The temporal impact of chronic intermittent psychosocial stress on high-fat diet-induced alterations in body weight.
Chronic stress and diet can independently or in concert influence the body's homeostasis over time. Thus, it is crucial to investigate the interplay of these parameters to gain insight into the evolution of stress-induced metabolic and eating disorders. C57BL/6J mice were subjected to chronic psychosocial (mixed model of social defeat and overcrowding) stress in combination with either a high- or low-fat diet for three or six weeks. To determine the evolution of stress and dietary effects, changes in body weight, caloric intake and caloric efficiency were determined as well as circulating leptin, insulin, glucose and corticosterone levels and social avoidance behaviour. Exposure to stress for three weeks caused an increase in weight gain, in caloric intake and in caloric efficiency only in mice on a low-fat diet. However, after six weeks, only stressed mice on a high-fat diet displayed a pronounced inhibition of body weight gain, accompanied by reduced caloric intake and caloric efficiency. Stress decreased circulating leptin levels in mice on a low-fat diet after three weeks and in mice on a high-fat diet after three and six weeks of exposure. Plasma levels of insulin and markers of insulin resistance were blunted in mice on high-fat diet following six weeks of stress exposure. Social avoidance following chronic stress was present in all mice after three and six weeks. This study describes the evolution of the chronic effects of social defeat/overcrowding stress in combination with exposure to high- or low-fat diet. Most importantly, we demonstrate that a six week chronic exposure to social defeat stress prevents the metabolic effects of high-fat diet, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance as well as in plasma leptin and insulin levels. This study highlights the importance of considering the chronic aspects of both parameters and their time-dependent interplay.


Ocular manifestations of head injury: a clinical study.
This prospective study aimed to clinically correlate the various ocular findings with the neurological status in cases of closed head injury. A total of 200 consecutive cases of closed head injury admitted to a major teaching hospital underwent a thorough ophthalmic assessment. The Glasgow coma scale (GCS) and the Revised trauma score (RTS) were applied to grade the severity of injury and assess the prognosis. Kendall's tau-b and Fisher's exact test were used in the analysis. The main causes of head injury were road traffic accidents 52.5% followed by assaults in 34%. Ocular involvement was found in 167(83.5%) cases. These included corneal and scleral tears in 2%, subconjunctival haemorrhage or ecchymosis in 46%, orbital fractures 12%, pupillary involvement 6.5%, papilloedema 5.5%, intraocular trauma 5.5%, proptosis 3%, lateral rectus palsy 2%, lacrimal gland prolapse 1%, and optic nerve trauma 0.5%. All 21 patients (10.5%) who died had eye involvement. In all, 150 cases (75%) with a RTS of 12 had a good prognosis. Of these 124 (82.6%) had ocular involvement of no neurological significance. Although sophisticated imaging techniques are available to localize lesions, early ophthalmic assessment in correlation with the GCS aids in prognosticating outcomes. Pupillary involvement, papilloedema, and ocular motor paresis pointed to a more severe head injury. To our knowledge, this is the only prospective study recording ocular findings in the first few hours and attempting a correlation with the final outcome.


Interested in Volunteering for EMBS? Here Are Two Students' Exciting Experiences.
The IEEE Engineering in Medicine and Biology Society (EMBS) is the world's largest international society of biomedical engineers. Volunteering for IEEE EMBS can be an enriching experience for students. We recently interviewed two exceptional EMBS volunteers to gain insight on their volunteering experience with EMBS.


Mutagenic and colicine-inducing activity of two antioxidants: pyrogallol and purpurogallin.
The antioxidants pyrogallol and its oxidative derivative, purpurogallin, both induce colicine E2 as well as base substitution and frameshift mutations. Because of the bactericidal effect of purpurogallin, its mutagenicity could be best demonstrated by short-term exposure followed by dilution on the test plates. The colicine-inducing potential of purpurogallin was also observed when tested directly on the plates.


[Intensive care during the 2019-coronavirus epidemic].
On 31 December 2019, the Health Commission of Hubei Province of China first unveiled a group of unexplained cases of pneumonia, which WHO subsequently defined as the new coronavirus of 2019 (SARS-CoV-2). SARS-CoV-2 has presented rapid person-to-person transmission and is currently a global pandemic. In the largest number of cases described to date of hospitalized patients with SARS-CoV-2 disease (2019-nCoViD), 26% required care in an intensive care unit (ICU). This pandemic is causing an unprecedented mobilization of the scientific community, which has been associated with an exponentially growing number of publications in relation to it. This narrative literature review aims to gather the main contributions in the area of intensive care to date in relation to the epidemiology, clinic, diagnosis and management of 2019-nCoViD.


Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis.
As an inhibitor of GSDMD, Disulfiram (DSL) can significantly inhibit cell pyroptosis. Cell pyroptosis plays an important role in renal fibrosis. HK-2 cells were induced by Lps and ATP to form a pyroptosis model, and the cells were treated by DSL. CCK-8 detected the cell activity. Immunofluorescence (IF) detected the GSDMD. ELISA detected the expression of inflammatory cytokines. Flow cytometry and Western blot detected cell apoptosis and pyroptosis. Collagen type I kit detected collagen secretion, and western blot detected fibrosis marker protein expression. Then, a rat model of unilateral ureteral obstruction (UUO) was established. HE staining detected the degree of renal tissue injury, and Masson staining detected the degree of fibrosis. What's more, the apoptosis level of tissue cells was detected by TUNEL. And the inflammatory factors in peripheral blood and renal tissue were detected by ELISA. Furthermore, the expression of GSDMD was detected by immunohistochemistry (IHC), and Western blot was used to detect the expression levels of apoptosis and pyroptosis-related proteins in tissues. It was found that DSL can inhibit the cell membrane perforation of GSDMD-N by inhibiting the cleavage of GSDMD, hence, it inhibited the occurrence of inflammation, cell pyroptosis, and the fibrosis of HK-2 cells. But if the cell has already undergone pyroptosis, DSL does not provide significant prevention. In vivo experiment, it further verified that pretreated DSL had inhibited renal fibrosis injury. Disulfiram can inhibit inflammation and fibrosis in renal fibrosis rats by inhibiting GSDMD.


Food and Environmental Virology: Use of Passive Sampling to Characterize the Presence of SARS-CoV-2 and Other Viruses in Wastewater.
Fecal shedding of SARS-CoV-2 leads to a renaissance of wastewater-based epidemiology (WBE) as additional tool to follow epidemiological trends in the catchment of treatment plants. As alternative to the most commonly used composite samples in surveillance programs, passive sampling is increasingly studied. However, the many sorbent materials in different reports hamper the comparison of results and a standardization of the approach is necessary. Here, we compared different cost-effective sorption materials (cheesecloths, gauze swabs, electronegative filters, glass wool, and tampons) in torpedo-style housings with composite samples. Despite a remarkable variability of the concentration of SARS-CoV-2-specific gene copies, analysis of parallel-deposited passive samplers in the sewer demonstrated highest rate of positive samples and highest number of copies by using cheesecloths. Using this sorption material, monitoring of wastewater of three small catchments in the City of Dresden resulted in a rate of positive samples of 50% in comparison with composite samples (98%). During the investigation period, incidence of reported cases of SARS-CoV-2 in the catchments ranged between 16 and 170 per 100,000 persons and showed no correlation with the measured concentrations of E gene in wastewater. In contrast, constantly higher numbers of gene copies in passive vs. composite samples were found for human adenovirus and crAssphage indicating strong differences of efficacy of methods concerning the species investigated. Influenza virus A and B were sporadically detected allowing no comparison of results. The study contributes to the further understanding of possibilities and limits of passive sampling approaches in WBE.


Modulation of thalamic neuron excitability by orexins.
Orexins (hypocretins) are peptides of hypothalamic origin that play an important role in maintaining wakefulness. Reduced orexin levels have been associated with an increased incidence of narcolepsy. Considering thalamic nuclei are interconnected with virtually all neocortical regions and the thalamus has been found to produce distinct activities related to different levels of arousal, we have examined the actions of orexins on thalamic neurons using an in vitro thalamic slice preparation. The orexins (orexin-A and orexin-B) produced distinct actions within different intralaminar nuclei. Orexin-B strongly depolarized the majority of centrolateral nucleus (CL) neurons (71%), but depolarized a significantly smaller population of parafascicular nuclei (Pf) neurons (10%). In the mediodorsal thalamic nucleus (MD), orexin-B depolarized 21% of the neurons tested. Overall, orexin-B was found to be more potent than Orexin-A. Orexin-A depolarized a significantly smaller population of CL neurons (23%), but had no effect on Pf neurons. In addition, orexin-A produced a small depolarization in 28% of neurons in the thalamic reticular nucleus (TRN). Both orexin-A and orexin-B had no effect on neurons in the lateral posterior (LP), lateralodorsal (LD), posterior thalamic (Po), ventrobasal (VB) nucleus and lateral geniculate nucleus (LGN). The depolarizing actions of orexins were sufficient to alter the firing mode of these neurons from a burst- to tonic-firing mode. The excitatory actions of orexin-B result from a decrease in the apparent leak potassium current (Kleak). The orexin-B mediated excitation was also attenuated by bupivacaine suggesting the involvement of Kleak current. Further, the actions of orexin-B were occluded by the classical neurotransmitter dopamine, indicating the orexins may share similar ionic mechanisms. Thus, the depolarizing actions of orexins may play a key role in altering the firing mode of thalamic neurons associated with different states of consciousness.


Effect of pH on functional, gas sensing and antimicrobial properties of bio-nanocomposite gelatin film for food packaging application.
A bio-nanocomposite film is a polymer blend with nanofiller dispersed in a biopolymer matrix. The aim of this study is to investigate the functional, gas sensing and antimicrobial properties of bio-nanocomposite films incorporated with chicken skin gelatin/ tapioca starch/zinc oxide at different pH levels (pH 4, 6, 7 and 8). Bio-nanocomposite films were prepared using a casting technique followed by the characterization of their functional, gas sensing and antimicrobial properties. Film formulations with pH at different levels showed increased thickness, colour and water vapour permeability (WVP) (p < 0.05). In addition, the increase of pH in films in chicken skin gelatin bio-nanocomposite films increased the tensile strength (TS), while decreasing the elongation at break (EAB). The highest response for ammonia gas in chicken skin gelatin bio-nanocomposite films was obtained at pH 7, with quick response time (τres) within 10 s. The inhibition zone of Staphylococcus aureus in chicken skin gelatin bio-nanocomposite films increased with increasing pH levels. Overall, chicken skin gelatin bio-nanocomposite films with a pH level of 8 were found to have the optimal formulation, with the highest values in thickness, and TS, with the lowest values for WVP and EAB. In conclusion, bio-nanocomposite chicken skin gelatin films with an alkaline pH are a superior packaging material.


Stem cells and bone diseases: new tools, new perspective.
Postnatal skeletal stem cells are a unique class of progenitors with biological properties that extend well beyond the limits of stemness as commonly defined. Skeletal stem cells sustain skeletal tissue homeostasis, organize and maintain the complex architectural structure of the bone marrow microenvironment and provide a niche for hematopoietic progenitor cells. The identification of stem cells in the human post-natal skeleton has profoundly changed our approach to the physiology and pathology of this system. Skeletal diseases have been long interpreted essentially in terms of defective function of differentiated cells and/or abnormal turnover of the matrix that they produce. The notion of a skeletal stem cell has brought forth multiple, novel concepts in skeletal biology that provide potential alternative concepts. At the same time, the recognition of the complex functions played by skeletal progenitors, such as the structural and functional organization of the bone marrow, has provided an innovative, unifying perspective for understanding bone and bone marrow changes simultaneously occurring in many disorders. Finally, the possibility to isolate and highly enrich for skeletal progenitors, enables us to reproduce perfectly normal or pathological organ miniatures. These, in turn, provide suitable models to investigate and manipulate the pathogenetic mechanisms of many genetic and non-genetic skeletal diseases. This article is part of a Special Issue entitled Stem cells and Bone.


The immunoreactivity and activity of adenylate cyclase type I are changed in the hippocampal CA1 region after transient forebrain ischemia in gerbils.
Adenylate cyclase (AC) has a specific sensitivity to Ca2+/calmodulin. AC-I, one of the mediator of learning and memory, plays an important role in signal transduction underlying learning and memory function. In the present study, we found ischemia-related changes of AC-I in the hippocampal CA1 region, but not in the CA2/3 region, after 5 min of transient forebrain ischemia in gerbils. In the sham-operated group, AC-I immunoreactive neurons were detected in pyramidal and non-pyramidal cells in the hippocampus proper. AC-I immunoreactivity was significantly increased at 3 h in the CA1 region after ischemic insult. Thereafter, AC-I immunoreactivity was gradually decreased. Four days after ischemic insult, AC-I-immunoreactive CA1 pyramidal cells in the stratum pyramidale were very few due to delayed neuronal death. The results of Western blot analysis showed that changes of AC-I protein contents were similar to immunohistochemical data after ischemic insult. Gpp(NH)p-dependent AC-I activity in hippocampal CA1 region was not changed in all groups, while Ca2+/calmodulin-dependent AC-I activity in hippocampal CA1 region was significantly decreased 24 h after ischemia-reperfusion. These results suggest that the decrease of AC-I activity may be associated with impairment of neurodevelopment and neuroplasticity including learning and memory although the AC-I immunoreactivity was maintained 24 h postischemic group compared to that of the sham-operated group.


Hepatitis B virus transcripts in a human hepatoma cell line, Hep 3B.
Hep 3B, a human hepatoma cell line was examined for its RNA hybridizable to the hepatitis B virus sequence. Using probes that covered different regions of the hepatitis B virus genome, five species of RNA were observed of sizes 4.0, 3.3, 2.9, 2.6 and 2.2 kilobases. The RNAs covered surface antigen gene, pre-S and X regions. None of them had a core antigen sequence. RNA with a 4.0 kilobase size was the most abundant. Using S1 nuclease analysis, its 5' end of hepatitis B virus sequence was mapped at pre-S region and its 3' end of viral sequence was mapped at DR region.


Unravelling the process of petroleum hydrocarbon biodegradation in different filter materials of constructed wetlands by stable isotope fractionation and labelling studies.
Maintaining and supporting complete biodegradation during remediation of petroleum hydrocarbon contaminated groundwater in constructed wetlands is vital for the final destruction and removal of contaminants. We aimed to compare and gain insight into biodegradation and explore possible limitations in different filter materials (sand, sand amended with biochar, expanded clay). These filters were collected from constructed wetlands after two years of operation and batch experiments were conducted using two stable isotope techniques; (i) carbon isotope labelling of hexadecane and (ii) hydrogen isotope fractionation of decane. Both hydrocarbon compounds hexadecane and decane were biodegraded. The mineralization rate of hexadecane was higher in the sandy filter material (3.6 µg CO2 g-1 day-1) than in the expanded clay (1.0 µg CO2 g-1 day-1). The microbial community of the constructed wetland microcosms was dominated by Gram negative bacteria and fungi and was specific for the different filter materials while hexadecane was primarily anabolized by bacteria. Adsorption / desorption of petroleum hydrocarbons in expanded clay was observed, which might not hinder but delay biodegradation. Very few cases of hydrogen isotope fractionation were recorded in expanded clay and sand & biochar filters during decane biodegradation. In sand filters, decane was biodegraded more slowly and hydrogen isotope fractionation was visible. Still, the range of observed apparent kinetic hydrogen isotope effects (AKIEH = 1.072-1.500) and apparent decane biodegradation rates (k = - 0.017 to - 0.067 day-1) of the sand filter were low. To conclude, low biodegradation rates, small hydrogen isotope fractionation, zero order mineralization kinetics and lack of microbial biomass growth indicated that mass transfer controlled biodegradation.


Histochemical and electron microscopy investigations on medullary bone.
Folliculin administration to pigeons stimulates the development of medullary bone in marrow spaces of the femora and other long bones. It is a specialized osseus tissue not devoted to mechanical functions and which is rapidly reabsorbed before egg-shell formation. Medullary bone is formed and reabsorbed in the same way as other types of bone. Consequently, because of its very rapid rate of formation and resorption, it represents an ideal tissue for studying osteoblastic, osteoclastic and osteocytic activity, and the calcification process. Medullary bone is deeply stained by PAS, Alcian blue and colloidal iron and is metachromatic after toluidine blue staining. This shows that its interfibrially ground substance contains relatively high amounts of glycoproteins and acid proteoglycans. Calcification initially occurs in maxtrix vesicles (or calcifying globules) which are very numerous between the collagen fibrils of the osteoid tissue, and successively spreads into the surrounding interfibrillar matrix. Here, the crystals are closely related to thin, filament-like organic structures which seem to be components of ground substance proteoglycans. These findings confirm that in medullary bone, as in other types of calcifying tissue, the inorganic substances is initially laid down within calcifying globules and is successively closely related to organic, non-collagenous, filamentous organic structures (crystal ghosts) which probably represent a framework for calcium salt deposition.


MicroRNAs: miRRORS of health and disease.
The review articles in this issue provide an improved appreciation for microRNA (miRNA) as an essential feature of lineage commitment and regulatory guidance during tissue development that, when absent or hampered, often lead to disease states. In the coming years, there is much to be learned about adaptive (and maladaptive) states by examining how the expression of miRNAs is influenced by the genetic architecture of miR genes, clusters, and mirtrons, as well as miRNA polymorphism and polymorphism in their mRNA targets. We are also introduced to several modes of miRNA regulation (negative feedback, positive feedback, and cross regulatory) that monitor, modulate, or resolve signaling pathways in a variety of biologic processes that include sepsis response, fibrosis, acute exercise, and steroid biology. Perhaps the homeostasis or micromanagement of these miRNA regulatory systems, when perturbed, arrive at new stable networked interactions that have an undesired effect of promoting or antagonizing disease severity and cancer progression. Clearly, a better understanding of these miRNA regulatory networks, as well as improved therapeutic tools for guiding miRNA expression and their targets toward desired outcomes, will be the subject of many advances in miRNA biology over the coming years.


Understanding burn injuries in children-A step toward prevention and prompt first aid.
This study was designed to examine knowledge, attitude and practices with regards to burns prevention and first aid in the Indian community. A total of 83 caregivers aged 19 and 40 years (mean 29 years) participated in survey. Sixty-one percent of those who responded to the survey had some knowledge of first aid, mostly through health education at schools (59%). Very few (2%) received first aid education from health workers. Approximately 2/3 of responders (66-70%) were aware of applying cool running water to a burn and to stop drop and roll in case of a flame burn. However, the same number also listed a myriad of household remedies that they would use as first aid. 66-71% responders were aware of some situational risks in the home and community but only 27% considered young children to be at greater risk. 31% responders had an enclosed kitchen and 16% were still cooking on the floor. A large percentage (83%) cooked outside on a traditional wooden open fire. A quarter of the responders still used oil lamps on the floor and had little regard for the flammability of clothes. There was a weak positive correlation between knowledge and attitude (r-square 0.379) and attitude and practice (r-square 0.373), but no correlation between knowledge and practice (r-square 0.089). Our survey suggests that many responders have limited knowledge of effective first-aid techniques and live in high-risk environments. The major sources of first aid information were from school-based health education, social and electronic media. These resources can be utilized to further disseminate knowledge on first aid and practical prevention techniques.


The effect of intermittent carbon monoxide exposure on experimental atherosclerosis in the rabbit.
(1) Twenty-four female New Zealand White rabbits were fed commercial diet plus 2% cholesterol. Twelve of these animals were exposed to carbon monoxide for 4 hours per day, seven days per week for 10 weeks. The carbon monoxide exposure was such that the mean blood carboxy-haemoglobin was raised to approximately 20% during each exposure period. Twelve control animals breathed atmospheric air under the same conditions of confinement as the carbon monoxide-exposed group. (2) No significant differences in the plasma levels of cholesterol, triglycerides or glutamate oxalacetate transaminase were observed between the two groups during the experiment. (3) When the animals were sacrificed at the end of the experiment no significant differences were observed between the two groups in the aortic content of triglycerides, cholesterol or phospholipids. (4) The extent of coronary artery atherosclerosis was statistically significantly higher in the carbon monoxide group than in the control group. (5) Ultracentrifugal analysis of plasma lipoproteins revealed that there was significantly more cholesterol in the d less than l.006 fraction from the CO-exposed rabbits. (6) These findings, are discussed with particular reference to the claim that the causal agent in tobacco smoke associated arterial disease is carbon monoxide.


Preclinical and exploratory human studies of novel 68Ga-labeled D-peptide antagonist for PET imaging of TIGIT expression in cancers.
While TIGIT has been propelled as a next-generation target in cancer immunotherapy, anti-TIGIT therapy seems to be promising for a fraction of patients in clinical trials. Therefore, patient stratification is critical for this therapy, which could benefit from a whole-body, non-invasive, and quantitative evaluation of TIGIT expression in cancers. In this study, a 68Ga-labeled D-peptide antagonist, 68Ga-GP12, was developed and validated for PET imaging of TIGIT expression in vitro, in vivo, and in an exploratory human study. The D-enantiomer peptide antagonists were modified and radiolabeled with 68Ga. In vitro binding assays were performed in human peripheral blood mononuclear cells (PBMCs) to assess their affinity and specificity. The imaging capacity, biodistribution, pharmacokinetics, and radiation dosimetry were investigated. Flow cytometry, autoradiography, and immunohistochemical staining were used to confirm the expression of TIGIT. The safety and potential of 68Ga-GP12 for PET/CT imaging of TIGIT expression were evaluated in NSCLC patients. 68Ga-labeled D-peptides were conveniently produced with high radiochemical yields, radiochemical purities and molar activities. In vitro binding assays demonstrated 68Ga-GP12 has high affinity and specificity for TIGIT with a KD of 37.28 nM. In vivo and ex vivo studies demonstrated the capacity of 68Ga-GP12 for PET imaging of TIGIT expression with high tumor uptake of 4.22 ± 0.68 %ID/g and the tumor-to-muscle ratio of 12.94 ± 2.64 at 60 min post-injection. In NSCLC patients, primary and metastatic lesions found in 68Ga-GP12 PET images were comparable to that in 18F-FDG PET images. Moreover, tracer uptake in primary and metastatic lesions and intra-tumoral distribution in the large tumor were inhomogenous, indicating the heterogeneity of TIGIT expression. 68Ga-GP12 is a promising radiotracer for PET imaging of TIGIT expression in cancers, indicating its potential as a potential companion diagnostic for anti-TIGIT therapies.


Tropomyosins as interpreters of the signalling environment to regulate the local cytoskeleton.
A key regulator of cell morphology is the actin cytoskeleton and it has long been appreciated that the cytoskeleton is characteristically altered in cancer. Actin is organized into polymeric structures with distinct dynamics which in turn participate in a wide variety of cell processes including adhesion, migration, cell division and apoptosis. Despite displaying an altered actin cytoskeleton, transformed cells retain--and in many cases increase--their ability to adhere, move, divide and respond to apoptotic stimuli. Thus cancer cells maintain responsive actin cytoskeletons. Actin dynamics are regulated by numerous actin-binding proteins and chief among these are the tropomyosins which are core components of the microfilament. Recent advances in genomic and proteomic profiling confirm that Tm expression profiles are profoundly changed in transformed cells. It is therefore timely to review the role of Tms in the regulation of actin dynamics that pertain to crucial phenotypic changes in cancer. In this review we discuss how actin filaments containing different Tm isoforms respond to the activation of cell signalling pathways and consider the implications of this for cancer progression and therapy.


Methodological improvements in quantifying cognitive change in clinical trials: an example with single-dose administration of donepezil.
Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD). Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day. Early phase I clinical trial. 15 healthy older adults; 14 older adults with mild Alzheimer's disease. Single acute dose of 5mg donepezil. Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring. A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing). The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.


Shoulder instability, performance, and return to play in National Hockey League players.
The shoulder is a commonly injured area in hockey, yet information is lacking on the prevalence and effect of shoulder instability. Our study investigates the incidence of shoulder dislocation events in the National Hockey League (NHL) and the effects on return-to-play (RTP) and player performance. We hypothesize that NHL players would have high RTP rates without significant changes in performance after injury. NHL players who suffered in-season shoulder instability events between 2003-2004 and 2017-2018 seasons were identified. Demographic characteristics, incidence of injury, recurrences, RTP, and statistical performance data were collected. Postinjury performance was compared with experience-matched, era-matched, position-matched, and age-matched controls. A mixed generalized linear regression model was used to compare postinjury performance as a function of operative and nonoperative treatment. A total of 57 players experienced 67 shoulder instability events with 98.5% of players returning to play after an average of 26.3 ± 20.8 regular season games missed. Surgery was performed in 47.8% of players with no recurrent injuries postoperatively. Nonoperatively managed players experienced a decrease in points per game (P = .034) compared with surgically treated patients. Recurrence occurred in 14.3% of conservatively managed players, with 33.3% experiencing a season-ending injury. Players with recurrent injuries missed significantly more career games compared with those treated initially with surgery (P = .00324). Professional hockey players experience high rates of RTP with acceptable performance outcomes after shoulder instability events; however, recurrent injuries led to significantly more career games missed when treated nonoperatively at the time of injury.


Effects of theophylline on hemodynamics and tissue oxygenation in patients with cirrhosis.
Since adenosine may play a role in the hyperdynamic circulation of cirrhosis, we examined the effects of theophylline (an adenosine receptor antagonist) on systemic and splanchnic hemodynamics, tissue oxygenation and sympathoadrenal activity in patients with cirrhosis and liver failure. Theophylline (aminophylline) was administered intravenously for 30 min. Six patients received a dose of 3 mg/kg and eight others a dose of 6 mg/kg. The low dose caused plasma theophylline concentrations of 7.4 +/- 1.8 mg/ml (mean +/- S.E.), and induced a significant increase in heart rate from 84 +/- 5 to 93 +/- 8 beats/min. This dosage did not significantly change other hemodynamic values, oxygen (O2) consumption, or sympathoadrenal activity. The high dose elicited plasma theophylline concentrations of 15.8 +/- 4.0 mg/ml. This dose significantly increased heart rate from 78 +/- 5 to 87 +/- 7 beats/min and significantly decreased right atrial pressure from 2.5 +/- 1.0 to 1.4 +/- 0.8 mmHg, stroke volume from 52 +/- 3 to 47 +/- 5 ml.beat-1.m-2 and systolic arterial pressure from 140 +/- 5 to 129 +/- 6 mmHg. In contrast, O2 consumption, sympathoadrenal activity, and all other hemodynamic values (including azygos blood flow) were not significantly modified. As a result, we conclude that, in patients with cirrhosis, theophylline may cause decreased stroke volume which lowers systolic arterial pressure. In our patients theophylline also had a positive chronotropic effect but no vasoconstrictor effect on systemic and splanchnic circulation. Finally, theophylline did not improve tissue oxygenation in patients with cirrhosis.


Clinical, radiologic, and histopathologic aspects of 13 cases of nevoid basal cell carcinoma syndrome.
Thirteeen patients with the characteristic signs and symptoms of the nevoid basal cell carcinoma syndrome (NBS) are presented. It is suggested that the chromosomal anomalies sporadically reported have hardly any connection with the syndrome. The jaw cysts removed from the patients with NBS were clinically, radiologically, and histopathologically typical keratocysts with a high occurrence of epithelial islands and/or microcyts in the connective tissue of the capsule. The significantly higher occurrence of proliferative epithelial remnants in the connective tissue of the cyst wall may be an explanation of the high recurrence rate seen in patients with NBS and of the recurrence of some solitary keratocysts in patients without any signs or symptoms of NBS. In a follow-up period of 2 years, 85% of the patients with NBS showed recurrence. One-third of these patients did not show any recurrence at the 1-year follow-up. Therefore, a follow-up period of 2 years or more is mandatory in the care of patients with the nevoid basal cell carcinoma syndrome.


Right ventricular diastolic function predicts clinical atrial fibrillation after coronary artery bypass graft.
Patients with moderate-severe left ventricular systolic dysfunction undergoing coronary artery bypass graft (CABG) surgery are at high risk of mortality and morbidity. Our aim is to evaluate the right ventricular (RV) diastolic function in these patients, and monitor its effects on postoperation outcomes. In a cohort study, patients with moderate-severe left ventricular systolic dysfunction (ejection fraction ≤35%) who were candidate for CABG were included. Baseline transthoracic echocardiography (TTE) was performed, and RV diastolic function measures were obtained. After CABG, the length of intubation, inotrope dependency, hospital stay in intensive care unit and ward, in-hospital and after discharge mortality, postoperative atrial fibrillation (POAF) were evaluated in all patients. Sixty-seven patients were prospectively included in the study. The mean ± standard deviation age of our patients was 61.4 ± 9.3. There was no difference between grades of RV diastolic function and postoperative outcomes. However, we found significant difference between grades of RV diastolic function and onset of in hospital, and total POAF (P-value = 0.017). Multivariate analysis demonstrated that preoperative tricuspidEt/E't (ratio of peak early-diastolic flow rate across the tricuspid valve orifice to peak early-diastolic velocity at the lateral tricuspid annulus), left atrial volume and "high risk" Euroscore II were independent predictors for POAF during hospitalization and total POAF in patients with moderate to severely impaired left ventricular systolic function (P-values were 0.04, 0.003 and 0.001, respectively). We believe that patients with increased tricuspid Et/E't are high risk for POAF; therefore, any risk score for POAF should include a comprehensive TTE including evaluation of RV diastolic function before surgery.


Maltreatment type differences in cortisol stress response trajectories across adolescence.
This study examined cortisol stress response trajectories across adolescence in 454 maltreated and comparison youth recruited from Los Angeles County between 2002 and 2005 (66.7% maltreated; 46.7% girls; 39.0% Latino; 37.7% Black; 12.3% Mixed or Biracial; 11.0% White; Mage = 10.9 years, SD = 1.2). Adolescents' peak activation and cortisol reactivity and recovery slopes following the Trier Social Stress Test for Children were calculated at four waves, then used to model peak activation and cortisol reactivity and recovery trajectories arrayed by age. Maltreated youth had blunted cortisol reactivity at age 9 relative to comparison youth (b = -.19, p = .02). Sexually and physically abused youth showed blunted cortisol reactivity and recovery trajectories relative to emotionally abused and neglected youth.


Chromatic micromaps in primary visual cortex.
The clustering of neurons with similar response properties is a conspicuous feature of neocortex. In primary visual cortex (V1), maps of several properties like orientation preference are well described, but the functional architecture of color, central to visual perception in trichromatic primates, is not. Here we used two-photon calcium imaging in macaques to examine the fine structure of chromatic representation and found that neurons responsive to spatially uniform, chromatic stimuli form unambiguous clusters that coincide with blobs. Further, these responsive groups have marked substructure, segregating into smaller ensembles or micromaps with distinct chromatic signatures that appear columnar in upper layer 2/3. Spatially structured chromatic stimuli revealed maps built on the same micromap framework but with larger subdomains that go well beyond blobs. We conclude that V1 has an architecture for color representation that switches between blobs and a combined blob/interblob system based on the spatial content of the visual scene.


Using deep reinforcement learning to reveal how the brain encodes abstract state-space representations in high-dimensional environments.
Humans possess an exceptional aptitude to efficiently make decisions from high-dimensional sensory observations. However, it is unknown how the brain compactly represents the current state of the environment to guide this process. The deep Q-network (DQN) achieves this by capturing highly nonlinear mappings from multivariate inputs to the values of potential actions. We deployed DQN as a model of brain activity and behavior in participants playing three Atari video games during fMRI. Hidden layers of DQN exhibited a striking resemblance to voxel activity in a distributed sensorimotor network, extending throughout the dorsal visual pathway into posterior parietal cortex. Neural state-space representations emerged from nonlinear transformations of the pixel space bridging perception to action and reward. These transformations reshape axes to reflect relevant high-level features and strip away information about task-irrelevant sensory features. Our findings shed light on the neural encoding of task representations for decision-making in real-world situations.


RNA silencing of GM-CSF in CAR-T cells reduces the secretion of multiple inflammatory cytokines.
Chimeric antigen receptor T (CAR-T) cell therapy has become a research hotspot in the field of hematological malignancies. However, CAR-T cell therapy can lead to immunotherapy-associated side effects including cytokine release syndrome and neurotoxicity. Gene depletion of GM-CSF in CAR-T cells was found preventive against adverse effects, but additional transfections were required to produce CAR-T cells. In this study, we interrupted GM-CSF expression in CAR-T cells by inserting the GM-CSF shRNA-expression cassette in the CAR vector. Reduction of GM-CSF in CAR-T cells could decrease the level of several proinflammatory cytokines without hampering the killing capacity. The manufacture of GM-CSF knockdown CAR-T cells does not require complicated transfections, which makes it more practical and feasible for clinical application.


Bioinformatic analysis identifies potential biomarkers and therapeutic targets of septic-shock-associated acute kidney injury.
Sepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI). Two gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI. We identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future. Septic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.


Synthesis and Biological Evaluation of Gentiopicroside Derivatives as Novel Cyclooxygenase-2 Inhibitors with Anti-Inflammatory Activity.
Nonsteroidal anti-inflammatory drugs cause a series of adverse reactions. Thus, the search for new cyclooxygenase-2 selective inhibitors have become the main direction of research on anti-inflammatory drugs. Gentiopicroside is a novel selective inhibitor of cyclooxygenase-2 from Chinese herbal medicine. However, it is highly hydrophilic owing to the presence of the sugar fragment in its structure that reduces its oral bioavailability and limits efficacy. This study aimed to design and synthesize novel cyclooxygenase-2 inhibitors by modifying gentiopicroside structure and reducing its polarity. We introduced hydrophobic acyl chloride into the gentiopicroside structure to reduce its hydrophilicity and obtained some new derivatives. Their in vitro anti-inflammatory activities were evaluated against NO, TNF-α, PGE2, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by lipopolysaccharide. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Molecular docking predicted that whether new compounds could effectively bind to target protein cyclooxygenase-2. The inhibitory activity of new compounds to cyclooxygenase-2 enzyme were verified by the in vitro experiment. A total of 21 novel derivatives were synthesized, and exhibit lower polarities than the gentiopicroside. Most compounds have good in vitro anti-inflammatory activity. The in vivo activity results demonstrated that 8 compounds were more active than gentiopicroside. The inhibition rate of some compounds was higher than celecoxib. Molecular docking predicted that 6 compounds could bind to cyclooxygenase-2 and had high docking scores in accordance with their potency of the anti-inflammatory activity. The confirmatory experiment proved that these 6 compounds had significant inhibitory effect against cyclooxygenase-2 enzyme. Structure-activity relationship analysis presumed that the para-substitution with the electron-withdrawing groups may benefit the anti-inflammatory activity. These gentiopicroside derivatives especially PL-2, PL-7 and PL-8 may represent a novel class of cyclooxygenase-2 inhibitors and could thus be developed as new anti-inflammatory agents.


Association between optic nerve sheath diameter and mortality in patients with severe traumatic brain injury.
Increased intracranial pressure (ICP) is associated with worse outcomes following traumatic brain injury (TBI). Studies have confirmed that ICP is correlated with optic nerve sheath diameter (ONSD) on ultrasound. The aim of our study was to assess the independent relationship between ONSD measured using CT and mortality in a population of patients admitted with severe TBI. We conducted a retrospective cohort study of patients with a TBI requiring ICP monitoring admitted to the ICU between April 2006 and May 2012 to two neurotrauma centers. ONSD was independently measured by two physicians blinded to patient outcomes. Multivariable logistic regression modeling was used to assess an association between ONSD and hospital mortality. A total of 220 patients were included in the analysis. Overall, the cohort had a mean age of 35 (SD 17) years and 171 of 220 (79 %) were male. The median admission GCS was 6 (IQR 3-8). Intra-class correlation coefficient between raters for ONSD measurements was 0.92 (95 % CI 0.90-0.94, P < 0.0001). On multivariable analysis, each 1 mm increase in ONSD was associated with a twofold increase in hospital mortality (OR 2.0, 95 % CI 1.2-3.2, P = 0.007). Using linear regression, ONSD was independently associated with increased ICP in the first 48 h after admission (β = 4.4, 95 % CI 2.5-6.3, P < 0.0001). In patients with TBI, ONSD measured on CT scanning was independently associated with ICP and mortality.


Conjugation behaviour of different monoclonal antibodies to f-methionyl-leucyl-phenylalanine.
Monoclonal antibodies (moab) are potentially useful carriers for the targeting of effector substances into tumors. Conjugation of the chemotactic peptide f-Met-Leu-Phe (fMLP) to tumor-directed antibodies yields compounds active in vitro and in vivo. The present experiments examine the conjugation of fMLP to four different moab iso- and idiotypes. Molar coupling rations and chemotactic activity are not dependent on the moab species used for conjugation.


Management of Anastomosis Leakage Post-RALP: A Simple Trick for a Complex Situation.
A case of 74 years old male patient who underwent RALP with bladder neck reconstruction. Persistent vesicourethral anastomotic leak was seen at cystography. A self-made side fenestrated Foley catheter was used and on the day after, a complete reversal in fluid output between the Foley catheter and the drain was seen.


Tight mechanism correlation between heart rate turbulence and baroreflex sensitivity: sequential autonomic blockade analysis.
Heart rate turbulence is a powerful de novo risk predictor for patients surviving acute myocardial infarction. However, little is known about its underlying physiologic mechanism. Hypothesizing that heart rate turbulence is barorceptor reflex related, we studied heart rate and blood pressure fluctuations at rest and after systematically introduced ventricular premature beats in 16 patients without structural heart disease (10 men and 6 women; mean age 45 +/- 17 years) before and after sequential sympathetic (esmolol 4-mg bolus followed by 120 microg/kg/min intravenously), parasympathetic (atropine 0.04 mg/kg intravenously), and combined autonomic blockade (esmolol plus atropine). Turbulence onset (%) and turbulence slope (msec/beat) were averaged from 10 respective ventricular premature beats. Spontaneous baroreflex sensitivity (msec/mmHg) was calculated from 5 minutes of sinus rhythm recording. The results showed that turbulence slope decreased after atropine (0.71 +/- 0.50 msec/beat vs 5.17 +/- 3.96 msec/beat at baseline; P < 0.01) and combined autonomic blockade (1.23 +/- 1.02 msec/beat; P < 0.01) but was unchanged after esmolol (4.53 +/- 3.30 msec/beat; P > 0.05). Turbulence onset increased after atropine (0.32% +/- 0.35% vs -0.45 +/- 0.94 at baseline; P < 0.05) and combined sympathetic and parasympathetic blockade (0.58% +/- 0.86%; P < 0.05) but was unchanged after esmolol (-0.62% +/- 1.33%; P > 0.05). Turbulence slope was positively correlated with baroreflex sensitivity at baseline (r = 0.78, P < 0.01) and after esmolol (r = 0.8, P < 0.01), but dissociated after atropine (r = 0.16, P > 0.05) and combined autonomic blockade (r = 0.31, P > 0.05). Turbulence onset was negatively correlated with baroreflex sensitivity at baseline (r = -0.61, P < 0.05), after esmolol (r = -0.80, P < 0.01), and after atropine (r = -0.53, P < 0.05). Heart rate turbulence of turbulence onset and turbulence slope is critically vagal dependent and highly correlated with spontaneous baroreflex sensitivity, which underscores its clinical importance in cardiovascular risk stratification.


mRNA m5C inhibits adipogenesis and promotes myogenesis by respectively facilitating YBX2 and SMO mRNA export in ALYREF-m5C manner.
Although 5-methylcytosine (m5C) has been identified as a novel and abundant mRNA modification and associated with energy metabolism, its regulation function in adipose tissue and skeletal muscle is still limited. This study aimed at investigating the effect of mRNA m5C on adipogenesis and myogenesis using Jinhua pigs (J), Yorkshire pigs (Y) and their hybrids Yorkshire-Jinhua pigs (YJ). We found that Y grow faster than J and YJ, while fatness-related characteristics observed in Y were lower than those of J and YJ. Besides, total mRNA m5C levels and expression rates of NSUN2 were higher both in backfat layer (BL) and longissimus dorsi muscle (LDM) of Y compared to J and YJ, suggesting that higher mRNA m5C levels positively correlate with lower fat and higher muscle mass. RNA bisulfite sequencing profiling of m5C revealed tissue-specific and dynamic features in pigs. Functionally, hyper-methylated m5C-containing genes were enriched in pathways linked to impaired adipogenesis and enhanced myogenesis. In in vitro, m5C inhibited lipid accumulation and promoted myogenic differentiation. Furthermore, YBX2 and SMO were identified as m5C targets. Mechanistically, YBX2 and SMO mRNAs with m5C modification were recognized and exported into the cytoplasm from the nucleus by ALYREF, thus leading to increased YBX2 and SMO protein expression and thereby inhibiting adipogenesis and promoting myogenesis, respectively. Our work uncovered the critical role of mRNA m5C in regulating adipogenesis and myogenesis via ALYREF-m5C-YBX2 and ALYREF-m5C-SMO manners, providing a potential therapeutic target in the prevention and treatment of obesity, skeletal muscle dysfunction and metabolic disorder diseases.


Prevalence and correlates of low medication adherence in apparent treatment-resistant hypertension.
Low medication adherence may explain part of the high prevalence of apparent treatment-resistant hypertension (aTRH). The authors assessed medication adherence and aTRH among 4026 participants taking ≥ 3 classes of antihypertensive medication in the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) trial using the 4-item Morisky Medication Adherence Scale (MMAS). Low adherence was defined as an MMAS score ≥ 2. Overall, 66% of participants taking ≥ 3 classes of antihypertensive medication had aTRH. Perfect adherence on the MMAS was reported by 67.8% and 70.9% of participants with and without aTRH, respectively. Low adherence was present among 8.1% of participants with aTRH and 5.0% of those without aTRH (P<.001). Among those with aTRH, female sex, residence outside the US stroke belt or stroke buckle, physical inactivity, elevated depressive symptoms, and a history of coronary heart disease were associated with low adherence. In the current study, a small percentage of participants with aTRH had low adherence.


Transcriptional signatures regulated by TRPC1/C4-mediated Background Ca2+ entry after pressure-overload induced cardiac remodelling.
After summarizing current concepts for the role of TRPC cation channels in cardiac cells and in processes triggered by mechanical stimuli arising e.g. during pressure overload, we analysed the role of TRPC1 and TRPC4 for background Ca2+ entry (BGCE) and for cardiac pressure overload induced transcriptional remodelling. Mn2+-quench analysis in cardiomyocytes from several Trpc-deficient mice revealed that both TRPC1 and TRPC4 are required for BGCE. Electrically-evoked cell shortening of cardiomyocytes from TRPC1/C4-DKO mice was reduced, whereas parameters of cardiac contractility and relaxation assessed in vivo were unaltered. As pathological cardiac remodelling in mice depends on their genetic background, and the development of cardiac remodelling was found to be reduced in TRPC1/C4-DKO mice on a mixed genetic background, we studied TRPC1/C4-DKO mice on a C57BL6/N genetic background. Cardiac hypertrophy was reduced in those mice after chronic isoproterenol infusion (-51.4%) or after one week of transverse aortic constriction (TAC; -73.0%). This last manoeuvre was preceded by changes in the pressure overload induced transcriptional program as analysed by RNA sequencing. Genes encoding specific collagens, the Mef2 target myomaxin and the gene encoding the mechanosensitive channel Piezo2 were up-regulated after TAC in wild type but not in TRPC1/C4-DKO hearts. Deletion of the TRPC1 and TRPC4 channel proteins protects against development of pathological cardiac hypertrophy independently of the genetic background. To determine if the TRPC1/C4-dependent changes in the pressure overload induced alterations in the transcriptional program causally contribute to cardio-protection needs to be elaborated in future studies.


Danhong injection enhances angiogenesis after myocardial infarction by activating MiR-126/ERK/VEGF pathway.
Danhong injection (DHI) is a Chinese drug used for relieving cardiovascular diseases. This study aimed to identify the effect and mechanism of action of DHI on post-infarct angiogenesis, especially the epigenetic regulation of angiogenesis. A myocardial infarction (MI) mouse model was induced by ligating the left anterior descending coronary artery. A 4-week daily treatment with or without DHI via intraperitoneal injection was started immediately following MI. The changes in cardiac function, pathology, and angiogenesis following MI were measured by echocardiography and immunostaining. Matrigel tube formation and scratch wound assays were used to evaluate the effect of DHI on the proliferation and migration of hypoxic human umbilical vein endothelial cells (HUVECs). The expression of miR-126, Spred-1, and angiogenesis-related mRNAs was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of related proteins and the phosphorylated levels of extracellular signal-regulated kinase (ERK) and protein kinase B were detected by Western blot analysis. The loss-of-function study was performed using antagomir-126. The DHI-treated mice had significantly reduced infarct area, improved ejection fraction, and increased capillary density 4 weeks after MI. Also, DHI promoted the proliferation and migration of hypoxic HUVECs. The qRT-PCR and Western blot analysis revealed that DHI intervention upregulated miR-126, suppressed Spred-1 expression, and activated the ERK pathway, but not the Akt pathway. The loss-of-function study showed the blockade of the pro-angiogenic effect of DHI by antagomir-126 involving the ERK/vascular endothelial growth factor (VEGF) pathway. DHI enhanced post-infarct angiogenesis after MI by activating the miR-126/ERK/VEGF pathway.


Residential dust lead levels and the risk of childhood lead poisoning in United States children.
The United States Environmental Protection Agency (EPA) recently lowered residential floor and windowsill dust lead hazard standards, but maintained previous post-abatement clearance standards. We examined whether the discrepancy in these regulations places children at higher risk of lead poisoning. In 250 children from Cincinnati, Ohio (2004-2008) living in homes built before 1978, we measured residential floor and windowsill dust lead loadings and blood lead concentrations at ages 1 and 2 years. Using linear regression with generalized estimating equations, we estimated covariate-adjusted associations of dust lead levels with blood lead concentrations and risk of lead poisoning. An increase in floor dust lead from 10 (revised dust lead hazard standard) to 40 μg/ft2 (post-abatement clearance standard) was associated with 26% higher (95% confidence interval (CI):15, 38) blood lead concentrations and 2.1 times the risk of blood lead concentrations ≥5 μg/dL (95% CI: 1.44, 3.06). Extrapolating our findings to US children age 1-5 years, we estimated that 6.9% (95% CI: 1.5, 17.2) of cases of blood lead concentrations ≥5 μg/dL are attributable to floor dust lead loadings between 10 and ≤40 μg/ft2. The EPA's residential dust lead regulations place children at increased risk of lead poisoning. We recommend adopting more protective dust lead standards. We determined whether children are at increased risk of lead poisoning with the 2019 EPA residential post-abatement lead clearance standards being higher than dust lead hazard standards. In this observational study, 2019 EPA dust lead clearance standards were associated with increased risk of lead poisoning compared to the revised dust lead hazard standard. Both EPA standards were associated with increased risk of lead poisoning compared to more stringent standards employed in our study. Extrapolating our findings to US children, the 2019 EPA dust lead clearance standards could place up to 36,700 children at risk of lead poisoning.


Exploring the feasibility of delivering standardized genomic care using ophthalmology as an example.
Broadening access to genomic testing and counseling will be necessary to realize the benefits of personalized health care. This study aimed to assess the feasibility of delivering a standardized genomic care model for inherited retinal dystrophy (IRD) and of using selected measures to quantify its impact on patients. A pre-/post- prospective cohort study recruited 98 patients affected by IRD to receive standardized multidisciplinary care. A checklist was used to assess the fidelity of the care process. Three patient-reported outcome measures-the Genetic Counselling Outcome Scale (GCOS-24), the ICEpop CAPability measure for Adults (ICECAP-A), and the EuroQol 5-dimension questionnaire (EQ-5D)-and a resource-use questionnaire were administered to investigate rates of missingness, ceiling effects, and changes over time. The care model was delivered consistently. Higher rates of missingness were found for the genetic-specific measure (GCOS-24). Considerable ceiling effects were observed for the generic measure (EQ-5D). The ICECAP-A yielded less missing data without significant ceiling effects. It was feasible to use telephone interviews for follow-up data collection. The study highlighted challenges and solutions associated with efforts to standardize genomic care for IRD. The study identified appropriate methods for a future definitive study to assess the clinical effectiveness and cost-effectiveness of the care model.Genet Med advance online publication 02 March 2017.


Impact of very early recurrence of atrial fibrillation after cryoballoon ablation.
Although much has been discussed about the early recurrence of atrial fibrillation (ERAF) after cryoballoon ablation (CBA), the clinical impact of very early recurrence of atrial fibrillation (VERAF) after CBA remains unclear. This study aimed to investigate the impact of VERAF after CBA. We enrolled 236 consecutive patients who underwent an initial CBA for paroxysmal atrial fibrillation between February 2017 and December 2020 in our hospital. These patients were categorized into three groups: VERAF group who experienced an initial recurrence of atrial tachyarrhythmia within 48 h after CBA, late-ERAF (LERAF) group who experienced an initial recurrence of atrial tachyarrhythmia between 48 h and 3 months after CBA, and non-ERAF (NERAF) group who did not experience a recurrence of atrial tachyarrhythmia within 3 months after CBA. We investigated the late recurrence of AF (LRAF, defined as recurrence of atrial tachyarrhythmia more than 3 months after CBA), and the incidence of non-pulmonary vein (PV) triggers in the patients who experienced a repeat ablation procedure due to LRAF. VERAF group had a higher incidence of freedom from LRAF than LERAF group (p = 0.032) and a lower incidence of freedom from LRAF than NERAF group (p = 0.002). Moreover, VERAF group had the highest incidence of non-PV triggers at repeat ablation procedure among the three groups (p = 0.003). While ERAF was a predictor of LRAF, VERAF was less related to LRAF among the patients with ERAF after CBA. Furthermore, VERAF might be associated with non-PV triggers.


Toxoplasma gondii Infection in Marine Animal Species, as a Potential Source of Food Contamination: A Systematic Review and Meta-Analysis.
Many marine animals are infected and susceptible to toxoplasmosis, which is considered as a potential transmission source of Toxoplasma gondii to other hosts, especially humans. The current systematic review and meta-analysis aimed to determine the prevalence of T. gondii infection among sea animal species worldwide and highlight the existing gaps. Data collection was systematically done through searching databases, including PubMed, Science Direct, Google Scholar, Scopus, and Web of Science from 1997 to July 2020. Our search strategy resulted in the retrieval of 55 eligible studies reporting the prevalence of marine T. gondii infection. The highest prevalence belonged to mustelids (sea otter) with 54.8% (95% CI 34.21-74.57) and cetaceans (whale, dolphin, and porpoise) with 30.92% (95% CI 17.85-45.76). The microscopic agglutination test (MAT) with 41 records and indirect immunofluorescence assay (IFA) with 30 records were the most applied diagnostic techniques for T. gondii detection in marine species. Our results indicated the geographic distribution and spectrum of infected marine species with T. gondii in different parts of the world. The spread of T. gondii among marine animals can affect the health of humans and other animals; in addition, it is possible that marine mammals act as sentinels of environmental contamination, especially the parasites by consuming water or prey species.


Decolorization of sulfonated azo dye Metanil Yellow by newly isolated bacterial strains: Bacillus sp. strain AK1 and Lysinibacillus sp. strain AK2.
Two different bacterial strains capable of decolorizing a highly water soluble azo dye Metanil Yellow were isolated from dye contaminated soil sample collected from Atul Dyeing Industry, Bellary, India. The individual bacterial strains Bacillus sp. AK1 and Lysinibacillus sp. AK2 decolorized Metanil Yellow (200 mg L(-1)) completely within 27 and 12h respectively. Various parameters like pH, temperature, NaCl and initial dye concentrations were optimized to develop an economically feasible decolorization process. The maximum concentration of Metanil Yellow (1000 mg L(-1)) was decolorized by strains AK2 and AK1 within 78 and 84 h respectively. These strains could decolorize Metanil Yellow over a broad pH range 5.5-9.0; the optimum pH was 7.2. The decolorization of Metanil Yellow was most efficient at 40°C and confirmed by UV-visible spectroscopy, TLC, HPLC and GC/MS analysis. Further, both the strains showed the involvement of azoreductase in the decolorization process. Phytotoxicity studies of catabolic products of Metanil Yellow on the seeds of chick pea and pigeon pea revealed much reduction in the toxicity of metabolites as compared to the parent dye. These results indicating the effectiveness of strains AK1 and AK2 for the treatment of textile effluents containing azo dyes.


Predictors of Health Deterioration Among Older New Zealanders Undergoing Dialysis: A Three-Year Accelerated Longitudinal Cohort Study.
Patient involvement in dialysis decision-making is crucial, yet little is known about patient-reported outcomes over time on dialysis. To examine health-related outcomes over 24 and 36 months in an older cohort of dialysis patients. The "Dialysis outcomes in those aged ≥65 years study" is a prospective longitudinal cohort study of New Zealanders with kidney failure. Three New Zealand nephrology units. Kidney failure (dialysis and predialysis) patients aged 65 or above. We have previously described outcomes after 12 months of dialysis therapy relative to baseline. Patient-reported social and health factors using the SF-36, EQ-5D, and Kidney Symptom Score questionnaires. This article describes and compares characteristics of 120 older kidney failure patients according to whether they report "Same/better" or "Worse" health 24 and 36 months later, and identifies predictors of "worse health." Modified Poisson regression modeling estimated relative risks (RR) of worse health. Of 120 patients at 12 months, 47.5% had worse health or had died by 24 months. Of those surviving at 24 months (n = 80), 40% had "Worse health" or had died at 36 months. Variables independently associated with reduced risk of "Worse health" (24 months) were as follows: Māori ethnicity (RR = 0.44; 95% CI = 0.26-0.75), Pacific ethnicity (RR = 0.39; 95% CI = 0.33-0.46); greater social satisfaction (RR = 0.57; 95% CI = 0.46-0.7). Variables associated with an increased risk of "Worse health" were as follows: problems with usual activities (RR = 1.32; 95% CI = 1.04-1.37); pain or discomfort (RR = 1.48; 95% CI = 1.34, 1.63). At 36 months, lack of sense of community (RR = 1.41; 95% CI = 1.18-1.69), 2 or more comorbidities (RR = 1.21; 95% CI = 1.13-1.29), and problems with poor health (RR = 1.47; 95% CI = 1.41-1.54) were associated with "Worse health." Participant numbers restricted the number of variables able to be included in the multivariable model, and hence there may have been insufficient power to detect certain associations. In this study, the majority of older dialyzing patients report "Same/better health" at 24 and 36 months. Māori and Pacific people report better outcomes on dialysis. Social and/or clinical interventions aimed at improving social satisfaction, sense of community, and help with usual activities may impact favorably on the experiences for older dialysis patients. Australian and New Zealand clinical trials registry: ACTRN12611000024943.


RSK-mediated phosphorylation in the C/EBP{beta} leucine zipper regulates DNA binding, dimerization, and growth arrest activity.
The bZIP transcription factor C/EBPbeta is a target of Ras signaling that has been implicated in Ras-induced transformation and oncogene-induced senescence (OIS). To gain insights into Ras-C/EBPbeta signaling, we investigated C/EBPbeta activation by oncogenic Ras. We show that C/EBPbeta DNA binding is autorepressed and becomes activated by the Ras-Raf-MEK-ERK-p90(RSK) cascade. Inducible phosphorylation by RSK on Ser273 in the leucine zipper was required for DNA binding. In addition, three other modifications (phosphorylation on Tyr109 [p-Tyr109], p-Ser111, and monomethylation of Arg114 [me-Arg114]) within an N-terminal autoinhibitory domain were important for Ras-induced C/EBPbeta activation and cytostatic activity. Apart from its role in DNA binding, Ser273 phosphorylation also creates an interhelical g<-->e' salt bridge with Lys268 that increases attractive electrostatic interactions between paired leucine zippers and promotes homodimerization. Mutating Ser273 to Ala or Lys268 to Glu decreased C/EBPbeta homodimer formation, whereas heterodimerization with C/EBPgamma was relatively unaffected. The S273A substitution also reduced the antiproliferative activity of C/EBPbeta in Ras(V12)-expressing fibroblasts and decreased binding to target cell cycle genes, while a phosphomimetic substitution (S273D) maintained growth arrest function. Our findings identify four novel C/EBPbeta-activating modifications, including RSK-mediated phosphorylation of a bifunctional residue in the leucine zipper that regulates DNA binding and homodimerization and thereby promotes cell cycle arrest.


Residual stress effects on fracture energies of cement-bone and cement-implant interfaces.
The effects of residual stresses, which are caused by the temperature difference arising after polymerisation of bone cement, on the fracture energies of cement bone and cement-implant interfaces have been examined by using both experimental and numerical works. Only fracture loads of the test specimen having interfacial cracks have been measured in the experimental stage. The values of fracture loads and temperature difference after polymerisation have been applied to finite element models of the test specimens to calculate critical J-integral values of these both interfaces in the numerical stage. In addition, fracture energies of bone and cement, have been obtained by experimentally, using three-point bending test method The results have shown that residual stresses can produce changes in the fracture energies of these bimaterial systems, especially in cement implant interface and J(Ic) values of interfaces are considerably smaller than the experimentally determined J(Ic) values of cement and bone.


Application of twin flash stimuli for some mascular diseases isolation of local responses by twin flashes.
Double flash ERG was examined for patients with visual loss from macular and optic nerve disorders, and the responses were compared. K values (= (B1-B2))/B1 x 100) of the former were larger than normal values when the stimulus intervals were between 200 and 500 mseconds, and abnormality of K values seemed to correspond to the functional impairment of macula. On the other hand, K values of the patients with optic nerve diseases remained in the normal range. These facts indicate that double flash ERG is a very useful method to estimate the cone function clinically, and can be employed as a routine examination for patients with suspected cone dysfunction.


Response to water deficit of semi-desert wild potato Solanum kurtzianum genotypes collected from different altitudes.
Drought-sensitive crops are threatened as a consequence of limited available water due to climate change. The cultivated potato (Solanum tuberosum) is susceptible to drought and within its wild relative species, Solanum kurtzianum is the Argentinian wild potato species best adapted to arid conditions. However, its physiological responses to water deficit (WD) are still missing. Within the distribution of S. kurtzianum, genotypes could be adapted to differential precipitation regimes. The aim of this work was to evaluate responses of three S. kurtzianum genotypes collected at 1100 (G1), 1900 (G2) and 2100 m a.s.l. (G3) to moderate and severe WD. Treatments were imposed since flowering and lasted 36 days. Yield components, morpho-physiological and biochemical responses; and phenotypic plasticity were evaluated. The three genotypes presented mechanisms to tolerate both WD treatments. G1 presented the lowest yield reduction under moderate WD, mainly through a rapid stomatal closure and a modest vegetative growth. The differences among genotypes suggest that local adaptation is taking place within its natural habitat. Also, G2 presented environmentally induced shifts in plasticity for stomatal length and carotenoids, suggesting that phenotypic plasticity has a role in acclimation of plants to WD until selection works.


Enhanced non-radical activation of persulfate with pompon-like NiO microspheres for removing sulfamethoxazole in water.
The development of efficient heterogeneous catalyst for non-radical activation of persulfate (PS) is highly desired for removing organic pollutants in water. Herein, four NiO samples were prepared by different methods, and their performance for PS activation was investigated using sulfamethoxazole (SMX) as the target pollutant. The structure, surface chemical state, and redox ability of these samples were measured by various characterization techniques, and the key property affecting PS activation efficiency was explored. The results showed that the degradation of SMX by these samples all followed the non-radical mechanism, and the activated PS was the dominant active species. Among them, pompon-like NiO microspheres exhibited the highest activity due to its large surface area and especially high oxidation ability. Catalyst with high oxidation ability or reducing ability should facilitate the non-radical or radical activation of PS, respectively. SMX was completely removed by pompon-like NiO microspheres within 10 min, and the reaction rate constant was calculated to be 0.4199 min-1. An adsorption-degradation experiment was designed to verify the high stability and oxidation potential of the adsorbed PS on NiO surface. Pompon-like NiO microspheres exhibited good reusability, and its performance was barely affected by water quality, demonstrating its potential application in water treatment.


External validation of urinary C-C motif chemokine ligand 14 (CCL14) for prediction of persistent acute kidney injury.
Persistent acute kidney injury (AKI) portends worse clinical outcomes and remains a therapeutic challenge for clinicians. A recent study found that urinary C-C motif chemokine ligand 14 (CCL14) can predict the development of persistent AKI. We aimed to externally validate urinary CCL14 for the prediction of persistent AKI in critically ill patients. This was a secondary analysis of the prospective multi-center SAPPHIRE study. We evaluated critically ill patients with cardiac and/or respiratory dysfunction who developed Kidney Disease: Improving Global Outcomes (KDIGO) stage 2-3 AKI within one week of enrollment. The main exposure was the urinary concentration of CCL14 measured at the onset of AKI stage 2-3. The primary endpoint was the development of persistent severe AKI, defined as ≥ 72 h of KDIGO stage 3 AKI or death or renal-replacement therapy (RRT) prior to 72 h. The secondary endpoint was a composite of RRT and/or death by 90 days. We used receiver operating characteristic (ROC) curve analysis to assess discriminative ability of urinary CCL14 for the development of persistent severe AKI and multivariate analysis to compare tertiles of urinary CCL14 and outcomes. We included 195 patients who developed KDIGO stage 2-3 AKI. Of these, 28 (14%) developed persistent severe AKI, of whom 15 had AKI ≥ 72 h, 12 received RRT and 1 died prior to ≥ 72 h of KDIGO stage 3 AKI. Persistent severe AKI was associated with chronic kidney disease, diabetes mellitus, higher non-renal APACHE III score, greater fluid balance, vasopressor use, and greater change in baseline serum creatinine. The AUC for urinary CCL14 to predict persistent severe AKI was 0.81 (95% CI, 0.72-0.89). The risk of persistent severe AKI increased with higher values of urinary CCL14. RRT and/or death at 90 days increased within tertiles of urinary CCL14 concentration. This secondary analysis externally validates urinary CCL14 to predict persistent severe AKI in critically ill patients.


Structural covariance of the salience network associated with heart rate variability.
The salience network (SN) anchored by the anterior insula and cingulate is crucial for the autonomic control of body homeostasis. Resting-sate fMRI studies have linked intrinsic SN connectivity with multiple autonomic measures, but little is known about the structural organization of this system relating to cardiac vagal function. To address the above issue, the current study used covariance analysis of MRI-based gray matter volume (GMV) to map structural covariance of SN with two independent datasets, and then determined whether interregional structural connections within SN related to individual differences in vagally-mediated heart rate variability (HRV). The results showed a significant positive association between structural covariance of the SN and vagal component of HRV in two independent samples. More importantly, the conjunction and pooled data analysis revealed that structural correlation from left anterior insula to dorsal anterior cingulate cortex positively interacted with vagally-mediated HRV. The current results demonstrated a crucial role of the SN in the cortical modulation of efferent vagal activity to the heart, and provided new insight into structural neural network implicated in cardiac vagal control.


WITHDRAWN: Catheter-Directed Thrombolysis for Acute Iliofemoral Deep Venous Thrombosis.
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.


Effects of sheltered ground habitats on the overwintering potential of the predacious mite Neoseiulus californicus (Acari: Phytoseiidae) in apple orchards on mainland Korea.
Neoseiulus californicus (McGregor) (Acari: Phytoseiidae) is an effective predator of spider mites. In Korea, it is distributed on Jeju Island, but is never found further north on the mainland. Due to poor natural control of spider mites by native predatory mites in mainland orchards, commercialization of the Jeju Island strain of N. californicus on the mainland is currently being considered. We conducted two field experiments in mainland apple orchards during winter 2008 and 2009 to assess the effects of sheltered ground habitats on the overwintering potential of N. californicus. In the first experiment, all of the N. californicus individuals that were experimentally placed on bare ground died within 27 days, whereas 70% of mites sheltered by fallen apple leaves or urethane foam survived for more than 27 days. In the second experiment, individuals were released directly onto the ground, either with or without urethane foam. More individuals were found within urethane foam plots than in plots without foam. Sheltered ground habitats would be an important factor for N. californicus when selecting overwintering sites, and could eventually lead to enhanced winter survival. On the other hand, no live N. californicus individuals were found by the end of the winter in either experiment, which suggests that N. californicus could not successfully overwinter in the study area, even in sheltered ground habitats.


Outcomes after primary intensity-modulated radiation therapy for oropharyngeal squamous cell carcinoma at a New Zealand regional cancer centre: Impact of p16 status.
The rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) in New Zealand is due to an increase in the numbers of human papilloma virus (HPV)-associated OPSCC. We evaluated the impact of positive p16 immunohistochemistry, as a surrogate for HPV positivity, on OPSCC outcomes after primary intensity-modulated radiotherapy (IMRT) with or without concurrent chemotherapy. Retrospective review was undertaken of electronic medical records of 90 patients with OPSCC who received primary IMRT with or without chemotherapy between 2008 and mid-2015 at the Regional Cancer Centre, Waikato Hospital, Hamilton, New Zealand. Median age was 57.5 years. Immunohistochemistry for p16 was positive in 53 (59%) OPSCC while 37 (41%) had negative or unknown p16 status. Median radiotherapy dose was 70 Gy. Chemotherapy was administered to 78 (87%) patients, most receiving high-dose cisplatin. Nine patients had residual disease following treatment completion. Seven patients relapsed, and 26 died during the study period. Five patients with p16-positive OPSCC had persistent or recurrent disease. Actuarial 3-year locoregional control, disease-free survival, and overall survival for all patients were 80.7%, 74.7%, and 77.1%, respectively. Among p16-positive OPSCC patients, 3-year locoregional control, disease-free survival, and overall survival were 89.5%, 80.8%, and 90.9%, respectively. Outcomes after IMRT for OPSCC at Waikato Hospital are in line with the reported literature. Human papilloma virus-related OPSCC has better outcomes compared with patients with unknown or HPV-unrelated OPSCC. Trials are underway evaluating reduced intensity of treatment for HPV-related OPSCC.


Does histamine stimulate cyclic AMP formation in the avian pineal gland via a novel (non-H1, non-H2, non-H3) histamine receptor subtype.
The effects of histamine (HA) and selective HA H1-, H2 and H3-receptor agonists on cyclic AMP formation were investigated in intact chick and duck pineal glands HA potently stimulated the pineal cycle AMP formation. The effect of HA was mimicked fully by N alpha-methylated histamines, and partially by several histaminergic drugs: 2-thiazolylethylamine (H1) amthamine (H2) and R alpha-methyl-histamine (H3). Dimaprit, another selective H2-agonist showed marginal activity. Forskolin highly potentiated the action of HA, and only weakly affected the effects of 2-thiazolylethylamine and amthamine. In the chick pineal, the stimulatory effects of HA and the tested histaminergic drugs were not blocked by mepyramine and thioperamide (H1- and H3-blockers, respectively), but they were antagonized by H2-receptor selective compounds ranitidine and aminopotentidine, which, however, acted in a noncompetitive manner. Another H2-selective blocker zolantidine antagonized the HA effect only when used at very high (30-100 microM) concentrations. In the duck pineal, the stimulatory effect of HA on cyclic AMP production was unaffected by mepyramine (H1), thioperamide (H3), and ranitidine (H2), and only partially inhibited by the H2-blocker aminopotentidine. Electrophysiological experiments revealed that HA is capable of evoking inward currents in most of the tested cells acutely isolated from chick pineal gland. The present findings further indicate that the pharmacological profile of the avian pineal HA receptor, whose stimulation leads to activation of cyclic AMP production, is different from any known HA receptor type (H1, H2, H3), and suggest the existence of either an avian-specific HA receptor, or a novel HA receptor subtype. Electrophysiological data suggest that the pineal HA receptor may be somehow linked to activation of an ionic channel.


Thymic epithelial neoplasms in transgenic mice expressing SV40 T antigen under the control of an erythroid-specific enhancer.
The beta-globin locus control region is known to be a powerful erythroid-specific enhancer. In an attempt to produce immortalized erythroid percursor cells, transgenic mice have been generated with the simian virus (SV) 40 T antigen gene under the control of the locus control region. As previously reported, transgenic mice did not develop erythroleukaemia, but rather succumbed to insulinomas and poorly differentiated rhabdomyosarcomas. This paper describes additional mice containing this transgene that developed thymomas of the mixed epithelial/lymphocytic type, in which only the epithelial component expressed the T antigen. Epithelial cell lines have been established from these tumours. This system may be useful in future studies on the pathogenesis of thymomas and the function of thymic epithelial cells.


SARS-CoV-2 asymptomatic and symptomatic patients and risk for transfusion transmission.
Oral swabs, sputum, and blood samples from 18 asymptomatic and symptomatic patients with SARS-CoV-2 infection were examined using RT-PCR testing in order to assess the risk of transfusion-related transmission. In asymptomatic patients as well as patients with flu-like symptoms and fever, no SARS-CoV-2 RNA could be detected in the blood or serum despite a clearly positive result in all throat swabs. As patients with symptoms of infectious disease will not be admitted to blood donation, the risk for transfusion transmission of SARS-CoV-2 seems to be negligible.


An overview of survival studies in patients with heart failure.
Heart failure is associated with poor prognosis, but recent large-scale investigations have generated valuable and practical information to help improve clinical management and patient survival. This review presents an overview of the findings of recent heart failure survival studies and how these may affect therapeutic strategy for patients with this condition.


A novel carboxylated polyacrylonitrile nanofibrous membrane with high adsorption capacity for fluoride removal from water.
To deal with the drinking water safety caused by fluoride, a novel carboxylated polyacrylonitrile nanofibrous membrane (C-PAN NFM) is designed and fabricated massively for the first time by adopting synchronously biaxial stretching and carboxylation. The C-PAN NFM is composed of the layered stack structure by cross-linked nanofibers. Due to its high specific surface area, excellent hydrophilicity, a large amount of carboxyl and amine groups, C-PAN NFM owns high fluoride adsorption capacity and outstanding selectivity. Both the carboxylation and acid treatment of C-PAN NFM improved the fluoride adsorption capacity remarkably. Specifically, C-PAN NFM shows excellent reusability without secondary pollution. The fluoride adsorption behavior of C-PAN NFM is dominated by chemical adsorption, and the adsorption mechanism is mainly driven by hydrogen bonding and ion exchange. The mass-produced C-PAN NFM is a novel polyacrylonitrile-based porous membrane that shows a great application potential for fluoride removal with good efficiency and recyclability.


Cancer chemotherapy in young children: challenges and solutions.
Young children with cancer are a therapeutic challenge both in terms of chemotherapeutic efficacy as well as toxicity. The ontogeny of each drug differs, and hence, general rules cannot easily apply. Each drug should be studied by itself before rational cancer therapy for young children can be offered. Much more focus on this age group is needed to improve survival, while ensuring their long-term quality of life of these children.


Development of β-Ga2O3 layers growth on sapphire substrates employing modeling of precursors ratio in halide vapor phase epitaxy reactor.
Gallium oxide is a promising semiconductor with great potential for efficient power electronics due to its ultra-wide band gap and high breakdown electric field. Optimization of halide vapor phase epitaxy growth of heteroepitaxial [Formula: see text]-Ga2O3 layers is demonstrated using a simulation model to predict the distribution of the ratio of gallium to oxygen precursors inside the reactor chamber. The best structural quality is obtained for layers grown at 825-850 °C and with a III/VI precursor ratio of 0.2. Although the structural and optical properties are similar, the surface morphology is more deteriorated for the [Formula: see text]-Ga2O3 layers grown on 5 degree off-axis sapphire substrates compared to on-axis samples even for optimized process parameters. Cathodoluminescence with a peak at 3.3 eV is typical for unintentionally doped n-type [Formula: see text]-Ga2O3 and shows the appearance of additional emissions in blue and green region at ~ 3.0, ~ 2.8, ~ 2.6 and ~ 2.4 eV, especially when the growth temperatures is lowered to 800-825 °C. Estimation of the band gap energy to ~ 4.65 eV from absorption indicates a high density of vacancy defects.


The university students' viewpoints on e-learning system during COVID-19 pandemic: the case of Iran.
The outbreak of COVID-19 closed educational institutions and universities. The aim of this study was to explain the strengths and weaknesses of the e-learning system in Iranian universities of medical sciences in the COVID-19 pandemic. This is a qualitative study that was conducted with students enrolled in Iranian medical universities. Data was collected through an open-ended electronic questionnaire based on the interview guide and was analyzed through content analysis. 122 students from 46 medical universities participated in this study. 122 questionnaires from 46 universities of medical sciences were completed. From a total of 54 codes extracted from the results, seven (strengths/positive experiences) and six (weaknesses/challenges) themes were extracted, each of which had several subsets. E-learning has both visible and hidden layers in terms of advantages and disadvantages. The e-learning system is an essential tool to continue education during the COVID-19 pandemic. Most students believe that e-learning was a great complement to prevent academic failure, but it cannot replicate the same efficiency of face-to-face training.


Correction: Effect of temperature variation on hospital admissions and outcomes in dogs with myxomatous mitral valve disease and new onset pulmonary edema.
[This corrects the article DOI: 10.1371/journal.pone.0227807.].


Imaging evidence for renomegaly in patients with POEMS syndrome.
Organomegaly in POEMS syndrome generally refers to the liver, spleen, and lymph nodes. This study investigates whether there is a significant difference in kidney sizes in patients with POEMS compared to normal controls. Calculated kidney volumes from 77 patients with POEMS syndrome who had undergone imaging by computed tomography or magnetic resonance imaging were compared to frequency-matched controls. For the POEMS patients and the controls, the volume of each kidney was obtained from a three-dimensional segmentation algorithm. Univariate and multiple variable linear regression models were used to identify any differences in kidney size between normal and POEMS patients. There was a univariate statistically significant association between disease state and the difference in kidney volume; having POEMS was associated with 16.3 cm(3) greater kidney volume difference compared to control patients, P < .001. Using a multiple variable model and after adjusting for age, sex, and the smaller kidney size, there was a statistically significant association between disease state and the difference in kidney volume; having POEMS was associated with 16.8 cm(3) greater kidney volume compared to control patients, P < .001. There was not an independent statistically significant association between age, sex, or volume of the smaller kidney and the difference in kidney volume. This confirms what is known or suspected clinically, that organomegaly in POEMS includes renomegaly.


Calcium-Permeable AMPA Receptors Promote Endocannabinoid Signaling at Parvalbumin Interneuron Synapses in the Nucleus Accumbens Core.
Synaptic plasticity is a key mechanism of learning and memory. Synaptic plasticity mechanisms within the nucleus accumbens (NAc) mediate differential behavioral adaptations. Feedforward inhibition in the NAc occurs when glutamatergic afferents onto medium spiny neurons (MSNs) collateralize onto fast-spiking parvalbumin (PV)-expressing interneurons (PV-INs), which exert GABAergic control over MSN action potential generation. Here, we find that feedforward glutamatergic synapses onto PV-INs in the NAc core selectively express Ca2+-permeable AMPA receptors (CP-AMPARs). Ca2+ influx by CP-AMPARs on PV-INs triggers long-term depression (LTD) mediated by endocannabinoid (eCB) signaling at presynaptic cannabinoid type-1 (CB1) receptors (CB1Rs). Moreover, CP-AMPARs authorize tonic eCB signaling to negatively regulate glutamate release probability. Blockade of CP-AMPARs in the NAc core in vivo is sufficient to disinhibit locomotor output. These findings elucidate mechanisms by which PV-IN-embedded microcircuits in the NAc undergo activity-dependent shifts in synaptic strength.


Sites of biosynthesis and storage of Taxol in Taxus media (Rehder) plants: Mechanism of accumulation.
Taxol is a cytotoxic agent against various types of cancers. The cytotoxic activities of Taxol can be extended to its synthesizing plant. Here, Taxol is shown to have special synthesis, storage and transport mechanisms that avoid the toxic effects on its source plant. The sites of Taxol biosynthesis, transport and storage were revealed by quantification of plant Taxol, its intermediate baccatin III, the polyphenol side chain precursor , gene expression analysis of the major Taxol biosynthetic genes and in situ immuno-labeling. Although the biosynthesis of Taxol was limited by the expression of its biosynthetic genes and the presence of baccatin III, its presence did not correlate to baccatin III accumulation, nor to the expression of biosynthetic genes. However, Taxol presence positively correlated to polyphenol accumulation (late stage in Taxol assembly) and the resin-like hydrophobic bodies (HB, storage organelles). These results indicate that the presence of Taxol requires two complementary steps, biosynthesis followed by storage. Each step is limited by the availability of different precursors, which differ in their localization within the plant. Thus, the sites of biosynthesis, transport and storage of Taxol are different. Taxus media (Rehder) plant wood showed high concentrations of baccatin III and the expression of biosynthetic genes. However, the concentrations of Taxol, polyphenol and HB were very high in the plant outer layers including phloem and dead bark (rhytidome). Furthermore, in situ immuno-labeling showed that taxadiene synthase (the rate-limiting enzyme in Taxol biosynthesis) was mainly found in the wood, while Taxol primarily localized to the outer tissues. Conclusively, wood can be considered as the site of Taxol biosynthesis. Our data also propose that Taxol then accumulates into HB in order to permit its transport within the living plant tissues without causing toxic effects. This is followed by Taxol storage in the outer tissues including phloem and dead bark.


Electrolytes Change the Interfacial Water Structure but Not the Vibrational Dynamics.
Heterogeneous ozone chemistry occurring on aerosols is driven by interfacial chemistry and thus affected by the surface state of aerosol particles. Therefore, the effect of electrolytes on the structure of interfacial water has been under intensive investigation. However, consequences for energy dissipation rates and mechanisms at the interface are largely unknown. Using time-resolved sum frequency generation spectroscopy, we reveal that the relaxation pathway is the same for neat water-air as for aqueous solutions of Na2SO4 and Na2CO3. We further show that similar lifetimes are extracted from all investigated systems and that these lifetimes show an excitation frequency dependent relaxation time from 0.2 ps up to 1 ps. Hence, despite static SFG on the same systems revealing that the interfacial aqueous structure changes upon adding electrolytes, the vibrational dynamics are indistinguishable for both pure water and different electrolyte solutions.


Regulation of the transbilayer movement of diacylglycerol in the plasma membrane.
This mini-review presents recent advances in the regulation of the membrane transbilayer movement (or flip-flop) of diacylglycerol (DAG), a key intermediate in lipid metabolism and a second messenger in lipid-mediated signaling. Despite progresses in lipid biophysics and imaging, little is known about the DAG dynamics across the two leaflets of the plasma membrane in living cells. Previous model membrane studies with DAG analogs demonstrated their fast flip-flop suggesting that DAG is evenly distributed between the two leaflets of the plasma membrane. However, recent molecular dynamics simulations indicate that DAG transbilayer movement depends on the lipid environment surrounding the lipid, i.e. DAG flips more slowly across a more ordered "lipid raft-like" bilayer (enriched in sphingomyelin/cholesterol) than across a more fluid bilayer (composed of unsaturated glycerophospholipids). Furthermore using the yellow fluorescent protein-tagged C1AB domain from protein kinase C-γ (EYFP-C1AB) that selectively binds DAG, we recently proved that the sphingomyelin (SM) content in the plasma membrane outer leaflet regulates DAG transbilayer movement in Madin-Darby canine kidney cells treated with bacterial phosphatidylcholine-specific phospholipase C. The dose-dependent inhibition of DAG flip-flop by SM could be reproduced in model membranes using fluorescent short chain DAG analog. Regulation of DAG transbilayer movement by the outer leaflet SM content is expected to modify the downstream recruitment of C1-domain containing effectors, thus bringing new insights on the role of DAG dynamics in cell pathophysiology.


Transport and evaporation of virus-containing droplets exhaled by men and women in typical cough events.
The spreading of the virus-containing droplets exhaled during respiratory events, e.g., cough, is an issue of paramount importance for the prevention of many infections such as COVID-19. According to the scientific literature, remarkable differences can be ascribed to several parameters that govern such complex and multiphysical problem. Among these, a particular influence appears associated with the different airflows typical of male and female subjects. Focusing on a typical cough event, we investigate this aspect by means of highly-resolved direct numerical simulations of the turbulent airflow in combination with a comprehensive Lagrangian particle tracking model for the droplet motion and evaporation. We observe and quantify major differences between the case of male and female subjects, both in terms of the droplet final reach and evaporation time. Our results can be associated with the different characteristics in the released airflow and thus confirm the influence of the subject gender (or other physical properties providing different exhalation profiles) on both short-range and long-range airborne transmission.