[A surgeon's fees in court (Vila Boa de Goiás, 1801)].
The article explores the lawsuit brought by Surgeon-Major André Villela da Cunha Roza against Joanna da Fonseca Coutinha in Vila Boa de Goiás in 1801 to recover fees for his services. It examines the health care rendered to slaves, the scarcity and rising prices of these captives, the precarious training received by doctores and surgeons, and the ethical issues entailed in charging the fees in question.


Design and construction of an urban runoff research facility.
As the urban population increases, so does the area of irrigated urban landscape. Summer water use in urban areas can be 2-3x winter base line water use due to increased demand for landscape irrigation. Improper irrigation practices and large rainfall events can result in runoff from urban landscapes which has potential to carry nutrients and sediments into local streams and lakes where they may contribute to eutrophication. A 1,000 m(2) facility was constructed which consists of 24 individual 33.6 m(2) field plots, each equipped for measuring total runoff volumes with time and collection of runoff subsamples at selected intervals for quantification of chemical constituents in the runoff water from simulated urban landscapes. Runoff volumes from the first and second trials had coefficient of variability (CV) values of 38.2 and 28.7%, respectively. CV values for runoff pH, EC, and Na concentration for both trials were all under 10%. Concentrations of DOC, TDN, DON, PO₄₋P, K(+), Mg(2+), and Ca(2+) had CV values less than 50% in both trials. Overall, the results of testing performed after sod installation at the facility indicated good uniformity between plots for runoff volumes and chemical constituents. The large plot size is sufficient to include much of the natural variability and therefore provides better simulation of urban landscape ecosystems.


Religion and Suicide Risk: A Systematic Review.
Although religion is reported to be protective against suicide, the empirical evidence is inconsistent. Research is complicated by the fact that there are many dimensions to religion (affiliation, participation, doctrine) and suicide (ideation, attempt, completion). We systematically reviewed the literature on religion and suicide over the last 10 years (89 articles) with a goal of identifying what specific dimensions of religion are associated with specific aspects of suicide. We found that religious affiliation does not necessarily protect against suicidal ideation, but does protect against suicide attempts. Whether religious affiliation protects against suicide attempts may depend on the culture-specific implications of affiliating with a particular religion, since minority religious groups can feel socially isolated. After adjusting for social support measures, religious service attendance is not especially protective against suicidal ideation, but does protect against suicide attempts, and possibly protects against suicide. Future qualitative studies might further clarify these associations.


Reduced expression of ethanol sensitization by α3β4 nicotinic acetylcholine receptors in DBA/2J mice.
Alcohol use disorder (AUD) is a leading cause of preventable death in the United States, however existing treatments are ineffective and produce aversive side effects such as nausea and fatigue. One potential therapeutic for AUD is the α3β4 nicotinic acetylcholine receptor (nAChR) antagonist 18-methoxycoronaridine (18-MC). Prior work has shown that 18-MC reduces ethanol consumption in rodent models. The present study sought to further examine the therapeutic potential of 18-MC by testing its effects on nonconsummatory behaviors. We examined 2 behavioral measures: ethanol-induced locomotor stimulation, which measures euphoric properties of the drug, and the expression of locomotor sensitization which models neuroadaptations in response to repeated exposure. We tested dose-dependent effects of 18-MC (0, 10, 20 and 30 mg/kg) administration on ethanol stimulation and locomotor sensitization in female and male DBA/2J mice. 18-MC had no effect on acute ethanol-induced stimulation, but the highest dose (30 mg/kg) significantly decreased the expression of locomotor sensitization. Our results support the involvement of α3β4 nAChR in the expression of ethanol-induced locomotor sensitization and suggest that 18-MC may be a therapeutic for AUD. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Synthesis of DNA-coupled isoquinolones and pyrrolidines by solid phase ytterbium- and silver-mediated imine chemistry.
DNA-encoded libraries of chemically synthesized compounds are an important small molecule screening technology. The synthesis of encoded compounds in solution is currently restricted to a few DNA-compatible and water-tolerant reactions. Encoded compound synthesis of short DNA-barcodes covalently connected to solid supports benefits from a broad range of choices of organic solvents. Here, we show that this encoded chemistry approach allows for the synthesis of DNA-coupled isoquinolones by an Yb(iii)-mediated Castagnoli-Cushman reaction under anhydrous reaction conditions and for the synthesis of highly substituted pyrrolidines by Ag(i)-mediated 1,3-dipolar azomethine ylide cycloaddition. An encoding scheme for these DNA-barcoded compounds based on a DNA hairpin is demonstrated.


Surgical management of complete atrioventricular canal.
Successful correction of complete atrioventricular (AV) canal depends on accurate assessment of surgical anatomy and preservation of valve tissue to avoid postoperative valvular insufficiency. From 1975 to 1980 there were 68 patients aged 2 months to 17 years (median age 12 months) who underwent correction for the complete form of AV canal. Forty-six percent had associated anomalies which included patent ductus arteriosus, right aortic arch, pulmonic stenosis, and ostium secundum defect. Two types of repairs were employed: group I-Teflon patch closure of the ventricular septal defect (VSD) by division of the common leaflets into mitral and tricuspid components: Group II-Teflon patch closure of the VSD without division of common leaflets by fashioning the patch between the chordae tendineae and under the common leaflets. The atrial septal defect component was closed separately with pericardium or Teflon. Overall mortality is related to presence of (1) elevated pulmonary vascular resistance (Wood units greater than 4), (2) prior palliative operations, or (3) associated cardiovascular anomalies. Repair of complete AV canal without splitting the common leaflets preserves valve tissue. The act of splitting the common leaflets and reattaching the mitral and tricuspid components to the VSD patch by necessity sacrifices valve tissue. Although this may not be significant in older children, it becomes important in infants, for the sacrificed valve tissue comprises a greater proportion of the whole. Moreover, patch disruption of the reattached mitral and tricuspid components can be avoided if the common leaflets are not split.


Variable inhibition of thrombospondin 1 against liver and lung metastases through differential activation of metalloproteinase ADAMTS1.
Metastasis relies on angiogenesis for tumor expansion. Tumor angiogenesis is restrained by a variety of endogenous inhibitors, including thrombospondin 1 (TSP1). The principal antiangiogenic activity of TSP1 resides in a domain containing three TSP1 repeats (3TSR), and TSP1 cleavage is regulated, in part, by the metalloproteinase ADAMTS1. In this study, we examined the role of TSP1 and ADAMTS1 in controlling metastatic disease in the liver and lung. TSP1 overexpression inhibited metastatic growth of colon or renal carcinoma cells in liver but not lung. Metastatic melanoma in liver grew more rapidly in Tsp1-null mice compared with controls, whereas in lung grew similarly in Tsp1-null mice or controls. Recombinant TSP1 was cleaved more efficiently in lysates from liver than lung. ADAMTS1 inhibition by neutralizing antibody, small interfering RNA, or genetic deletion abrogated cleavage activity. To confirm that lack of cleavage of TSP1 ablated its antiangiogenic function in the lung, we generated colon cancer cells stably secreting only the 3TSR domain and found that they inhibited formation of both liver and lung metastases. Collectively, our results indicate that the antiangiogenic activity of TSP1 is differentially regulated by ADAMTS1 in the liver and lung, emphasizing the concept that regulation of angiogenesis is varied in different tissue environments.


Exploring the Potential Use of Wearable Devices as a Prognostic Tool among Patients in Hospice Care.
Background: Smartphones and wearable devices have become a part and parcel of the healthcare industry. The use of wearable technology has already proved its potentials in improving healthcare research, clinical work, and patient care. The real time data allows the care providers to monitor the patients' symptoms remotely, prioritize the patients' visits, assist in decision-making, and carry out advanced care planning. Objectives: The primary objective of our study was to investigate the potential use of wearable devices as a prognosis tool among patients in hospice care and palliative care, and the secondary objective was to examine the association between wearable devices and clinical data in the context of patient outcomes, such as discharge and deceased at various time intervals. Methods: We employed a prospective observational research approach to continuously monitor the hand movements of the selected 68 patients between December 2019 and June 2022 via an actigraphy device at hospice or palliative care ward of Taipei Medical University Hospital (TMUH) in Taiwan. Results: The results revealed that the patients with higher scores in the Karnofsky Performance Status (KPS), and Palliative Performance Scale (PPS) tended to live at discharge, while Palliative Prognostic Score (PaP) and Palliative prognostic Index (PPI) also shared the similar trend. In addition, the results also confirmed that all these evaluating tools only suggested rough rather than accurate and definite prediction. The outcomes (May be Discharge (MBD) or expired) were positively correlated with accumulated angle and spin values, i.e., the patients who survived had higher angle and spin values as compared to those who died/expired. Conclusion: The outcomes had higher correlation with angle value compared to spin and ACT. The correlation value increased within the first 48 h and then began to decline. We recommend rigorous prospective observational studies/randomized control trials with many participants for the investigations in the future.


Sequence of rat intestinal vitamin D-dependent calcium-binding protein derived from a cDNA clone. Evolutionary implications.
We have recently reported molecular cloning of the cDNA synthesized from rat duodenal mRNA-encoding intestinal calcium-binding protein (ICaBP), a vitamin D3-induced protein (Desplan, C., Thomasset, M., and Moukhtar, M. S. (1983) J. Biol. Chem. 258, 2762-2765). Nucleotide sequence analysis of the longest cDNA insert (375 base pairs) permitted the assignment of 207 nucleotides of the coding region and 104 nucleotides of the entire 3'-noncoding region of the mRNA. Although the derived amino acid sequence for rat ICaBP differed from the bovine and porcine sequences by 16 and 14 residues, respectively, all the residues of each calcium-binding site met the proposed requirements of the "EF hand" theory. In contrast, several differences found in the linker regions might explain the absence of cross-immunoreactivity between rat and porcine ICaBPs. Analysis of nucleotide sequence homologies between the coding and noncoding regions showed that the region coding for the two calcium-binding sites (I and II) was immediately followed in the noncoding region by a sequence very similar to the sequence coding for site I. This suggests that rat ICaBP mRNA contains the remains of an untranslated calcium-binding site III-like structure and that low Mr ICaBP could result in early termination of the translation of a larger molecule containing four sites.


Thrombosis risk associated with COVID-19 infection. A scoping review.
Infection by the 2019 novel coronavirus (COVID-19) has been reportedly associated with a high risk of thrombotic complications. So far information is scarce and rapidly emerging. We conducted a scoping review using a single engine search for studies assessing thrombosis and coagulopathy in COVID-19 patients. Additional studies were identified by secondary review and alert services. Studies reported the occurrence of venous thromboembolism and stroke in approximately 20% and 3% of patients, respectively. A higher frequency seems to be present in severely ill patients, in particular those admitted to intensive care units. The thrombotic risk is elevated despite the use of anticoagulant prophylaxis but optimal doses of anticoagulation are not yet defined. Although an increase of biomarkers such as D-dimer has been consistently reported in severely ill COVID-19, the optimal cut-off level and prognostic value are not known. A number of pressing issues were identified by this review, including defining the true incidence of VTE in COVID patients, developing algorithms to identify those susceptible to develop thrombotic complications and severe disease, determining the role of biomarkers and/or scoring systems to stratify patients' risk, designing adequate and feasible diagnostic protocols for PE, establishing the optimal thromboprophylaxis strategy, and developing uniform diagnostic and reporting criteria.


Mutations in DHDPSL are responsible for primary hyperoxaluria type III.
Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.


Effect of rearing system and mixing at loading on transport and lairage behaviour and meat quality: comparison of outdoor and conventionally raised pigs.
The effect of raising pigs outdoors or conventionally in a barren environment was investigated with respect to behaviour during a 3 to 4 h journey and a 2 h lairage, blood chemistry at slaughter and meat quality characteristics. Pigs were either kept in farm pen groups or were mixed at loading and kept in the groups, so formed, until slaughter. Non-mixed outdoor pigs settled more quickly during transport and lay down to a greater extent at the end of the journey and lairage period compared with conventionally raised pigs. Mixing led to fewer pigs sitting and lying during transport for conventionally raised pigs, where nearly 80% were still standing at the end of the journey. Mixing had no effect on pig posture in the lairage. Outdoor pigs were less aggressive than conventionally raised pigs especially during lairage and had a lower frequency of unacceptable skin damage in the rear and shoulder area. Aggressive interactions were almost exclusively confined to mixed groups and occurred mainly between pigs from different farm pens, i.e. between unfamiliar animals. Mixing at loading led therefore to higher levels of unacceptable skin damage. Cortisol concentrations in slaughter blood were not affected by rearing system or mixing, but mixed, conventionally raised pigs had higher plasma creatine kinase (CK) activities than non-mixed ones (1132 v. 761 U/l, respectively, P < 0.05). Outdoor pigs had similar CK activities, irrespective of mixing (682 and 771 U/l for mixed and non-mixed, respectively). Muscle pH early post mortem was highest in outdoor pigs and muscle temperature lower, but no pig showed pH values below 6.0. Ultimate pH values were both higher (Semimembranosus (S)) and lower (Semispinalis capitis (SC)) than in conventionally raised pigs, and outdoor pigs tended to have a lower frequency of higher than normal pH values. Internal reflectance (MQM) values in Biceps femoris (BF) were highest in outdoor pigs but the incidence of pale, soft and exudative (PSE) meat was low, varying between 0% and 1% for experimental groups. In general, the effects of rearing system and mixing on meat quality measurements taken early post mortem or the day after slaughter were slight, but the trends seen support the CK results, and show that conventionally raised pigs may have found mixing pre-slaughter to be more physically stressful than outdoor pigs did.


Malaria incidence trends and their association with climatic variables in rural Gwanda, Zimbabwe, 2005-2015.
Malaria is a public health problem in Zimbabwe. Although many studies have indicated that climate change may influence the distribution of malaria, there is paucity of information on its trends and association with climatic variables in Zimbabwe. To address this shortfall, the trends of malaria incidence and its interaction with climatic variables in rural Gwanda, Zimbabwe for the period January 2005 to April 2015 was assessed. Retrospective data analysis of reported cases of malaria in three selected Gwanda district rural wards (Buvuma, Ntalale and Selonga) was carried out. Data on malaria cases was collected from the district health information system and ward clinics while data on precipitation and temperature were obtained from the climate hazards group infrared precipitation with station data (CHIRPS) database and the moderate resolution imaging spectro-radiometer (MODIS) satellite data, respectively. Distributed lag non-linear models (DLNLM) were used to determine the temporal lagged association between monthly malaria incidence and monthly climatic variables. There were 246 confirmed malaria cases in the three wards with a mean incidence of 0.16/1000 population/month. The majority of malaria cases (95%) occurred in the > 5 years age category. The results showed no correlation between trends of clinical malaria (unconfirmed) and confirmed malaria cases in all the three study wards. There was a significant association between malaria incidence and the climatic variables in Buvuma and Selonga wards at specific lag periods. In Ntalale ward, only precipitation (1- and 3-month lag) and mean temperature (1- and 2-month lag) were significantly associated with incidence at specific lag periods (p < 0.05). DLNM results suggest a key risk period in current month, based on key climatic conditions in the 1-4 month period prior. As the period of high malaria risk is associated with precipitation and temperature at 1-4 month prior in a seasonal cycle, intensifying malaria control activities over this period will likely contribute to lowering the seasonal malaria incidence.


The Growing Interest in Development of Innovative Optical Aptasensors for the Detection of Antimicrobial Residues in Food Products.
The presence of antimicrobial residues in food-producing animals can lead to harmful effects on the consumer (e.g., allergies, antimicrobial resistance, toxicological effects) and cause issues in food transformation (i.e., cheese, yogurts production). Therefore, to control antimicrobial residues in food products of animal origin, screening methods are of utmost importance. Microbiological and immunological methods (e.g., ELISA, dipsticks) are conventional screening methods. Biosensors are an innovative solution for the development of more performant screening methods. Among the different kinds of biosensing elements (e.g., antibodies, aptamers, molecularly imprinted polymers (MIP), enzymes), aptamers for targeting antimicrobial residues are in continuous development since 2000. Therefore, this review has highlighted recent advances in the development of aptasensors, which present multiple advantages over immunosensors. Most of the aptasensors described in the literature for the detection of antimicrobial residues in animal-derived food products are either optical or electrochemical sensors. In this review, I have focused on optical aptasensors and showed how nanotechnologies (nanomaterials, micro/nanofluidics, and signal amplification techniques) largely contribute to the improvement of their performance (sensitivity, specificity, miniaturization, portability). Finally, I have explored different techniques to develop multiplex screening methods. Multiplex screening methods are necessary for the wide spectrum detection of antimicrobials authorized for animal treatment (i.e., having maximum residue limits).


Shifts in metabolic scaling, production, and efficiency across major evolutionary transitions of life.
The diversification of life involved enormous increases in size and complexity. The evolutionary transitions from prokaryotes to unicellular eukaryotes to metazoans were accompanied by major innovations in metabolic design. Here we show that the scalings of metabolic rate, population growth rate, and production efficiency with body size have changed across the evolutionary transitions. Metabolic rate scales with body mass superlinearly in prokaryotes, linearly in protists, and sublinearly in metazoans, so Kleiber's 3/4 power scaling law does not apply universally across organisms. The scaling of maximum population growth rate shifts from positive in prokaryotes to negative in protists and metazoans, and the efficiency of production declines across these groups. Major changes in metabolic processes during the early evolution of life overcame existing constraints, exploited new opportunities, and imposed new constraints.


Survival benefit and biomarker of PD-1 inhibitor combination therapy in first-line of advanced biliary tract cancer: A retrospective study.
Immune checkpoint inhibitor (ICI) combination therapies have shown promise in the first-line treatment of advanced biliary tract cancer (BTC). However, the best partner remains to be validated. Moreover, progress on biomarkers predicting the efficacy of ICI in BTC is slow. This study aimed to assess the efficacy and investigate reliable predictive biomarkers of programmed cell death protein-1 (PD-1) antibody combination therapy in the first-line treatment of advanced BTC. Clinical data from patients with advanced BTC who received chemotherapy or anti-PD-1 combination therapy as first-line were collected. The primary outcome was overall survival (OS). Biomarkers, including peripheral blood inflammation scores, genetic alterations, and tumor microenvironment were investigated. Sixty-four patients were recruited and divided into four treatment groups: chemotherapy, anti-PD-1 plus chemotherapy, anti-PD-1 plus targeted therapy, and triple group (anti-PD-1 plus chemotherapy and targeted therapy). The median OS was 7.9, 11.3, 12.8, and 28.7 months, respectively. Compared to chemotherapy, mOS significantly prolonged in the triple group (p = 0.031). It showed that patients with five different peripheral blood inflammation scores had significantly prolonged mOS (p < 0.05). Genetic testing results suggested that patients with poor survival all had TP53 mutations and higher levels of KRAS and ERBB2 mutations. Low FOXP3/CD8 ratio was associated with prolonged OS (p = 0.029). With CD4-low, CD8-high, CD56-positive, CD163-high, FOXP3-high and MPO-high in TME as one factor, we calculated PLUS score according to the number of factors. The high-PLUS (>2) group showed significantly superior OS (p = 0.003). First-line anti-PD-1 combination therapy was superior to chemotherapy, and triple therapy significantly improved survival. Peripheral blood immune-inflammation score, FOXP3/CD8 ratio, and PLUS have potential as biomarkers for predicting the efficacy of first-line anti-PD-1 therapy in advanced BTC.


Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men.
Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.


Temporal-spatial analysis of mortality from cardiovascular diseases in the State of Ceará, Brazil, between 2009-2019.
To analyze the spatial distribution of mortality from cardiovascular diseases in the municipalities of the state of Ceará, Brazil, between 2009-2019. This is an ecological study with a spatial focus on the state of Ceará, considering the period from 2009 to 2019. Death data from the Brazilian Mortality Information System and population data from the Brazilian Institute of Geography and Statistics were used to calculate crude and standardized mortality rates from cardiovascular diseases. Temporal analysis was carried out using the Joinpoint Regression Program 4.9.0 software and spatial analysis of the municipalities' average mortality. The values were smoothed by the local empirical Bayesian method using QGIS 3.16. For spatial clusters, the Global and Local Moran Index was used through Moran Map and LISA Map, with analyses carried out in TerraView 4.2.2. A total of 132,145 deaths from cardiovascular diseases were recorded in the period, with an average increase of 3% per year. Higher mortality rates were observed in men, people aged ≥80 years, mixed-race ethnicity/skin color, married, and with lower level of education. There was the formation of clusters of municipalities with high mortality rates in the regions of Vale do Jaguaribe, Sertão Central, Centro Sul, Sertão dos Inhamuns and Serra da Ibiapaba. This study identified municipalities with high mortality and exposed the need for strategies aligned with the reality and particularities of these locations.


Surveillance and early diagnosis of hepatocellular carcinoma.
Patients at high risk for developing hepatocellular carcinoma (HCC) should be enrolled in surveillance programs based on ultrasound (US) examinations performed at 6-month intervals. Nodules found during US surveillance that are smaller than 1 cm should be followed-up with US at 3-month intervals. If the nodule found during US surveillance is larger than 1 cm, it should be investigated further with contrast-enhanced dynamic radiological studies, including US, multidetector computed tomography, or magnetic resonance imaging. If the appearance is typical for HCC (i.e., the lesion shows hypervascularization in the arterial phase with washout in the portal venous or the equilibrium phase), biopsy is considered unnecessary and the lesion can be treated as HCC. For nodules between 1 and 2 cm, it is currently recommended that such non-invasive diagnosis be based on the evidence of coincidental features typical for HCC from at least two dynamic imaging techniques. If the vascular profile on imaging is not characteristic or the nodule is detected in a non-cirrhotic liver, biopsy should be performed. If the biopsy is negative for HCC, patients should be followed-up by imaging studies performed at 3-month intervals until the nodule either disappears, enlarges, or displays diagnostic characteristics of HCC.


Exploiting loss of heterozygosity for allele-selective colorectal cancer chemotherapy.
Cancer chemotherapy targeting frequent loss of heterozygosity events is an attractive concept, since tumor cells may lack enzymatic activities present in normal constitutional cells. To find exploitable targets, we map prevalent genetic polymorphisms to protein structures and identify 45 nsSNVs (non-synonymous small nucleotide variations) near the catalytic sites of 17 enzymes frequently lost in cancer. For proof of concept, we select the gastrointestinal drug metabolic enzyme NAT2 at 8p22, which is frequently lost in colorectal cancers and has a common variant with 10-fold reduced activity. Small molecule screening results in a cytotoxic kinase inhibitor that impairs growth of cells with slow NAT2 and decreases the growth of tumors with slow NAT2 by half as compared to those with wild-type NAT2. Most of the patient-derived CRC cells expressing slow NAT2 also show sensitivity to 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine (APA) treatment. These findings indicate that the therapeutic index of anti-cancer drugs can be altered by bystander mutations affecting drug metabolic genes.


A proposed role for endomembrane trafficking processes in regulating tonoplast content and vacuole dynamics under ammonium stress conditions in Arabidopsis root cells.
Ammonium (NH4+) stress has multiple effects on plant physiology, therefore, plant responses are complex, and multiple mechanisms are involved in NH4+ sensitivity and tolerance in plants. Root growth inhibition is an important quantitative readout of the effects of NH4+ stress on plant physiology, and cell elongation appear as the principal growth inhibition target. We recently proposed autophagy as a relevant physiological mechanisms underlying NH4+ sensitivity response in Arabidopsis. In a brief overview, the impaired macro-autophagic flux observed under NH4+ stress conditions has a detrimental impact on the cellular energetic balance, and therefore on the energy-demanding plant growth. In contrast to its inhibitory effect on the autophagosomes flux to vacuole, NH4+ toxicity induced a micro-autophagy-like process. Consistent with the reduced membrane flux to the vacuole related to macro-autophagy inhibition and the increased tonoplast degradation due to enhanced micro-autophagy, the vacuoles of the root cells of the NH4+-stressed plants showed lower tonoplast content and a decreased perimeter/area ratio. As the endosome-to-vacuole trafficking is another important process that contributes to membrane flux toward the vacuole, we evaluated the effects of NH4+ stress on this process. This allows us to propose that autophagy could contribute to vacuole development as well as possible avenues to follow for future studies.


Malignant schwannoma in the head and neck.
The authors' experience in dealing with three cases of malignant Schwannoma in the head and neck is outlined. The symptomatology of this tumor is discussed with its investigation and management. A correct diagnosis with a CT scan to delineate tumor extent is imperative. A wide surgical resection is the preferred method of treatment with postoperative irradiation of value for residual microscopic disease. The pernicious nature of this tumor often leads to a dismal outcome despite aggressive therapy.


Rendering protein mutation movies with MutAmore.
The success of AlphaFold2 in reliable protein three-dimensional (3D) structure prediction, assists the move of structural biology toward studies of protein dynamics and mutational impact on structure and function. This transition needs tools that qualitatively assess alternative 3D conformations. We introduce MutAmore, a bioinformatics tool that renders individual images of protein 3D structures for, e.g., sequence mutations into a visually intuitive movie format. MutAmore streamlines a pipeline casting single amino-acid variations (SAVs) into a dynamic 3D mutation movie providing a qualitative perspective on the mutational landscape of a protein. By default, the tool first generates all possible variants of the sequence reachable through SAVs (L*19 for proteins with L residues). Next, it predicts the structural conformation for all L*19 variants using state-of-the-art models. Finally, it visualizes the mutation matrix and produces a color-coded 3D animation. Alternatively, users can input other types of variants, e.g., from experimental structures. MutAmore samples alternative protein configurations to study the dynamical space accessible from SAVs in the post-AlphaFold2 era of structural biology. As the field shifts towards the exploration of alternative conformations of proteins, MutAmore aids in the understanding of the structural impact of mutations by providing a flexible pipeline for the generation of protein mutation movies using current and future structure prediction models.


Assessing the knowledge, attitude and practice of osteoporosis among Pakistani women: A national social-media based survey.
There are numerous risk factors for osteoporosis and understanding and recognizing these risk factors is critical when deciding whether to take preventive measures. It is critical to reduce the healthcare expenditure burden of the Pakistani population by raising awareness and implementing osteoporosis-preventable measures. This survey aims to assess the knowledge, attitudes, and practices (KAP) of Pakistani women as well as their misconceptions about osteoporosis. A cross-sectional survey was conducted from August 2021 to January 2022 by the Bone & Mineral Disease research group at Section of Chemical Pathology, Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, with exemption from the ethical review committee. Using snowball sampling, a validated Osteoporosis Prevention and Awareness Tool (OPAAT) was disseminated online via social media. With informed consent, 400 Pakistani women aged ≥ 18 years were included in the study. SPSS Statistics version 25.0 was used for data analysis. Chi-square test for association and Fisher-exact test were applied, and significance level was α<0.05. Based on the OPAAT scores of all (n = 400) participants, 22% (n = 88) had low knowledge, 44% (n = 176) had average knowledge, while 34% (n = 136) had good knowledge of osteoporosis. The most common misconceptions were about age-related risk, presentation of symptoms, radiation risk, associated risk factors like tooth loss, osteoarthritis, and knowledge about predictors of bone health. Adult Pakistani women have a fair understanding of osteoporosis, but the OPAAT tool clarifies some common misconceptions. There is a need to develop educational strategies to increase the knowledge of osteoporosis among Pakistani adults and to promote a bone-healthy lifestyle.


Antigenic relationships among human rotaviruses as determined by outer capsid protein VP4.
cDNA clones representing the VP4 gene of symptomatic human rotavirus strain KU (VP7 serotype 1) or DS-1 (VP7 serotype 2) or asymptomatic human rotavirus strain 1076 (VP7 serotype 2) were constructed and inserted into a baculovirus expression vector under the control of the polyhedrin promoter. The resulting recombinants expressed the appropriate authentic VP4 rotavirus outer capsid protein. Guinea pigs immunized with these VP4 proteins developed antibodies that neutralized infectivity of the rotavirus from which the immunizing VP4 was derived. These antisera were then used in neutralization tests to define the extent and distribution of VP4 antigenic polymorphism among human rotaviruses. Three distinct serotypes and one subtype of the VP4 outer capsid protein were identified among 17 human rotavirus strains that had previously been assigned to five distinct VP7 serotypes. For the most part, VP4 serotype segregated independently of VP7 serotype. Ten strains of human rotavirus that were associated with symptomatic infection and that exhibited VP7 serotype 1, 3, 4, or 9 specificity, each possessed a VP4 of the same serotype and subtype, designated VP4 serotype 1A. Both symptomatic human rotavirus strains with VP7 serotype 2 specificity were related by neutralization to the VP4 serotype 1A strains and were classified as a subtype of VP4 serotype 1--i.e., serotype 1B--since viruses of serotype 1A appeared to be prime strains. Four human rotavirus strains that were recovered from healthy infants in newborn nurseries in which virus transmission persisted over a long interval, belonged to VP7 serotype 1, 2, 3, or 4, but each strain possessed the same VP4 antigenic specificity that was designated VP4 serotype 2. Finally, a single strain of symptomatic human rotavirus of VP7 serotype 1 specificity possessed a unique VP4 that was provisionally classified as VP4 serotype 3 but this remains to be confirmed because neutralization tests were performed in only one direction. Among the 10 rotavirus strains whose VP4 gene was previously sequenced, there was complete concordance between assignment of VP4 serotype by neutralization and classification according to VP4 amino acid homology. Thus, rotaviruses that exhibited a VP4 amino acid homology of 89% or greater belonged to the same VP4 serotype and subtype as determined by neutralization. Finally, evidence was obtained that the serotype-specific domain is located on the VP8 subunit of VP4.


Fluorine in protein environments: a QM and MD study.
Noncanonical amino acids with newly designed side-chain functionalities represent powerful tools to improve structural, biological, and pharmacological properties of peptides and proteins. In this context, fluorinated amino acids have increasingly gained importance. Despite the current wide use of fluorination in protein engineering, the basic properties of fluorine in protein environments are still not completely understood. Our aim has been to characterize the physicochemical properties of fluorinated amino acids by using quantum mechanics (QM) and molecular dynamics (MD) approaches. We have analyzed geometry, charges, and hydrogen bonding abilities of several ethane fluorinated derivatives at different QM theory levels and have used them as simplified models for fluorinated amino acid side chains. We have parametrized four fluorinated L-amino acids for the AMBER ff94/99 force field: 4-monofluoroethylglycine (MfeGly), 4,4-difluoroethylglycine (DfeGly), 4,4,4-trifluoroethylglycine (TfeGly), and 4,4-difluoropropylglycine (DfpGly). We have characterized them in terms of molecular volumes, conformational preferences, and hydration properties. The obtained results illustrate that fluorine and hydrogen atoms of fluoromethyl groups could be potential acceptors or donors of weak hydrogen bonds in protein environments. Hydration of the studied fluorinated amino acids was found to be more favorable than for their nonfluorinated analogues, and hydrophobicity was observed to increase with the number of fluorine atoms, which is in accordance with the experimental retention times we obtain for these amino acids. This study broadens our understanding of the properties of fluorine within protein environments, which is important to exploit the full potential of fluorine's unique properties for applications in the field of protein engineering.


Comparing maternal styles in bonobos (Pan paniscus) and chimpanzees (Pan troglodytes).
Studies on Cercopithecine primate maternal styles, using factor analysis on a set of maternal behaviors, commonly render two factors that describe separate dimensions of maternal behavior: protectiveness and rejection. The aims of this study were to 1) investigate whether this method for determining maternal styles in Cercopithecine species can be applied to bonobos (Pan paniscus) and chimpanzees (Pan troglodytes), 2) determine whether they follow the same pattern, and 3) assess whether species differences in maternal style are apparent. We performed a factor analysis on nine maternal behaviors using data on eight mother-infant pairs of each species. This resulted in three factors: protectiveness, distance, and refusal. Protectiveness is positively correlated with time spent in ventral contact, making contact, approaching, and restraining. Distance is positively related with breaking contact and leaving. Refusal is positively correlated with rejecting and nipple-rejecting. The pattern of protectiveness corresponds with the pattern found in Cercopithecine species, suggesting a high consistency of this dimension across species and higher taxa. The retention of the other two factors indicates that in the Pan species, breaking contact and leaving represent another dimension, apart from rejecting and nipple-rejecting, which usually fall under one dimension in Cercopithecine species. An interspecific comparison of the factor scores for each dimension of maternal behavior reveals that, on average, bonobos and chimpanzees score equally on protectiveness. Scores on distance increase positively with infant age in chimpanzees, and negatively in bonobos, and on average bonobos have higher scores on refusal. These interspecies differences in maternal style are discussed in the light of interspecies differences in infant development, infant vulnerability to aggression, interbirth intervals, and female sociality.


Serotyping and Genetic Characterization of Hand, Foot, and Mouth Disease (HFMD)-Associated Enteroviruses of No-EV71 and Non-CVA16 Circulating in Fujian, China, 2011-2015.
BACKGROUND Hand, foot, and mouth disease (HFMD) is a common contagious disease in infants; it is caused by multiple serotypes of human enterovirus (EV), which belongs to the enterovirus genus of the picornavirus family. According to sentinel surveillance, infection with EVs other than EV71 and CVA 16 have become increasingly common in recent years among HFMD patients, posing new challenges for HFMD control. This study aimed to explore the spectrum of serotypes in the other EVs (non-EV71 and non-CVA16) in Fujian province in southeastern China. MATERIAL AND METHODS We investigated 562 samples from EVs-infected HFMD patients with diagnosis confirmed by real-time RT-PCR with other EVs infection between 2011 and 2015. Nucleotide acid detection and the serotyping of the enteroviruses were also performed. The complete VP1 gene was amplified and sequenced. VP1-based phylogenetic analyses of CVA6, CVA10, CVA4, and CVA2 were also performed. RESULTS Among the samples, 22 serotypes of the other EVs, which belong to 4 species of human enterovirus A-D, were identified. Of the 22 serotypes, CVA6 (57.8%) and CVA10 (21.0%) were most common, followed by CVA4 (6.8%) and CVA2 (2.7%). The other 18 serotypes accounted for 11.7% of samples, none of which exceeded 2%. Among 47 (8.4%) samples from patients with severe HFMD, 10 serotypes were identified and most samples belonged to CVA6 (20/47), followed by CVA10 (11/47). Entire VP1 comparison revealed that overall genetic identities were 96.7%, 96.3%, 94.4%, and 94.9% among strains within CVA6, CVA10, CVA4, and CVA2, respectively. CONCLUSIONS VP1-based phylogenetic analysis for the 4 predominant serotypes indicated various clades or sub-clades, which suggests the complex transmissions of other enteroviruses in Fujian.


Effects of steroids on endometrial oxytocin mRNA production.
In this study, the roles of oestrogen and progesterone in the regulation of oxytocin gene expression in equine endometrium were examined. Anoestrous mares (n=19) were assigned randomly to one of the following treatment groups: control (vehicle control for 1 day; n=3); progesterone (250 mg progesterone per day for 6 days; n=4); oestradiol (5 mg beta-oestradiol 17-valerate per day for 6 days; n=4); oestradiol plus short duration progesterone (5 mg beta-oestradiol 17-valerate per day for 6 days followed by 250 mg progesterone per day for 6 days; n=4); and oestradiol plus long duration progesterone (5 mg beta-oestradiol 17-valerate per day for 6 days followed by 250 mg progesterone per day for 12 days; n=4). Jugular venous blood samples were obtained for oestrogen and progesterone radioimmunoassays. Endometrial biopsies were obtained and total RNA was extracted. Expression of mRNA for oxytocin and glyceraldehyde 3'-phosphate dehydrogenase was assessed by RT-PCR and Southern blotting. Oxytocin mRNA abundance was significantly higher (P < 0.05) in the oestrogen-treated group than in all other groups. These data demonstrate that oestradiol priming for 6 days upregulated expression of the endometrial oxytocin gene. Progesterone treatment for either 6 or 12 days after oestradiol priming returned oxytocin mRNA abundance to levels similar to those of controls.


Impact of a national medical fee schedule revision on the cessation of physician home visits among older patients in Tokyo: A retrospective study.
As Japan's population continues to age rapidly, the national government has implemented several measures to improve the efficiency of healthcare services and to control rising medical expenses for older patients. One such measure was the revision of the medical fee schedule for physician home visits in April 2014, in which eligibility for these visits was restricted to patients who are unable to visit outpatient clinics without assistance. Through an investigation of patients who were receiving physician home visits in Tokyo, this study examines whether this fee schedule revision resulted in an increase in patients who transitioned from home visits to outpatient care. In a retrospective analysis of health insurance claims data, we examined 80,914 Tokyo residents aged 75 years or older who had received at least one physician home visit between January and May 2014. The study period was divided into four periods (January-February, February-March, March-April, and April-May), and we examined the number of patients receiving home visits in the index month of each period who subsequently transitioned to outpatient care in the following month. Potential factors associated with this transition to outpatient care were examined using a generalised estimating equation. The March-April period that included the fee schedule revision was significantly associated with a higher number of patients who transitioned from home visits in the index month to outpatient care in the following month (odds ratio: 4.46, p < 0.001) than the other periods. In addition, patients receiving home visits at residential facilities were more likely to transition to outpatient care (odds ratio: 10.40, p < 0.001). These findings indicate that the fee schedule revision resulted in an increase in patients who ceased physician home visits and began visiting outpatient clinics for treatment.


Roaming: A Phase Space Perspective.
In this review we discuss the recently described roaming mechanism for chemical reactions from the point of view of nonlinear dynamical systems in phase space. The recognition of the roaming phenomenon shows the need for further developments in our fundamental understanding of basic reaction dynamics, as is made clear by considering some questions that cut across most studies of roaming: Is the dynamics statistical? Can transition state theory be applied to estimate roaming reaction rates? What role do saddle points on the potential energy surface play in explaining the behavior of roaming trajectories? How do we construct a dividing surface that is appropriate for describing the transformation from reactants to products for roaming trajectories? How should we define the roaming region? We show that the phase space perspective on reaction dynamics provides the setting in which these questions can be properly framed and answered. We illustrate these ideas by considering photodissociation of formaldehyde. The phase-space formulation allows an unambiguous description of all possible reactive events, which also allows us to uncover the phase space mechanism that explains which trajectories roam, as opposed to evolving toward a different reactive event.


Blood pressure profile is associated with microalbuminuria and retinopathy in hypertensive nondiabetic patients.
Target organ damage is important for global cardiovascular risk assessment. The aim of this study was to explore the association between the blood pressure profile and end-organ damage in a hypertensive non-diabetic cohort. A total of 560 consecutive hypertensive nondiabetic patients (mean age: 58.2 ± 13.3 years, 221 men) were included in the study. All patients underwent thorough physical examination including fundoscopic examination. First morning urine samples were obtained from each patient and measurement of the albumin-to-creatinine ratio in first morning urine collection samples was used for diagnosis of microalbuminuria. All patients underwent a 24-h ambulatory blood pressure monitoring and were grouped as dippers and non-dippers according to the presence or absence of >10% decrease in blood pressure during the night, respectively. The non-dipper group consisted of 247 patients with a non-dipper blood pressure profile, 31 patients with reverse dipping and 4 patients with extreme dipping. Non-dipper patients were significantly older. Coronary artery disease, cerebrovascular disease, hypertensive retinopathy and microalbuminuria were significantly more prevalent in the non-dipper patients. Non-dipping hypertension increased the risk of hypertensive retinopathy by 1.89 times (95% confidence interval, CI:1.35-2.65, p < 0.001) and the risk of microalbuminuria by 2.23 times (95% CI:1.49-3.33, p < 0.001). Non-dipping hypertension was still significantly associated with hypertensive retinopathy and microalbuminuria when adjusted by age and sex. Non-dipping hypertension was associated with increased risk of hypertensive retinopathy and microalbuminuria. Blood pressure profiles should also be considered in assessing the risk for hypertensive patients.


Hitting Reset on Sediment Toxicity: Sediment Homogenization Alters the Toxicity of Metal-Amended Sediments.
Laboratory testing of sediments frequently involves manipulation by amendment with contaminants and homogenization, which changes the physicochemical structure of sediments. These changes can influence the bioavailability of divalent metals, and field and mesocosm experiments have shown that laboratory-derived thresholds are often overly conservative. We assessed the mechanisms that lead to divergence between laboratory- and field-derived thresholds; specifically, we assessed the importance of slow equilibration to solid-phase ligands and vertical stratification. To mimic natural physicochemical conditions, we uniquely aged sediment with a flow-through exposure system. These sediments were then homogenized and compared, toxicologically, with freshly metal-amended sediments in a 28-d chronic toxicity bioassay with the amphipod Hyalella azteca. We assessed concentration-response relationships for 3 metals (copper, nickel, and zinc) and 5 geochemically distinct sediments. We observed minimal differences in growth and survival of H. azteca between aged and freshly spiked sediments across all sediments and metals. These trends suggest that a loss of toxicity observed during long-term sediment aging is reversed after sediment homogenization. By comparison with mesocosm experiments, we demonstrate that homogenizing sediment immediately before toxicity assays may produce artificially high toxicity thresholds. We suggest that toxicity assays with sediments that maintain vertical redox gradients are needed to generate field-relevant sediment metal toxicity thresholds. Environ Toxicol Chem 2019;38:1995-2007. © 2019 SETAC.


Identification of missense mutation (I12T) in the BSND gene and bioinformatics analysis.
Nonsyndromic hearing loss is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness and nonsyndromic nearing loss. We studied a Pakistani consanguineous family. Clinical examinations of affected individuals did not reveal the presence of any associated signs, which are hallmarks of the Bartter syndrome type IV. Linkage analysis identified an area of 18.36 Mb shared by all affected individuals between markers D1S2706 and D1S1596. A maximum two-point LOD score of 2.55 with markers D1S2700 and multipoint LOD score of 3.42 with marker D1S1661 were obtained. BSND mutation, that is, p.I12T, cosegregated in all extant members of our pedigree. BSND mutations can cause nonsyndromic hearing loss, and it is a second report for this mutation. The respected protein, that is, BSND, was first modeled, and then, the identified mutation was further analyzed by using different bioinformatics tools; finally, this protein and its mutant was docked with CLCNKB and REN, interactions of BSND, respectively.


Role of Cytokinins in Senescence, Antioxidant Defence and Photosynthesis.
Cytokinins modulate a number of important developmental processes, including the last phase of leaf development, known as senescence, which is associated with chlorophyll breakdown, photosynthetic apparatus disintegration and oxidative damage. There is ample evidence that cytokinins can slow down all these senescence-accompanying changes. Here, we review relationships between the various mechanisms of action of these regulatory molecules. We highlight their connection to photosynthesis, the pivotal process that generates assimilates, however may also lead to oxidative damage. Thus, we also focus on cytokinin induction of protective responses against oxidative damage. Activation of antioxidative enzymes in senescing tissues is described as well as changes in the levels of naturally occurring antioxidative compounds, such as phenolic acids and flavonoids, in plant explants. The main goal of this review is to show how the biological activities of cytokinins may be related to their chemical structure. New links between molecular aspects of natural cytokinins and their synthetic derivatives with antisenescent properties are described. Structural motifs in cytokinin molecules that may explain why these molecules play such a significant regulatory role are outlined.


A non-proteolytic release mechanism for HMCES-DNA-protein crosslinks.
The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we report a non-proteolytic release mechanism for HMCES-DNA-protein crosslinks (DPCs), which is regulated by DNA context. In ssDNA and at ssDNA-dsDNA junctions, HMCES-DPCs are stable, which efficiently protects AP sites against spontaneous incisions or cleavage by APE1 endonuclease. In contrast, HMCES-DPCs are released in dsDNA, allowing APE1 to initiate downstream repair. Mechanistically, we show that release is governed by two components. First, a conserved glutamate residue, within HMCES' active site, catalyses reversal of the crosslink. Second, affinity to the underlying DNA structure determines whether HMCES re-crosslinks or dissociates. Our study reveals that the protective role of HMCES-DPCs involves their controlled release upon bypass by replication forks, which restricts DPC formation to a necessary minimum.


Cardiac nuclear medicine, part I: the methods.
With the rapid improvement in instrumentation and radiopharmaceuticals, cardiovascular nuclear medicine has undergone dramatic growth. Radiotracer techniques for the estimation of myocardial blood flow, metabolism and cardiac hemodynamics have been accepted into routine clinical practice. These techniques are also providing sensitive tools to help us elucidate cardiac physiology and pathophysiology. Three commonly used examinations are: technetium-99m pyrophosphate imaging for the detection of irreversibly damaged myocardium; thallium-201 imaging for the evaluation of myocardial perfusion and integrity; and cardiac wall motion studies with technetium-99m labeled red blood cells for the assessment of ventricular contraction. This is the first part of a three-part series on cardiac nuclear medicine. Part II will focus on diagnosis of coronary artery disease, and part III will focus on myocardial infarction and other cardiac diseases.


[Transient ischemic attack: the only presenting syndrome of dural sinus thrombosis].
Intracranial hypertension (ICHT) is the most frequent presenting syndrome of dural vein sinus thrombosis (CVT). A transient ischemic attack as an acute mode of onset is exceptional. A right handed, forty years old man with a medical history of recurrent headaches, microcephalia and calcifications in his brain, presenting to the emergency department with left paresis that lasted a few minutes and with a complete recovery. The cerebral and neck magnetic resonance (MR) including MR angiography showed superior sagittal sinus, both transverse sinuses and right sigmoid sinus thrombosis with an increase in size of superficial cerebral venous that drained to the left sigmoid sinus. There was no evidence of intracranial dural malformations. The cerebral MR did not show any abnormal parenchymal enhancement (edema, arterial or venous infarctions, hemorrhage) including diffusion-weighted IMR. The digital subtraction angiography (ADC) confirmed the same findings as the MR angiography. The diagnosis was a chronic CVT. We studied stroke in a young adult and we did not find other irregularities. The neurological examination was normal when the patient left the hospital with an antiplatelet drug. Focal neurological deficit is an exceptional event of a chronic vein sinus thrombosis during follow-up. Isolated cases regarding an acute time course have been described. The interest of this case lies in the fact that venous sinus thrombosis rarely has transitory focal deficit in its course and we found no such description as onset symptoms.


Silicon microprotrusions with tailored chirality enabled by direct femtosecond laser ablation.
Here, we report on formation of nanoprotrusions on the surface of a bulk crystalline silicon wafer under femtosecond-laser ablation with a donut-shaped laser beam. By breaking circular symmetry of the irradiating donut-shaped fs-pulse beam, a switch in geometry of the formed surface nanoprotrusions from regular to chiral was demonstrated. The chirality of the obtained Si nanostructures was promoted with an asymmetry degree of the laser beam. An uneven helical flow of laser-melted Si caused by asymmetry of the initial intensity and temperature pattern on the laser-irradiated Si surface explains this phenomenon. Chirality of the formed protrusions was confirmed by visualizing cross-sectional cuts produced by focused ion beam milling as well as Raman activity of these structures probed by circularly polarized light with opposite handedness. Our results open a pathway towards easy-to-implement inexpensive fabrication of chiral all-dielectric nanostructures for advanced nanophotonic applications and sensing of chiral molecules.


Biological activity of IgE specific for cross-reactive carbohydrate determinants.
The clinical relevance of IgE specific for cross-reactive carbohydrate determinants (CCDs) has been a matter of controversy. Until now, no convincing experiments have been performed to test the biologic significance of individual multivalent allergens that carry multiple carbohydrate epitopes. We sought to contribute to the understanding of the role of CCD-specific IgE antibodies and to study whether CCD-specific IgE antibodies are able to activate basophils using different multivalent glycoproteins as antigens. Purified natural tomato beta-fructofuranosidase (nLyc e 2) and rLyc e 2.02 expressed in Escherichia coli were compared by means of histamine release tests. In addition, native and deglycosylated horseradish peroxidase and a neoglycoprotein consisting of a defined glycopeptide (Manalpha1-6[Xylbeta1-2]Manbeta1-4GlcNAcbeta1-4[Fucalpha1-3]GlcNAc) coupled to BSA were used in histamine release assays using stripped basophils from normal donors resensitized with IgE from CCD-reactive patients with food allergy to tomato. Ten CCD-positive and 2 CCD-negative sera from patients with tomato allergy underwent histamine release testing by using the glycoproteins and nonglycosylated controls as antigens, respectively. All sera induced histamine release with tomato extract (up to 100%), confirming the allergic status of the donors. Four of the CCD-positive sera induced releases ranging from 12% to 82% with all of the glycoproteins but not with the nonglycosylated or monovalent controls. All other sera showed no response or only very weak response to the glycoproteins. Approximately one third of the CCD-positive sera from patients with tomato allergy have biologically relevant CCD-specific IgE antibodies. Therefore the general claim that CCD-specific IgE is clinically irrelevant has to be reconsidered critically. Hence IgE specific for CCDs should be taken into consideration in the diagnosis and therapy of certain allergies. In the subgroup of patients sensitized to CCDs, the use of natural allergens should be preferred over the use of recombinant allergens expressed in prokaryotic organisms.


Niche breadth predicts geographical range size: a general ecological pattern.
The range of resources that a species uses (i.e. its niche breadth) might determine the geographical area it can occupy, but consensus on whether a niche breadth-range size relationship generally exists among species has been slow to emerge. The validity of this hypothesis is a key question in ecology in that it proposes a mechanism for commonness and rarity, and if true, may help predict species' vulnerability to extinction. We identified 64 studies that measured niche breadth and range size, and we used a meta-analytic approach to test for the presence of a niche breadth-range size relationship. We found a significant positive relationship between range size and environmental tolerance breadth (z = 0.49), habitat breadth (z = 0.45), and diet breadth (z = 0.28). The overall positive effect persisted even when incorporating sampling effects. Despite significant variability in the strength of the relationship among studies, the general positive relationship suggests that specialist species might be disproportionately vulnerable to habitat loss and climate change due to synergistic effects of a narrow niche and small range size. An understanding of the ecological and evolutionary mechanisms that drive and cause deviations from this niche breadth-range size pattern is an important future research goal.


Measuring, reversing, and modeling the mechanical changes due to the absence of Fibulin-4 in mouse arteries.
Mice with a smooth muscle cell (SMC)-specific deletion of Fibulin-4 (SMKO) show decreased expression of SMC contractile genes, decreased circumferential compliance, and develop aneurysms in the ascending aorta. Neonatal administration of drugs that inhibit the angiotensin II pathway encourages the expression of contractile genes and prevents aneurysm development, but does not increase compliance in SMKO aorta. We hypothesized that multidimensional mechanical changes in the aorta and/or other elastic arteries may contribute to aneurysm pathophysiology. We found that the SMKO ascending aorta and carotid artery showed mechanical changes in the axial direction. These changes were not reversed by angiotensin II inhibitors, hence reversing the axial changes is not required for aneurysm prevention. Mechanical changes in the circumferential direction were specific to the ascending aorta; therefore, mechanical changes in the carotid do not contribute to aortic aneurysm development. We also hypothesized that a published model of postnatal aortic growth and remodeling could be used to investigate mechanisms behind the changes in SMKO aorta and aneurysm development over time. Dimensions and mechanical behavior of adult SMKO aorta were reproduced by the model after modifying the initial component material constants and the aortic dilation with each postnatal time step. The model links biological observations to specific mechanical responses in aneurysm development and treatment.


Maternal comorbidity index and severe maternal morbidity during delivery hospitalizations in Texas, 2011-2014.
Severe maternal morbidity (SMM) prevalence was 194.0 per 10 000 deliveries in Texas in 2015. Chronic, behavioral, and pregnancy-induced conditions, as captured by a maternal comorbidity index, increase the risk for delivery-related morbidity and mortality. The objective of the study was to examine the association between maternal comorbidity index and SMM among delivery hospitalizations in Texas. Delivery-related hospitalizations among Texan women aged 15-49 years were identified using the 2011-2014 Texas all-payer inpatient hospitalization public use data files (n = 1 434 441). The primary outcome of interest was SMM, based on the Alliance for Innovation on Maternal Health's coding scheme. The exposure of interest was a maternal comorbidity index. Multivariable logistic regression model was used to examine the association between maternal comorbidity index and SMM. SMM prevalence remained consistent between 2011 and 2014 (196.0-197.0 per 10 000 deliveries, P > .05; n = 1 434 441). Nearly 40% of delivery-related hospitalizations had a maternal comorbidity index of at least 1, and the proportion of deliveries in the highest risk category of comorbidity index (≥5) increased by 12.0% from 2011 to 2014. SMM prevalence was highest among the youngest and oldest age groups. With each unit increase in maternal comorbidity index, the odds of SMM increase was 1.43 (95% CI 1.42-1.43). Maternal comorbidity index is associated with SMM; however, the low predictive power of the model suggests that other, unmeasured factors may influence SMM in Texas. These findings highlight a need to understand broader contextual factors (practitioner, facility, systems of care, and community) that may be associated with SMM to reduce maternal morbidity and mortality in Texas.


Thermodynamics and kinetics of phospholipid monomer-vesicle interaction.
Resonance energy transfer between acyl chain labeled (7-nitro-2,1,3-benzoxadiazol-4-yl)phosphatidylcholine (NBD-PC) and head group labeled (lissamine rhodamine B sulfonyl)phosphatidylethanolamine (N-Rh-PE) was used to monitor the rate of NBD-PC transfer between two populations of dioleoylphosphatidylcholine (DOPC) vesicles. Equilibration of NBD-PC between DOPC vesicles occurs by the diffusion of soluble monomers through the water phase, which is a first-order process. Conditions were used such that the apparent transfer rate constant is equal to the rate constant for monomer-vesicle dissociation into solution. The partition distribution of NBD-PC between DOPC vesicles and water was determined by measuring the loss of NBD-PC from vesicles into solution following the dilution of small amounts of vesicles in buffer. The acyl chain length and temperature dependence of both the rate and partition measurements were determined, and a free energy diagram for NBD-PC-soluble monomer-vesicle interactions was constructed. The conclusions of this analysis are the following: NBD-PC dissociation from and association with the bilayer require passage through a high-energy transition state resulting predominantly from enthalpic energy. The activation energy for NBD-PC-vesicle dissociation becomes more positive and the standard free energy of NBD-PC transfer from water to vesicles becomes more negative with increasing acyl chain length. The standard free energy of transfer for NBD-PC from water to vesicles results predominantly from differences in enthalpy between the membrane and water phases. The enthalpy of activation for association increases with acyl chain length and is larger than expected for an aqueous diffusion-limited process in bulk water.


Prevalence of antimicrobial resistance among gram-negative isolates in an adult intensive care unit at a tertiary care center in Saudi Arabia.
Patients in the ICU have encountered an increasing emergence and spread of antibiotic-resistant pathogens. We examined patterns of antimicrobial susceptibility in gram-negative isolates to commonly used drugs in an adult ICU at a tertiary care hospital in Riyadh, Saudi Arabia. A retrospective study was carried out of gram-negative isolates from the adult ICU of King Fahad National Guard Hospital (KFNGH) between 2004 and 2009. Organisms were identified and tested by an automated identification and susceptibility system, and the antibiotic susceptibility testing was confirmed by the disk diffusion method. The most frequently isolated organism was Acinetobacter baumannii, followed by Pseudomonas aeruginosa, Escherichia coli, Klebsiella pnemoniae, Stenotrophomonas maltophilia, and Enterobacter. Antibiotic susceptibility patterns significantly declined in many organisms, especially A baumannii, E coli, S marcescens, and Enterobacter. A baumannii susceptibility was significantly decreased to imipenem (55% to 10%), meropenem (33% to 10%), ciprofloxacin (22% to 10%), and amikacin (12% to 6%). E coli susceptibility was markedly decreased (from 75% to 50% or less) to cefuroxime, ceftazidime, cefotaxime, and cefepime. S marcescens susceptibility was markedly decreased to cefotaxime (100% to 32%), ceftazidime (100% to 35%), and cefepime (100% to 66%). Enterobacter susceptibility was markedly decreased to ceftazidime (34% to 5%), cefotaxime (34% to 6%), and pipracillin-tazobactam (51% to 35%). Respiratory samples were the most frequently indicative of multidrug-resistant pathogens (63%), followed by urinary samples (57%). Antimicrobial resistance is an emerging problem in the KFNGH ICU, justifying new more stringent antibiotic prescription guidelines. Continuous monitoring of antimicrobial susceptibility and strict adherence to infection prevention guidelines are essential to eliminate major outbreaks in the future.


Effects of substituting dietary soybean protein and oil for milk protein and fat in subjects with hypercholesterolemia.
To determine whether, in individuals with hypercholesterolemia, substituting dietary soybean products for cows' milk products improves the plasma lipid profile and whether any change in the profile is due partially to soy oil. Randomized 3-treatment crossover trial. Family practice clinics and an outpatient clinic in London, Ont. Seventeen healthy men and 17 healthy women with elevated plasma levels of total and low-density-lipoprotein (LDL) cholesterol and with normal plasma levels of triglycerides. Participants incorporated into their normal diet either 2% cows' milk products, soybean products or a combination of skim milk products and soy oil, each over period of 4 weeks, with 22-week wash-out periods. Plasma lipid profile, blood pressure and body weight were assessed after each dietary and wash-out period. Plasma levels of total and lipoprotein cholesterol, plasma levels of triglycerides, apolipoprotein B and A1 levels, blood pressure and plasma lipid peroxidation. The change in diet had no effect on body mass index, levels of apolipoproteins B and A1 and most plasma lipids. During the soybean period, the subjects' mean level of high-density-lipoprotein (HDL) cholesterol increased 9% (p < 0.04) and their mean LDL/HDL cholesterol ratio decreased 14% (p < 0.007). These effects were less pronounced during the skim milk/soy oil period. In the 24 subjects with the highest initial LDL cholesterol level and LDL/HDL cholesterol ratio, the mean LDL cholesterol level decreased 11% after the soybean period. In all subjects, changes in the LDL/HDL cholesterol ratio induced by a soybean diet were negatively correlated with the initial LDL/HDL cholesterol ratio and positively correlated with the initial HDL cholesterol level. In people with hypercholesterolemia, the plasma lipid profile improved after treatment with a soybean-product diet, and this improvement was partially due to soy oil. The degree of responsiveness was associated with initial risk factors for coronary artery disease.


[The relationship between astronauts erroneous actions, their psychophysiological state and work and rest regimen].
The correlation analysis of the data obtained in the MIR 18, and 21 through to 23 main missions was supportive of the strong dependence of erroneous actions by cosmonauts, their psychophysiologic state and the work/rest schedule. This conclusion guidelined the development of a prototype of technique to perform an integrated analysis of erroneous crew actions which can also help to identification of impacts of psychophysiologic state and deviations from the requisite rest/work schedule in order to set the origin of erroneous actions, and to work out recommendations towards the enhancement of ground-based crew training and other matters. With these findings, the predictive virtues of the technique has been demonstrated.


Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System.
We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1β and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects.


The mutual overlapping impact of stress and infection on mental health problems in adolescents and youths during and after COVID-19 pandemic in China.
It is unclear about the mutual impact of COVID-19 related psychological stress and infection on mental health of adolescent and youth students. This study aimed to explore the mutual impact of COVID-19 related psychological stress and infection on mental health problems among students. This study was conducted from December 14, 2022 to February 28, 2023 in Sichuan, China. Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, PTSD Checklist for DSM-5, Insomnia Severity Index, and Internet Addiction Test were used. Participants were grouped by COVID-19 infection and psychological stress level. The differences among groups were compared, and logistic regression analysis was used to investigate risk factors for depression, anxiety, PTSD and insomnia among groups. Of 90,118 participants, 82,873 (92.0 %) finished the questionnaires and were included in the study. Of 82,873 participants, 33,314 (40.2 %) reported to be infected with COVID-19. Participants had depression symptoms (38.1 %), anxiety symptoms (31.8 %), PTSD (33.9 %), insomnia (34.0 %), and internet addiction (60.3 %). Compared with participants uninfected with low psychological stress level, the risk for symptoms of depression, anxiety, PTSD and insomnia increased by 9.6 %, 12.3 %, 6.6 %, and 12.0 % in participants infected with low psychological stress level (p < 0.001), 106.8 %, 125.9 %, 125.2 %, and 95.7 % in participants uninfected with high psychological stress level (p < 0.001), and 147.3 %, 161.1 %, 158.7 %, and 141.0 % in participants infected with high psychological stress level (p < 0.001). This study is a cross-sectional design, and no causal associations should be inferred. Infection status was based on self-report of participants with infectious symptoms. COVID-19 related psychological stress and infection per se have mutually overlapping impacts on mental health problems among students. Further health policies and psychosocial interventions should be developed to reduce mutually overlapping impact and improve the long-term mental health among students.


Big data and artificial intelligence (AI) methodologies for computer-aided drug design (CADD).
There have been numerous advances in the development of computational and statistical methods and applications of big data and artificial intelligence (AI) techniques for computer-aided drug design (CADD). Drug design is a costly and laborious process considering the biological complexity of diseases. To effectively and efficiently design and develop a new drug, CADD can be used to apply cutting-edge techniques to various limitations in the drug design field. Data pre-processing approaches, which clean the raw data for consistent and reproducible applications of big data and AI methods are introduced. We include the current status of the applicability of big data and AI methods to drug design areas such as the identification of binding sites in target proteins, structure-based virtual screening (SBVS), and absorption, distribution, metabolism, excretion and toxicity (ADMET) property prediction. Data pre-processing and applications of big data and AI methods enable the accurate and comprehensive analysis of massive biomedical data and the development of predictive models in the field of drug design. Understanding and analyzing biological, chemical, or pharmaceutical architectures of biomedical entities related to drug design will provide beneficial information in the biomedical big data era.


Sensing the light environment in plants: photoreceptors and early signaling steps.
Plants must constantly adapt to a changing light environment in order to optimize energy conversion through the process of photosynthesis and to limit photodamage. In addition, plants use light cues for timing of key developmental transitions such as initiation of reproduction (transition to flowering). Plants are equipped with a battery of photoreceptors enabling them to sense a very broad light spectrum spanning from UV-B to far-red wavelength (280-750nm). In this review we briefly describe the different families of plant photosensory receptors and the mechanisms by which they transduce environmental information to influence numerous aspects of plant growth and development throughout their life cycle.


The Ameliorating Effect of Lactobacillus gasseri OLL2716 on Functional Dyspepsia in Helicobacter pylori-Uninfected Individuals: A Randomized Controlled Study.
Probiotics appear to improve Helicobacter pylori-associated dyspepsia via an inhibitory effect on H. pylori; however, uncertainty exists regarding their effects in H. pylori-uninfected individuals. We evaluated the efficacy of Lactobacillus gasseri OLL2716 (L. gasseri OLL2716) on H. pylori-uninfected individuals with functional dyspepsia (FD). A double-blind, parallel-group, placebo-controlled, randomized, controlled trial was performed. Participants were randomly assigned to ingest L. gasseri OLL2716-containing yogurt (L. gasseri OLL2716 group) or L. gasseri OLL2716-free yogurt (placebo group) for 12 weeks. Participants completed questionnaires that dealt with a global assessment as well as symptom severity. The per-protocol (PP) population was evaluated for efficacy in accordance with a plan prepared beforehand. Randomization was performed on 116 individuals; the PP population consisted of 106 individuals (mean age 42.8 ± 9.0). The impressions regarding the overall effect on gastric symptoms were more positive in the L. gasseri OLL2716 group compared to that in the placebo group (statistical trend; p = 0.073). The elimination rate for major FD symptoms was 17.3 and 35.3% in the placebo and L. gasseri OLL2716 groups respectively (p = 0.048). L. gasseri OLL2716 has beneficial effects on FD without H. pylori involvement.


Pharmacokinetics of haloperidol decanoate. A 2-year follow-up.
Plasma haloperidol levels were assayed in 181 chronic schizophrenic inpatients, who were monthly injected intramuscularly with haloperidol decanoate. Steady state levels are reached after the third monthly injection and then remain constant, being associated with a remarkably stable control of the psychotic condition. Between two subsequent injections the haloperidol levels decrease gradually by about half their initial value. The haloperidol plasma levels strongly correlate with the injected doses of the decanoate form. For a single dose of 100 mg haloperidol decanoate monthly the minimal steady state value is about 4 ng/ml.


Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4.
Maternal cannabis use in pregnancy is linked with long-term adverse behavioral outcomes in offspring. Epigenetic processes established in utero that affect dopaminergic (reward) signaling may mediate risks. Associations between cannabis use and offspring DNA methylation have not been investigated; however, maternal tobacco smoking in pregnancy is associated with distinct patterns of DNA methylation at birth and beyond. To determine whether maternal cannabis use is associated with methylation of the dopamine receptor gene DRD4 promoter in infants. Mothers in the Triple B study provided detailed information on drug use in each trimester of pregnancy. Buccal swabs were collected from neonates at 8 weeks (n = 804, 51.7% male, and 48.3% female). DRD4 promoter DNA methylation was measured using SEQUENOM MassARRAY. Fifty-seven of the women in the study reported drug use during pregnancy, of whom 44 used cannabis. Of 19 cytosine-phosphate-guanine dinucleotides (CpG) units tested in DRD4, gestational cannabis use was associated with offspring methylation at 1 CpG unit in multivariate models (β + 1.48, CI: 0.02 to 2.93, and p = 0.047). At another site there was weak evidence that both cannabis and other drug use were independently associated with increased methylation, while the association with tobacco was in the reverse direction (cannabis use β + 0.67, CI: -0.12 to 1.46, and p = 0.09; other drug use β + 1.11, CI: 0.17 to 2.05, and p = 0.02; tobacco use β -0.41, CI: -0.85 to 0.03, and p = 0.07). None of the associations would remain significant after correction for multiple testing. There is no strong evidence that maternal cannabis use in pregnancy is associated with offspring DRD4 methylation.


Enhanced anticancer activity of siRNA and drug codelivered by anionic biopolymer: overcoming electrostatic repulsion.
Aim: To codeliver an anticancer drug (doxorubicin) and siRNA in the form of nanoparticles into CD44-overexpressing colon cancer cells (HT-29) using an anionic, amphiphilic biopolymer comprising modified hyaluronic acid (6-O-[3-hexadecyloxy-2-hydroxypropyl]-hyaluronic acid). Materials & methods: Characterization of nanoparticles was performed using dynamic light scattering, scanning electron microscopy, transmission electron microscopy, molecular docking, in vitro drug release and gel mobility assays. Detailed in vitro experiments, including a gene silencing study and western blot, were also performed. Results: A 69% knockdown of the target gene was observed, and western blot showed 5.7-fold downregulation of the target protein. The repulsive forces between siRNA and 6-O-(3-hexadecyloxy-2-hydroxypropyl)-hyaluronic acid were overcome by hydrogen bonding and hydrophobic interactions. Conclusion: The authors successfully codelivered a drug and siRNA by anionic vector.


Mutation-specific effects on thin filament length in thin filament myopathy.
Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap. These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. Ann Neurol 2016;79:959-969.


Are the gender gaps in informal caregiving intensity and burden closing due to the COVID-19 pandemic? Evidence from the Netherlands.
This research note presents the findings of changes in the gender gap in informal care provision and caregiver burden during the Spring 2020 COVID-19 lockdown in the Netherlands. Government measures in response to the pandemic strongly restricted informal caregivers in providing help and care to persons with health-related needs. At the same time, formal care was scaled back and informal caregivers' urge to help their loved ones was likely higher than before the pandemic. Generally, women pick up a larger share of informal care and experience more caregiver burden. We assessed whether the COVID-19 pandemic affected the gender gaps in informal caregiving by analyzing unique data on Dutch informal caregivers (N = 1672 caregiving situations in 1196 respondents). Results showed that women, compared to men, were more likely to have stopped and reduced caregiving, but also to have cared more during the pandemic. Moreover, based on longitudinally comparing levels during and before the lockdown, we found that the gender gap in caregiver burden narrowed down, especially because burden decreased for women. This means that the caregiver burden was more equally distributed among women and men during the Spring 2020 COVID-19 lockdown than before.


Transfection of prion protein gene suppresses coxsackievirus B3 replication in prion protein gene-deficient cells.
The susceptibility of prion protein gene (Prnp)-null cells to coxsackievirus B3 (CVB3) was investigated. Primary cultures of murine Prnp(-/-) brain cells were more sensitive to CVBs than corresponding cells from wild-type mice. The viral susceptibility of a Prnp-null cell line (HpL3-4) derived from the murine hippocampus was compared with that of two established cell lines (HeLa and HEp-2) that are widely employed for CVB3 studies. After infection with CVB3, HpL3-4 cells showed a very rapid and complete cytopathic effect (CPE). CPE developed earlier and viruses replicated at higher titres in HpL3-4 cells compared with HeLa and HEp-2 cells. Under a semi-solid medium, plaques developed rapidly in CVB3-infected HpL3-4 cells. To confirm the effect of Prnp on virus infection, a Prnp(-/-) cell line and a Prnp-transfected neuronal cell line were analysed. The replication and release of infectious particles of CVB3 in Prnp(-/-) cells were significantly more effective than those of the Prnp-transfected cell line. Levels of type I interferon (IFN) after CVB3 infection were higher in the Prnp-transfected cell line than in Prnp(-/-) cells, whereas apoptotic cells were more obvious in the Prnp(-/-) cells than in those of the Prnp-transfected cell line. These findings suggest that the absence of Prnp retards the induction of CVB3-induced IFNs, resulting in an enhanced CVB3 production and apoptotic cell death. Furthermore, our data indicate that the HpL3-4 cell line may provide a novel and sensitive system for isolation of CVB3 from clinical specimens.


Spatially localized wavelength-selective absorption in morphology-modulated semiconductor nanowires.
In this study, we proposed morphology-modulated Si nanowires (NWs) with a hexagonal cross-section and numerically investigated their resonant optical absorption and scattering properties. The calculated absorption and scattering efficiency spectra of the NWs exhibited optical resonances that could be controlled by tuning the aspect ratio (AR) of the NW cross-sectional shapes. The spectra also revealed interesting spectral behaviors including resonant peak shifts in the absorption spectrum and asymmetric line shapes in the scattering spectrum. To achieve spatially confined and wavelength-selective light absorption, we periodically modulated the geometry of the diameter in a single NW by combining two different ARs; we call these "diameter-modulated NWs." We designed various diameter-modulated NWs with short and long pitch sizes, and we observed unique and interesting features in the optical resonance and corresponding light absorption spectra such as grating modes and three-dimensional cavity modes. The proposed diameter-modulated NWs can be promising building blocks for the nanoscale localized light absorption and detection in compact nanophotonic integrated circuits.


Clinical withdrawal symptom profile of synthetic cannabinoid receptor agonists and comparison of effects with high potency cannabis.
Synthetic cannabinoid receptor agonists (SCRAs) may be used as an alternative to natural cannabis; however, they may carry a greater risk of problematic use and withdrawal. This study aimed to characterise the withdrawal symptom profile of SCRAs and compare their profile of effect with high-potency herbal cannabis. Global Drug Survey data (2015 and 2016) were used to access a clinically relevant sample of people reporting use of SCRAs >10 times in the past 12-months, a previous SCRA quit attempt, and lifetime use of high-potency herbal cannabis. Participants completed an 11-item SCRA withdrawal symptom checklist and compared SCRAs and high-potency herbal cannabis on their onset and duration of effects, speed of the development of tolerance, severity of withdrawal, and difficulty with dose titration. Participants (n = 284) reported experiencing a mean of 4.4 (95% CI: 4.1, 4.8) withdrawal symptoms after not using SCRAs for >1 day; most frequently reported were sleep issues (59.2%), irritability (55.6%), and low mood (54.2%). Withdrawal symptoms were significantly associated with frequency (>51 vs. 11-50 times per year: IRR = 1.43, 95% CI: 1.16, 1.77, p = 0.005) and quantity (grams per session: IRR = 1.13, 95% CI: 1.05, 1.22, p = 0.001) of SCRA use. Compared to high-potency herbal cannabis, SCRAs were rated as having a faster onset and shorter duration of effects, faster development of tolerance, and more severe withdrawal (p's < 0.001). In conclusion, SCRA withdrawal symptoms are more likely to occur after greater SCRA exposure. The effects of SCRA indicate a more severe withdrawal syndrome and a greater risk of problematic use than natural cannabis.


[Relation between the sequelae of craniocerebral injuries and the site of cerebral contusion].
The study of the consequences of the craniocerebral trauma in 58 patients with brain contusion of moderate severity has shown that the localization of contusion foci largely determines the nature and degree of posttraumatic changes.


Mutations affecting the indirect flight muscles of Drosophila melanogaster.
The development of the indirect flight muscles of Drosophila melanogaster was studied by analysing mutations that cause flightlessness. Twenty-five mutations on the X-chromosome and two on the third chromosome were examined. The X-chromosomal mutations form ten complementation units. The ten loci were assigned preliminary map positions by meiotic recombination and deficiencies and duplications. The two autosomal mutations represent two genes. Gynandromorph analyses suggest that many of these mutations have their primary effect in the presumptive thoracic muscle region of the embryo. The mutations cause a variety of characteristic defects, such as absence of the bulk of the thoracic muscle mass, or absence of only one of the two fibrillar muscle groups. Electronmicroscopic studies of sixteen mutants representing all twelve loci reveal abnormal myofibrillar organization in some of these mutants, e.g. aberrant or missing Z-bands, or absence of the thin filaments. Mutant protein patterns, obtained by SDS-polyacrylamide gel electrophoresis, show the following differences from wild type: ten mutants are characterized by absence of reduction of the 54 K protein, and most mutants exhibit a reduction and modification of the 80 and 90 K proteins. The absence of reduction of the 54 K protein was strongly correlated with aberrant Z-bands.


Green coffee methanolic extract and silymarin protect against CCl4-induced hepatotoxicity in albino male rats.
During the last few decades, patients worldwide have been interested in using alternative medicine in treating diseases to avoid the increased side effects of chemical medications. Green coffee is unroasted coffee seeds that have higher amounts of chlorogenic acid compared to roasted coffee. Green coffee was successfully used to protect against obesity, Alzheimer disease, high blood pressure and bacterial infection. This study aimed to investigate the probable protective activity of the green coffee methanolic extract, silymarin and their combination on CCl4-induced liver toxicity in male rats. Thirty Sprague - Dawley male albino rats were divided into 5 groups; control negative (G1) just got the vehicle (olive oil) and the other four groups received CCl4 dissolved in olive oil through an intraperitoneal injection and were divided into untreated control positive group (G2), the third group (G3) was treated with green coffee methanolic extract, the fourth group (G4) was treated with silymarin, and the fifth group (G5) was treated with a combination of green coffee methanolic extract and silymarin. In the positive control group treated with CCl4 (G2), the CCl4-induced toxicity increased lipid peroxidation, IL-6, kidney function parameters, liver function enzymes, total cholesterol, triglycerides and low-density lipoproteins, and decreased irisin, antioxidants, CYP450 and high-density lipoprotein levels. Hepatic tissues were also injured. However, treating the injured rats in G3, G4 and G5 significantly improved the altered parameters and hepatic tissues. Green coffee methanolic extract, silymarin, and their combination succeeded in protecting the male rats against CCl4 hepatotoxicity due to their antioxidant activity. Effect of green coffee methanolic extract mixed with silymarin in G5 was more efficient than that of green coffee methanolic extract in G3 or silymarin in G4.


Exonic Re-Sequencing of the Chromosome 2q24.3 Parkinson's Disease Locus.
Genome-wide association studies (GWAS) in Parkinson's disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a STK39 exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11-1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.