Ca/P ratio were determined. At the age of 10, 13 and 14 years Ca levels were higher as related to 10, 13 and 14 for cuspid and to 13 and 14 years for paracervical specimen. After 10 years, cuspid Ca content was higher than cervical. At the age of 10 to 14 cuspid P content was reduced. Age-related increase in molar Ca/P ratio was also found. The values attained those characteristic of adult intact enamel at cuspid by the age of 9, and at cervix by 12 years. The data suggest that cuspid enamel matures earlier than pericervical one.


Evaluation of reference genes for transcript normalization in Fragaria chiloensis fruit and vegetative tissues.
Quantitative real-time PCR (RT-qPCR) is used extensively in gene expression studies. For adequate comparisons, the identification and use of reliable reference genes are crucial. Nevertheless, the availability of such genes in strawberry species is limited and has yet to be described for the Chilean strawberry, Fragaria chiloensis. In this study, the expression dynamics of a set of 10 candidate reference genes were analyzed in various F. chiloensis vegetative tissues (root, runners, stem, leaf, and flower), and fruits at different ripening stages or subjected to different hormonal treatments (ABA, auxin). The expression stability of candidate genes was examined by a series of algorithms, such as geNorm, NormFinder, BestKeeper, and ΔCt, for comparisons and rankings. Finally, by using RefFinder, a comprehensive and comparative ranking of the four methods was achieved. The results highlight that the expression stability of candidate reference genes fluctuates depending on tissue type, fruit stage, and hormonal treatment. As reference genes, the use of FcCHP2 and FcACTIN1 is recommended for F. chiloensis vegetative tissues; FcDBP and FcCHP1 for fruit ripening stages; FcGAPDH and FcDBP for fruit subjected to ABA and NDGA treatments; FcCHP1 and FcCHP2 for fruit under AUXIN and TIBA treatments; and FcDBP and FcCHP2 when all fruit stages and hormonal treatments are compared. If just one reference gene is employed as a normalizer, FcDBP should be chosen as it is the most stable internal control in most conditions. Therefore, the present study delivers a set of reliable reference genes for RT-qPCR expression analysis in F. chiloensis tissues and fruits subjected to several hormonal treatments. The online version contains supplementary material available at 10.1007/s12298-022-01227-y.


Long-term potentiation is associated with increases in quantal content and quantal amplitude.
Long-term potentiation (LTP) of synaptic transmission in CA1 neurons of the hippocampus, elicited by the conjunction of presynaptic firing and postsynaptic depolarization, is an important model of plasticity, which may underlie memory storage. Although induction of LTP takes place in the postsynaptic cell, it is not clear whether it is expressed through an enhancement of transmitter release or through an increased postsynaptic response to the same amount of transmitter. Analysis of the trial-to-trial amplitude fluctuations of synaptic signals, that is quantal analysis, gives an important insight into the probabilistic mechanisms of transmission, although attempts to apply it to the mode of expression of LTP have so far yielded inconsistent results, at least in part because they have relied on models of transmitter release that have not been confirmed experimentally. Here we report clear evidence for quantal fluctuation in a subset of cells. Induction of LTP in these cells causes abrupt increases in either quantal content or quantal amplitude, or both. This shows that two different mechanisms can underlie the maintenance of LTP.


Corrigendum to "Polydopamine/poly(sulfobetaine methacrylate) Co-deposition coatings triggered by CuSO4/H2O2 on implants for improved surface hemocompatibility and antibacterial activity" [ Bioactive materials 6 (2021) 2546-2556].
[This corrects the article DOI: 10.1016/j.bioactmat.2021.01.025.].


Hydrogen bonding in C-substituted nitroanilines: molecular ladders in 2-trifluoromethyl-4-nitroaniline and sheets of R(4)(4)(12) and R(4)(4)(32) rings in 3-trifluoromethyl-4-nitroaniline.
In 2-trifluoromethyl-4-nitroaniline, C(7)H(5)F(3)N(2)O(2), (I), the molecules lie across a mirror plane in space group Pnma. The molecules are linked by paired N-H...O hydrogen bonds to form a C(8)[R(2)(2)(6)] chain of rings, pairs of which are linked into a molecular ladder by a single C-H...O hydrogen bond. The isomeric 3-trifluoromethyl-4-nitroaniline, (II), has Z' = 2 in space group P2(1)/c. Each molecule is linked to four others by N-H...O hydrogen bonds to form sheets built from alternating R(4)(4)(12) and R(4)(4)(32) rings.


Two novel mutations affecting splicing in the IRF6 gene associated with van der Woude syndrome.
van der Woude syndrome (VWS) is a rare autosomal dominant oral facial disorder characterized by high penetrance and variable expression, manifesting with lower lip pits, cleft lips with or without cleft palate, and isolated cleft palate. The phenotypic expression of clefts ranges from incomplete to complete. Different studies have demonstrated an association between VWS and mutations of the IRF6 (interferon regulatory factor) gene. In this study, we describe 2 novel Italian families with VWS harboring 2 distinct splice site mutations in the IRF6 gene. These results add to the previous 9 splicing mutations identified in patients with VWS and strengthen the importance of this type of alterations in the pathogenesis of the disease.


Aqueous Co(II) adsorption using 8-hydroxyquinoline anchored γ-Fe2O3@chitosan with Co(II) as imprinted ions.
A novel, bio-based 8-hydroxyquinoline (8-HQ) anchored magnetic chitosan using Co(II) as imprinted ions was prepared and applied for selective removal of Co(II) from aqueous solutions. At first, γ-Fe2O3 has been synthesized by solvent free precipitation route and then combined with 8-hydroxyquinoline anchored chitosan using epichlorohydrin (EPH) as crosslinking agent. The FT- IR spectra showed that 8-HQ has been successfully anchored onto chitosan structure. Moreover, TEM analysis confirmed that the nanocomposite has core-shell structure. The experimental results showed that equilibrium time was 10min moreover, the maximum adsorption capacity of Co(II) with non-imprinted and surface imprinted polymer at pH 8 were 66.6 and 100mgg(-1), respectively. The selectivity coefficient of Co(II) ions relative to Cd(II), Ni(II) and Pb(II) were 11, 42 and 2, respectively. Prepared biosorbent represented good stability and good repeatability after three cycle of sorption and desorption using 0.5molL-(1) of HNO3 as eluent. Kinetic and thermodynamic behavior were also investigated and result showed that cobalt adsorption followed second order model and endothermic path.


Exploring the quality of life of cosmetic users: A cross-sectional analysis from eight Arab countries in the Middle East.
The use of cosmetic products is growing in dominance in the Arab population, making it essential to measure its effects on users. The production of cosmetics has been largely driven by consumerism and a bid to keep abreast with the latest trends in the beauty industry with less attention on how the users' quality of life (QoL) is affected. This study aims to investigate the effect of cosmetic products on users' quality of life in eight Arab countries. A cross-sectional study was carried out using an online data collection approach. A validated and specialist instrument tool called BeautyQoL, which consists of five domains and a total of 52 questions, was distributed to a sample of 2219 cosmetic users. Descriptive and inferential statistical analysis was done using SPSS® version 26.0. The mean age of participants was 34 ± 11.25 years, and more women were represented in the sample (71%) than men. The majority of respondents had oily skin type (39.6%) and tan skin tone (30.4%). QoL through cosmetic use is computed with a mean score of 51 out of 100. The users' mean score satisfaction from cosmetic use is centred on attractiveness (56.1), followed by self-confidence (51.8). Cosmetics have a statistically significant effect on participants who are young adults, women, single, and employed with high income. As the respondents' skin tone deepens from very fair to dark, the mean score for each domain significantly increases, whereas when skin type changes from very oily to dry, the mean score for each domain decreases. The effect of cosmetics on the users' QoL is limited, contrary to the narrative commonly portrayed in cosmetics' advertisements. Therefore, the use of cosmetics among the Arab population should be from an informed perspective of their specific needs instead of conforming to the viral trends pedaled by influencers and bloggers on social media, which might be irrelevant for them.


Purification and characterization of neutrophil chemotactic factors of Streptococcus sanguis.
Two neutrophil chemotactic factors were isolated from the culture filtrates of Streptococcus sanguis ATCC 10556 and were chemically characterized as N-terminal blocked peptides of low molecular weight. One of the factors consisted of proline, valine, methionine, isoleucine and leucine and the other of methionine, isoleucine, leucine and phenylalanine. In both factors, methionine was detected as the sole N-terminal amino acid, but the amino group was blocked. The removal of N-terminal methionine yielded several N-terminal amino acids, suggesting that S. sanguis produced several N-terminal blocked methionyl peptides, all of which could be chemotactically active.


Regular molecular nano-dot patterns for RW-data storage in the optical near field.
In this contribution further steps to realize our concept of optical data storage in molecular nano-dots as storage bits are reported. A preparation method has been developed successfully to achieve regular nano-dot patterns of high density. This is considered a breakthrough because regularity is prerequisite for the use of nano-dots in storage media. Optical imaging of dot patterns and individual writing/reading access is realized by confocal and near-field optical microscopy (fluorescence detection mode). Examples for regular patterns at different dot densities are shown. Perspectives towards terabit per square inch density are outlined.


Hedgehog-GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells.
Colorectal cancer (CRC) is a leading cause of cancer death. Chemoresistance is a pivotal feature of cancer cells leading to treatment failure and ATP-binding cassette (ABC) transporters are responsible for the efflux of several molecules, including anticancer drugs. The Hedgehog-GLI (HH-GLI) pathway is a major signalling in CRC, however its role in chemoresistance has not been fully elucidated. Here we show that the HH-GLI pathway favours resistance to 5-fluorouracil and Oxaliplatin in CRC cells. We identified potential GLI1 binding sites in the promoter region of six ABC transporters, namely ABCA2, ABCB1, ABCB4, ABCB7, ABCC2 and ABCG1. Next, we investigated the binding of GLI1 using chromatin immunoprecipitation experiments and we demonstrate that GLI1 transcriptionally regulates the identified ABC transporters. We show that chemoresistant cells express high levels of GLI1 and of the ABC transporters and that GLI1 inhibition disrupts the transporters up-regulation. Moreover, we report that human CRC tumours express high levels of the ABCG1 transporter and that its expression correlates with worse patients' prognosis. This study identifies a new mechanism where HH-GLI signalling regulates CRC chemoresistance features. Our results indicate that the inhibition of Gli1 regulates the ABC transporters expression and therefore should be considered as a therapeutic option in chemoresistant patients.


Delayed images of glucoheptonate distribution after renal transplant.
Thirteen consecutive patients who had undergone renal transplantation were scanned 24 hours after glucoheptonate injection to document the incidence of gastrointestinal activity mimicking urinary extravasation. In six of the 13 patients, the activity was clearly within the small bowel or the colon but, in seven patients, the activity was noted surrounding the renal allograft. Using scintigraphy alone, it could not be determined whether this appearance represented cecal activity or urinary extravasation.


Pan-cancer whole-genome comparison of primary and metastatic solid tumours.
Metastatic cancer remains an almost inevitably lethal disease1-3. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours and late-stage treated metastatic tumours using a harmonized pan-cancer analysis (or reanalysis) of two unpaired primary4 and metastatic5 cohorts of 7,108 whole-genome-sequenced tumours. Metastatic tumours in general have a lower intratumour heterogeneity and a conserved karyotype, displaying only a modest increase in mutations, although frequencies of structural variants are elevated overall. Furthermore, highly variable tumour-specific contributions of mutational footprints of endogenous (for example, SBS1 and APOBEC) and exogenous mutational processes (for example, platinum treatment) are present. The majority of cancer types had either moderate genomic differences (for example, lung adenocarcinoma) or highly consistent genomic portraits (for example, ovarian serous carcinoma) when comparing early-stage and late-stage disease. Breast, prostate, thyroid and kidney renal clear cell carcinomas and pancreatic neuroendocrine tumours are clear exceptions to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. Exposure to treatment further scars the tumour genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcase the potential of pan-cancer whole-genome analysis to identify distinctive features of late-stage tumours and provide a valuable resource to further investigate the biological basis of cancer and resistance to therapies.


Prostaglandin-dependent osmotic water permeability of the frog and trout urinary bladder.
Washout of autacoids from serosal Ringer solution, using a repeated change of the solution of the frog and trout urinary bladder, was accompanied by a pronounced rise in the osmotic water permeability: the water transport in the frog rose from 0.05 +/- 0.02 to 1.21 +/- 0.26 microliter min-1.cm-2, in the trout, from 0.041 +/- 0.011 to 0.26 +/- 0.034 microliter min-1.cm-2. Such an increase in the osmotic water permeability in the trout and frog urinary bladder occurred in the background of a decrease in the prostaglandin E2 concentration in the serosal Ringer solution. This permeability increase was accompanied by the formation of aggregates of intramembranous particles in the apical plasma membrane of the trout and frog urinary bladder. A decrease in the osmotic water permeability was achieved by the addition to the serosal Ringer solution of 10-8 M prostaglandin. Experiments on the frog urinary bladder have shown that prostaglandins E1, I2 and F2 alpha also decrease the osmotic water permeability. Vasotocin increased the osmotic water permeability in the frog urinary bladder but did not affect the osmotic water permeability of the trout urinary bladder. The data obtained indicates a role of the endogenous prostaglandin production in maintaining the low osmotic water permeability in the frog and trout urinary bladder. A suggestion is made that in the vertebrate evolution, colonisation of the fresh-water was connected with the maintenance of the low osmotic water permeability via participation of prostaglandins, whereas the vasotocin hydroosmotic effect developed in the vertebrate evolution later and provided for the possibility of the water absorption, osmotic homeostasis and animal migration from fresh-water to the land.