Differential gene expression by RNA-seq during Alzheimer's disease-like progression in the Drosophila melanogaster model.
Alzheimer's disease (AD) is characterized by progressive, irreversible loss of memory and cognitive function. Drosophila melanogaster and other animal models are used to study several diseases, in order to elucidate unknown mechanisms and develop potential therapies. Molecular studies require biological samples and, for neuropathologies such as AD biopsy of the human brain, are invasive and potentially damaging. The solution is to use animal models, such as D. melanogaster, which is a model organism that can replace mammalian organisms in such studies. In this study, we evaluated the climbing ability and differential gene expression during AD progression due to the amylodoigenic pathway using RNA-seq, and we performed an in silico analysis of a fruit fly AD-like GFP (Green Fluorescent Protein) model with GFP expression in the pan-neural elav driver. A total of 1388 genes were differentially expressed in all analyzed groups. The main pathways related to those Differentially Expressed Genes (DEGs) during aging and AD progression were evaluated using the fly genes and human orthologs, in order to link genomic information to higher-order functional information with gene pathway mapping. We identified pathways present in all analyzed groups, such as metabolic pathways, ribosomal pathways, proteasome pathways and immune system pathways. Some of the genes were validated by qPCR. Knockdown of CG17754 gene by RNAi promoted degeneration in the fly eye, validating these findings in vivo. The identification of similarities in molecular pathways between the transgenic fly AD-like GFP model and mammals related to AD provides new insights into the use of this fly in screening novel anti-AD drugs.


Clinicopathological Features and Survival Outcomes of Metaplastic Breast Carcinoma - An Observational Multi-Centric Study.
To describe the clinicopathological features, and subtypes of metaplastic breast cancer (MpBC) in Pakistan and further to understand its response to treatment, including region-specific survival outcomes. This retrospective cohort study was conducted at two private tertiary care hospitals in Karachi, Pakistan. Our selection criteria included a total of 215 patients who were diagnosed with MpBC at an age older than 18 years from 1994 to 2021. Data regarding clinicopathological features, staging, receptor status, treatment modalities, recurrence, and survival was obtained. Death was scored as an event, and patients who were alive were censored at the time of the last follow-up. The incidence of MpBC at our study centers is 3.21%. The median age of diagnosis was 50 years (range 22 to 80 years) and most patients presented at Stages II (45.1%) and III (44.2%). Among patients who received neoadjuvant chemotherapy, 31.7% achieved complete pathological response. The 3-year survival of those who received neoadjuvant chemotherapy was 96%. During our study, 19.1% of patients died and the median survival duration was 9 years 7 months 9 days. Survival of patients was significantly lower in patients who had metastasis (p-value = 0.042) and those who had tumor recurrence (p-value = 0.001). Metaplastic breast cancer is an extremely rare variant of breast cancer with features that exist as a spectrum. Our study demonstrated considerable success with the use of neoadjuvant chemotherapy. The pathological complete response achieved in our study is one of the highest ever reported. Our success, though limited, warrants further research in the use of neoadjuvant chemotherapy in MpBC.


Transfer of bromocriptine across the blood-brain barrier in man.
The transfer of 14C-bromocriptine across the blood-brain barrier was studied in 10 patients using the double indicator single injection method. The extraction (E) of bromocriptine was 8 % (quartiles: 6 and 14 %). Based on the results the cerebral uptake velocity of bromocriptine was calculated assuming constant arterial drug concentration. Its T 1/2 was found to be 12--24 minutes, depending on the tissue-blood partition coefficient.


Quantifying the wet deposition of reactive nitrogen over China: Synthesis of observations and models.
Accurate estimation on reaction nitrogen (Nr) deposition is highly demanded for assessing the impacts on the environment and human beings. This study investigated the wet deposition of inorganic nitrogen (IN) in mainland China by measurements from over 500 sites from five observational networks/databases and ensemble results of eleven chemical transport models (CTMs). Each data source has its focus and limitations and together formed a comprehensive view over China. But the inconsistency among different sources may hinder the appropriate usage of data. Model evaluation results demonstrated the models' deficiency in simulating the wet NO3- deposition over Southeast China (40 % underestimation) and showed an overall underestimation of wet NH4+ deposition over the hotspot regions (5-60 % underestimation). A synthesis of this study and twelve reference studies was conducted to quantify the national amount of wet IN deposition. The estimations by CTMs ranged 2.4-3.9 Tg(N) yr-1 for wet NOy deposition and 4-6.7 Tg(N) yr-1 for wet NHx deposition, after adjusting the results with 10-19 % underestimations in wet NOy deposition and 1-40 % underestimations in wet NHx deposition. The estimations by ground observations ranged 7.1-9 Tg(N) yr-1 for wet NOy deposition and 8-13.1 Tg(N) yr-1 for wet NHx deposition, which were 20-275 % higher than the estimation by CTMs, but the results were strongly influenced by the abundances and representative of measurements. Studies using statistical techniques to interpolate site observations predicted 3-5.5 Tg(N) yr-1 for wet NOy deposition and 3.9-7.2 Tg(N) yr-1 for wet NHx deposition. This approach benefited from high accuracy and good robustness of the statistical models, but the uncertainty in the interpolation methods could be a potential drawback.


Influence of bromocriptine administration to mothers on the development of pup thymocyte and splenocyte subsets and on mitogen-induced proliferation in the mouse.
The influence of prolactin (PRL) on the development of the immune system in the mouse was studied by injecting mothers with bromocriptine (CB-154) to produce hypoprolactinemic milk. Alterations in pup thymocyte and splenocyte cell subsets were observed to graded doses of CB-154 administered to mothers. There was an increase in the relative percentages of neonate thymic CD4 and CD8 cells at 5 days of age when mothers were injected with 100 micrograms of CB-154 2 x daily from day 1 to 5 of lactation, however, there was no alteration in absolute thymic subset cell numbers. The relative percentage of pup spleen CD4, CD8 and B cells were increased when mothers were administered 50 or 100 micrograms of CB-154 and the 50 micrograms dose resulted in a significant increase in the absolute number of CD4 cells while the 100 micrograms dose induced a significant decrease in the three splenic cell subsets examined. Graded doses of CB-154 administered to mothers resulted in decreases in the PRL concentration of stomach milk as measured by the Nb2 cell proliferation assay. The serum PRL level of the pups, however, was not altered by any dose of CB-154 injected to the mothers. The administration of PRL to pups nursing mothers given the 100 micrograms dose of CB-154 did not alter the pup thymocyte and splenocyte subset population from that of litter-mate controls. The administration of mouse PRL and mouse growth hormone antisera to pups nursing saline-injected mothers did not alter thymocyte and splenocyte subsets from that of saline-injected litter mate controls. The proliferation of neonatal thymocytes by Con-A stimulation was not altered by CB-154 injection to mothers and PRL administration to pups. However, since the percentage of thymic CD4 and CD8 cells in the thymus was increased 2 to 3 fold, the apparent lack of effect was in fact a decrease in the responsiveness of the thymocytes. Con-A stimulation of neonatal splenocytes resulted in a significant increase in proliferation for mothers administered CB-154 in keeping with the increase relative percentage of CD4 and CD8 cells observed. Prolactin administration to the pups did not alter the response. LPS stimulation of neonatal splenocytes increased the proliferation of B cells taken from pup nursing mothers administered CB-154 and PRL administration appeared to partially block this proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)


Correction to: Human behavior and Homo-mammal interactions at the first European peopling: new evidence from the Pirro Nord site (Apricena, Southern Italy).
In the original publication of this article, one of the author names was incorrectly captured. The first name should be Razika, then family name should be Chelli-Cheheb.


Geographic Access Disparities to Clinical Trials in Diabetic Eye Disease in the United States.
To identify geographic and socioeconomic variables predictive of residential proximity to diabetic eye disease clinical trial locations. Cross-sectional, retrospective study. De-identified census tract-level data from public datasets and trial-level data from ClinicalTrials.gov. Using public data from ClinicalTrials.gov, we identified all active interventional clinical trials in diabetic eye disease since 2017. After geolocating every trial site, we used an origin-destination cost-matrix to calculate the driving distance and travel time from the population-weighted United States census tract centroid to the nearest site. We then used public databases to identify census tract-level socioeconomic factors predictive of driving distance and time. Driving distance > 60 miles and time traveled > 60 minutes to the nearest clinical trial site. In a multivariate model, driving distance of more than 60 miles had a significant association with rural versus urban location (adjusted odds ratio, 5.22; 95% confidence interval [CI], 3.75-7.26; P < 0.001), percentage of population at less than 200% of federal poverty level compared with the fourth quartile (first quartile: adjusted odds ratio, 0.40 [95% CI, 0.29-0.55]; second quartile: adjusted odds ratio, 0.60 [95% CI, 0.47-0.77]; third quartile: adjusted odds ratio, 0.76 [95% CI, 0.63-0.91]; P < 0.001) and the Midwest (adjusted odds ratio, 2.15; 95% CI, 1.13-4.07; P = 0.02), South (adjusted odds ratio, 2.71; 95% CI, 1.23-5.99; P = 0.01), and West (adjusted odds ratio, 3.01; 95% CI, 1.21-7.54; P = 0.02) regions as compared with the Northeast. Driving distance was associated with county-level prevalence of diabetes in the univariate model (odds ratio, 1.12; 95% CI, 1.06-1.19; P < 0.001), although it was nonsignificant in the multivariate model. Similar predictors were found for time traveled in minutes. Geographic maldistributions of clinical trial sites exist for diabetic eye disease in the United States. Those with higher travel burden are more likely to reside in a census tract that is rural, low income, and from areas outside the Northeast.


A Risk Score for Adults With Congenital Heart Disease Undergoing Heart Transplantation.
This study derived and validated a risk score for 1-year mortality in patients with adult congenital heart disease (ACHD) undergoing orthotopic heart transplantation (OHT). The United Network for Organ Sharing registry identified patients with ACHD (≥18 years of age) who underwent OHT between 1987 and 2018. The primary outcome was 1-year mortality. Associated covariates (univariate P < .2) were entered into a multivariable logistic regression model. Variable inclusion in the model was assessed by improvement in the McFadden pseudo-R2, likelihood ratio test, and C-index. A risk score was created using the absolute magnitude of the odds ratios from the derivation cohort, and its ability to predict 1-year mortality was tested in the validation cohort. A total of 1388 recipients were randomly divided into derivation (66.7%, n = 950) and validation (33.3%, n = 438) cohorts. A 13-point risk score incorporating 4 pretransplant variables (age, dialysis dependence, serum bilirubin level, and mechanical ventilation) was created. The predicted 1-year mortality ranged from 14.6% (0 points) to 49.9% (13 points) (P < .001). In weighted regression analysis, there was a strong correlation between predicted 1-year mortality and observed 1-year mortality in the validation cohort (r = 0.85, P < .001). Logistic regression also demonstrated a significant association (odds ratio, 1.18; 95% confidence interval, 1.1-1.3; P = .004). The Brier score of the composite score in the validation cohort was 0.14. Kaplan-Meier analysis demonstrated that risk scores of 4 points or higher portended worse survival at 1-year posttransplant (P < .001). This 13-point risk score for ACHD is predictive of mortality within 1 year after OHT and has potential utilization in improving recipient selection for OHT in adult patients with CHD.


Atypical findings in cephalic herpes zoster polyneuritis: case reports and radiographic findings.
The purpose of this presentation is to report six patients who were seen because of multiple cranial nerve deficits occurring within a clinical picture of herpes zoster of the head and trunk. The clinical behavior, diagnostic methods, treatment, and outcome of the patients in this series are reviewed. The vagus and cochleovestibular nerves were affected in all of the patients. Three patients had radiographic evidence of a mass in the nasopharyngeal region. Malignancies were ruled out by repeated biopsies.


Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents.
Sonographic evaluation of arterial wall morphology and elasticity is increasingly accepted as a non-invasive tool in cardiovascular assessment. Several studies suggest that intima-media thickness (IMT) and arterial elasticity indices may sensitively reflect different vasculopathic processes in children. However, normative values and the impact of adolescent growth are largely unknown. We assessed the IMT of the common carotid (cIMT) and femoral arteries (fIMT), carotid elasticity indices and interacting anthropometric factors in 247 healthy subjects aged 10-20 years. cIMT, fIMT, incremental elastic modulus (Einc) and circumferential wall stress (CWS) were positively, and distensibility coefficient (DC) inversely, correlated with age, height, body mass index (BMI), systolic blood pressure (BP) and brachial pulse pressure (r = 0.56 to -0.45, P < 0.05 to 0.0001). DC (r = -0.29, P < 0.0001) and stiffness index beta (r = 0.25, P < 0.0001), but not Einc, were significantly associated with cIMT independently of age. All vascular parameters showed non-Gaussian distributions. Excessively high IMT was associated with BMI and pulse pressure above the 90th percentile, and elevated Einc with high-normal BMI. Multivariate analysis identified independent positive effects of standardized BMI and brachial pulse pressure on normalized cIMT, negative effects of systolic BP and cIMT on DC, a positive effect of cIMT on stiffness, and positive effects of systolic BP and BMI on Einc and CWS. Morphological and functional measures of large arteries should be normalized to take account of changes during adolescence and skewed distributions. Relative body mass, systolic blood pressure and/or pulse pressure are determinants of IMT and elasticity.


Lymphatic vessels and related factors in adenoid cystic carcinoma of the salivary gland.
Adenoid cystic carcinoma of the salivary gland preferentially metastasizes to distant organs. It rarely metastasizes to lymph nodes. Recently, lymphangiogenesis has been associated with lymph node metastasis. Therefore, lymphangiogenesis in adenoid cystic carcinoma was evaluated from the number of lymphatic vessels and the expression of lymphangiogenic factors. Immunohistochemistry and molecular analysis were performed on clinical materials (29 cases for immunohistochemistry and 9 cases for molecular analysis). Normal submandibular gland was used as a negative control of lymphangiogenesis (10 cases for immunohistochemistry and 5 cases for molecular analysis). In adenoid cystic carcinoma, podoplanin-positive lymphatic vessels were small and often constricted, and localized to the tumor periphery. They did not have Ki67-positive endothelial cells. The lymphatic vessel density of the tumor did not exceed that of the salivary gland. By reverse transcriptase-polymerase chain reaction, adenoid cystic carcinoma and the salivary gland expressed vascular endothelial growth factor receptor-3 (VEGFR-3) similarly but VEGF-C and VEGF-D differently. Adenoid cystic carcinoma expressed VEGF-C, whereas the salivary gland expressed both VEGF-C and VEGF-D. VEGF-C was weak in adenoid cystic carcinoma and strong in the salivary gland. Real-time reverse transcriptase-polymerase chain reaction of VEGF-C showed that the ratio of the tumor to the salivary gland was 1 to 30 (P<0.01). Immunohistochemistry barely detected VEGF-C in adenoid cystic carcinoma. VEGF-C was expressed faintly by the tumor cells. VEGF-C and VEGF-D were detected in the serous acinar and duct cells and in the duct contents in the salivary gland. VEGFR-3 appeared to be expressed by lymphatic vessels in both adenoid cystic carcinoma and the salivary gland. These results indicate that lymphangiogenesis does not occur in adenoid cystic carcinoma. This condition would lead to the uncommon lymphatic metastasis.


Studies on DNA repair in Bacillus subtilis. I. A cellular factor acting on gamma-irradiated DNA and promoting its priming activity for DNA polymerase I.
Initiation of new DNA synthesis was observed in B. subtilis cells upon gamma-ray irradiation followed by toluene treatment and incubation in the presence of the four deoxynucleotide triphosphates and Mg2+. This DNA synthesis took place in the absence of ATP and was refractory to 6-(p-hydroxyphenylazo)-uracil which is a specific inhibitor for the type III polymerase of Bacillus subtilis. This repair-type DNA synthesis was greatly reduced in mutant cells deficient in DNA polymerase I. Restoration of transforming activity of cellular DNA was found to occur in parellel with the above repair type DNA synthesis. A protein factor which enhances the priming activity of gamma-irradiated DNA for DNA polymerase I was detected in DNA-free extracts prepared from B. subtilis cells by means of lysis with a buffer containing lysozyme, Brij-58 and EDTA.


Genetic and activity dependent-mechanisms wiring the cortex: Two sides of the same coin.
The cerebral cortex is responsible for the higher-order functions of the brain such as planning, cognition, or social behaviour. It provides us with the capacity to interact with and transform our world. The substrates of cortical functions are complex neural circuits that arise during development from the dynamic remodelling and progressive specialization of immature undefined networks. Here, we review the genetic and activity-dependent mechanisms of cortical wiring focussing on the importance of their interaction. Cortical circuits emerge from an initial set of neuronal types that engage in sequential forms of embryonic and postnatal activity. Such activities further complement the cells' genetic programs, increasing neuronal diversity and modifying the electrical properties while promoting selective connectivity. After a temporal window of enhanced plasticity, the main features of mature circuits are established. Failures in these processes can lead to neurodevelopmental disorders whose treatment remains elusive. However, a deeper dissection of cortical wiring will pave the way for innovative therapies.


Bacterial communities associated with biofouling materials used in bench-scale hydrocarbon bioremediation.
Biofouling material samples from the Arabian (Persian) Gulf, used as inocula in batch cultures, brought about crude oil and pure-hydrocarbon removal in a mineral medium. Without any added nitrogen fertilizers, the hydrocarbon-removal values were between about 10 and 50 %. Fertilization with NaNO3 alone or together with a mixture of the vitamins thiamine, pyridoxine, vitamin B12, biotin, riboflavin, and folic acid increased the hydrocarbon-removal values, to reach 90 %. Biofouling material samples harbored total bacteria in the magnitude of 10(7) cells g(-1), about 25 % of which were hydrocarbonoclastic. These numbers were enhanced by NaNO3 and vitamin amendment. The culture-independent analysis of the total bacterioflora revealed the predominance of the gammaproteobacterial genera Marinobacter, Acinetobacter, and Alcanivorax, the Flavobacteriia, Flavobacterium, Gaetbulibacter, and Owenweeksia, and the Alphaproteobacteria Tistrella, Zavarzinia, and others. Most of those bacteria are hydrocarbonoclastic. Culture-dependent analysis of hydrocarbonoclastic bacteria revealed that Marinobacter hydrocarbonoclasticus, Dietzia maris, and Gordonia bronchialis predominated in the fouling materials. In addition, each material had several more-specific hydrocarbonoclastic species, whose frequencies were enhanced by NaNO3 and vitamin fertilization. The same samples of fouling materials were used in four successive crude-oil-removal cycles without any dramatic loss of their hydrocarbon-removal potential nor of their associated hydrocarbonoclastic bacteria. In the fifth cycle, the oil-removal value was reduced by about 50 % in only one of the studied samples. This highlights how firmly biofouling materials were immobilizing the hydrocarbonoclastic bacteria.


Therapy-related acute myeloid leukemia with favorable cytogenetics: still favorable?
Therapy-related acute myeloid leukemia (t-AML) is occasionally associated with favorable risk cytogenetics including core binding factor AML and acute promyelocytic leukemia (APL). It is unclear if these leukemias have the same favorable outcomes as their de novo counterparts. Interpretation of published data is difficult due to lack of data on the contribution of the original neoplasm as well as its treatment to overall mortality. Based on available evidence, we conclude that t-AML with favorable risk cytogenetics have superior outcomes among t-AMLs and should be treated similar to de novo AML in patients who are candidates for definitive therapy. Therapy-related APL has similar outcome as de novo APL. There is no evidence at the present time to support the routine use of allogeneic HSCT in first complete remission in t-AML with favorable cytogenetics.


Author guidelines for conducting systematic reviews and meta-analyses.
This article is a guidance how to write systematic reviews (SR's) and meta-analyses (MA) in orthopaedics and which aspects to focus on for transparency, systematicity and readability. Both SR and MA summarise and synthesise the best evidence available on a specific topic. This requires a systematic, structured and transparent process of analysis. The title should be concise, indicate type of review and ideally report the most important finding. Next, the structured abstract (no more than 350 words) should also raise key points and report the overall level of evidence. A relevant clinical question must be defined before the literature search is started. Methodological details such as databases searched, the exact search strategy (including time frame), inclusion/exclusion criteria, method of literature appraisal and statistical analysis must be described briefly. The primary and secondary outcomes should be mentioned. SR's be pre-registered before data extraction, to ensure transparency and the reduction of risk of bias. If registered, registration number should be stated in the abstract and the funding sources. A clear summary of the findings is important including the number of identified studies (depicted in a flowchart) and for meta-analyses a forest plot. The results of the literature appraisal and statistical analyses should be reported precisely. Subsequently, a general interpretation of findings and their significance and relevance to clinical practice should be provided. Clinical implications from the analysis should be drawn carefully and further research questions should be addressed. Finally, a conclusion, based solely on the results of the study is a necessity. Up to ten keywords are requested representing the main content of the article. Most applicable keywords should facilitate finding the manuscript in the databases and therefor considered carefully.


The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells.
Breast cancer is the most common malignancy amongst women worldwide but despite enormous efforts to address this problem, there is still limited success with most of the current therapeutic strategies. The current study describes the anti-cancer activity of a binuclear palladacycle complex (AJ-5) in oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB-231) breast cancer cells as well as human breast cancer stem cells. AJ-5 is shown to induce DNA double strand breaks leading to intrinsic and extrinsic apoptosis and autophagy cell death pathways which are mediated by the p38 MAP kinase. This study provides evidence that AJ-5 is potentially an effective compound in the treatment of breast cancer.


Some effects of combination chemotherapy with cis-platinum on renal function in patients with nonseminomatous testicular carcinoma.
Renal function in 24 patients with disseminated nonseminomatous testicular carcinoma treated with combination chemotherapy including cis-platinum was examined prospectively. Renal function was monitored by several determinations of glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and serum creatinine, and beta-2-microglobulin. A reduction in GFR and ERPF was found at the end of the induction chemotherapy and at six weeks thereafter. Median GFR and ERPF decreased both 23% (P less than 0.01). Serum creatinine and beta-2-microglobulin concentrations however did not rise. It is suggested that under the influence of chemotherapy with platinum the production of creatinine and beta-2-microglobulin is decreased rendering their serum levels unsuitable as parameters of renal function.


Assessment of the association between dust storms and COVID-19 infection rate in southwest Iran.
This study assesses a plausible correlation between a dust intrusion episode and a daily increase in COVID-19 cases. A surge in COVID-19 cases was observed a few days after a Middle East Dust (MED) event that peaked on 25th April 2020 in southwest Iran. To investigate potential causal factors for the spike in number of cases, cross-correlations between daily combined aerosol optical depths (AODs) and confirmed cases were computed for Khuzestan, Iran. Additionally, atmospheric stability data time series were assessed by covering before, during, and after dust intrusion, producing four statistically clustered distinct city groups. Groups 1 and 2 had different peak lag times of 10 and 4-5 days, respectively. Since there were statistically significant associations between AOD levels and confirmed cases in both groups, dust incursion may have increased population susceptibility to COVID-19 disease. Group 3 was utilized as a control group with neither a significant level of dust incursion during the episodic period nor any significant associations. Group 4 cities, which experienced high dust incursion levels, showed no significant correlation with confirmed case count increases. Random Forest Analysis assessed the influence of wind speed and AOD, showing relative importance of 0.31 and 0.23 on the daily increase percent of confirmed cases, respectively. This study may serve as a reference for better understanding and predicting factors affecting COVID-19 transmission and diffusion routes, focusing on the role of MED intrusions.


Loss of Krüppel-like factor 9 facilitates stemness in ovarian cancer ascites-derived multicellular spheroids via Notch1/slug signaling.
The ascites that develops in advanced OC, both at diagnosis and upon recurrence, is a rich source of multicellular spheroids/aggregates (MCSs/MCAs), which are the major seeds of tumor cell dissemination within the abdominal cavity. However, the molecular mechanism by which specific ascites-derived tumor cells survive and metastasize remains largely unknown. In this study, we elucidated cancer stem cell (CSC) properties of ascites-derived MCSs, concomitant with enhanced malignancy, induced EMT, and low KLF9 (Krüppel-like factor 9) expression, compared with PTCs. KLF9 was also downregulated in OC cell line-derived spheroids and the CD117+ CD44+ subpopulation in MCSs. Functional experiments demonstrated that KLF9 negatively modulated stem-like properties in OC cells. Mechanistic studies revealed that KLF9 reduced the transcriptional expression of Notch1 by directly binding to the Notch1 promoter, thereby inhibiting the function of slug in a CSL-dependent manner. Clinically, expression of KLF9 was associated with histological grade and loss of KLF9 predicts poor prognosis in OC.


Assessment of a creatine kinase isoform M defect as a cause of myotonic dystrophy and the characterization of two novel CKMM polymorphisms.
Recent studies have shown the gene encoding creatine kinase isoform M (CKMM) to be very closely linked to the myotonic dystrophy (DM) locus on the long arm of chromosome 19. Given this close linkage to DM and the postulated role of CKMM in skeletal muscle contraction, the possibility of a defect in CKMM causing DM was investigated. CKMM cDNA was isolated from the skeletal muscle of an individual with DM. Sequencing of the CKMM cDNA from the DM chromosome 19 revealed two novel polymorphisms but no translationally significant mutation. This work rules out a defect in the coding segment of CKMM as a cause of DM in this family and, in light of genetic homogeneity shown to date for DM, probably in all cases of DM.


Role of two proline-containing turns in the folding of porcine ribonuclease.
Unfolded ribonuclease (RNase) from porcine pancreas consists of a mixture of fast and slow-refolding species. The equilibrium distribution of these species differs strongly from other homologous RNases, because an additional proline residue is present at position 115 of the porcine protein. The major slow-folding species of porcine RNase contains incorrect proline isomers at Pro93 and at Pro114-Pro115. Both positions are presumably part of beta-turn structures in the native protein, as deduced from the structure of the homologous bovine RNase A. The folding kinetics of these molecules depend strongly on the conditions used. Under unfavorable conditions (near the unfolding transition), refolding is virtually blocked by the presence of the incorrect proline peptide bonds and partially folded intermediates with incorrect isomers could not be detected. As a consequence, folding is very slow under such conditions and the re-isomerization of Pro114-Pro115 is the first and rate-limiting step of folding. Under strongly native conditions (such as in the presence of ammonium sulfate), refolding is much faster. A largely folded intermediate accumulates with the turns around Pro93 and Pro114-Pro115 still in the non-native conformation. These results suggest that incorrect proline isomers strongly influence protein folding and that, under favorable conditions, the polypeptide chain can fold with two beta-turns locked into a non-native conformation. We conclude, therefore, that early formation of correct turn structure is not necessarily required for protein folding. However, the presence of incorrect turns, locked-in by non-native proline isomers, strongly decreases the rate of refolding. Alternative pathways of folding exist. The choice of pathway depends on the number and distribution of incorrect proline isomers and on the folding conditions.


A nomogram to predict survival and guide individualized induction chemotherapy in T3-4N1M0 nasopharyngeal carcinoma.
Induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) and CCRT alone were the optional treatment regimens for T3-4N1M0 nasopharyngeal carcinoma (NPC) patients. Therefore, we established a nomogram to predict clinical prognosis and guide individualized IC in T3-4N1M0 NPC. Overall, 699 T3-4N1M0 NPC patients treated with CCRT with or without IC between January 2010 and December 2018 were examined. Overall survival (OS) was the main endpoint. A nomogram was developed that included prognostic variables selected by multivariable analysis. The risk score, which was calculated according to the nomogram, was used for risk stratification. The survival difference of patients undergoing CCRT with or without IC was then compared in risk-stratified subgroups. The nomogram yielded C-indexes of 0.708 (95% confidence interval [CI]: 0.682-0.734) in the training cohort and 0.670 (95% CI: 0.625-0.715) in the validation cohort. Calibration curves for 1-, 3- and 5-year OS suggested a good association between the nomogram predicted and observed probabilities. High-risk patients stratified by nomogram benefited from IC (IC + CCRT vs CCRT: 5-year OS: 77.8% vs 58.8%; P = 0.040; 5-year disease-free survival: 75.0% vs 58.2%; P = 0.017), whereas in the low-risk group, the application of IC was associated with worse locoregional recurrence-free survival and distant metastasis-free survival. This nomogram can serve as a reliable model for prognostic prediction and can be used to guide individualized treatment of T3-4N1M0 NPC. High-risk patients are candidates for IC before CCRT, while the use of IC for low-risk patients should be considered carefully.


Costing a community based screening programme for the detection of glaucoma.
The cost of detecting a case of glaucoma in a community based screening programme was calculated using data from a pilot study on a population aged 50 and over. The cost per screen was estimated at 3.35 pounds with a total cost of 311 pounds per case detected. These estimates include the cost of both the algorithmically based screening programme and the hospital assessment of true and false positives. These costs are considered to compare favourably with the potential costs incurred by paying optometrists to screen high risk groups whilst providing the opportunity to detect over twice the number of cases of occult glaucoma.


Pancreatobiliary Flow Dynamics: Association Between Bile and Pancreatic Juice Evaluated With Cine-Dynamic Magnetic Resonance Cholangiopancreatography Using Spatially Selective Inversion Recovery Pulse.
The physiological flow patterns and the reciprocal relationship between pancreatic juice and bile excretion dynamics have not been clearly elucidated by imaging. To assess the physiological flow patterns of bile and pancreatic juice simultaneously in order to clarify the pancreatobiliary flow dynamics using cine-dynamic magnetic resonance cholangiopancreatography (MRCP) with a spatial selective inversion recovery (IR) pulse. Retrospective. A total of 85 patients with physiologically normal pancreatobiliary flow without ductal dilatation (normal group) and 19 patients with dilated pancreatic duct. A 3 T, fast spin echo sequence with IR pulse to nullify the signal of static pancreatic juice and bile. The frequency and secretion grade of the antegrade and reverse flow of the pancreatic juice and bile on cine-dynamic MRCP were visually evaluated. Additionally, the reciprocal relationship between pancreatic juice and bile flow was evaluated based on its flow patterns. Spearman's rank correlation coefficient analysis and the Kruskal-Wallis and Mann-Whitney U tests were used. P values of <0.05 were considered to indicate statistical significance. In the normal group, the antegrade pancreatic juice flow and no bile flow pattern was most frequently observed (29%), followed by the no pancreatic juice flow and no bile flow pattern (23%), the antegrade pancreatic juice flow and antegrade bile flow pattern (22%), and the no pancreatic juice flow and reverse bile flow pattern (9%). The flow of the pancreatic juice and bile were synchronized with each other in 47%, while they were not in 53%. In the dilated pancreatic duct group, the mean secretion grade of the antegrade bile and pancreatic juice flow was significantly lower than in the normal group. Cine-dynamic MRCP with a spatially selective IR pulse can visualize the variations of the physiological flow patterns of bile and pancreatic juice including 53% of unsynchronized patterns. 4 TECHNICAL EFFICACY: Stage 5.


Structural insights into the substrate-binding proteins Mce1A and Mce4A from Mycobacterium tuberculosis.
Mycobacterium tuberculosis (Mtb), which is responsible for more than a million deaths annually, uses lipids as the source of carbon and energy for its survival in the latent phase of infection. Mtb cannot synthesize all of the lipid molecules required for its growth and pathogenicity. Therefore, it relies on transporters such as the mammalian cell entry (Mce) complexes to import lipids from the host across the cell wall. Despite their importance for the survival and pathogenicity of Mtb, information on the structural properties of these proteins is not yet available. Each of the four Mce complexes in Mtb (Mce1-4) comprises six substrate-binding proteins (SBPs; MceA-F), each of which contains four conserved domains (N-terminal transmembrane, MCE, helical and C-terminal unstructured tail domains). Here, the properties of the various domains of Mtb Mce1A and Mce4A, which are involved in the import of mycolic/fatty acids and cholesterol, respectively, are reported. In the crystal structure of the MCE domain of Mce4A (MtMce4A39-140) a domain-swapped conformation is observed, whereas solution studies, including small-angle X-ray scattering (SAXS), indicate that all Mce1A and Mce4A domains are predominantly monomeric. Further, structural comparisons show interesting differences from the bacterial homologs MlaD, PqiB and LetB, which form homohexamers when assembled as functional transporter complexes. These data, and the fact that there are six SBPs in each Mtb mce operon, suggest that the MceA-F SBPs from Mce1-4 may form heterohexamers. Also, interestingly, the purification and SAXS analysis showed that the helical domains interact with the detergent micelle, suggesting that when assembled the helical domains of MceA-F may form a hydrophobic pore for lipid transport, as observed in EcPqiB. Overall, these data highlight the unique structural properties of the Mtb Mce SBPs.


Improved technique for anaestesia of Macaca speciosa with methohexitone sodium.
Injection of methohexitone sodium, 5% w/v in 0.9 % saline, into the deltoid muscle at a dose of 16-17 mg/kg bodyweight was satisfactory for dailty general anaesthesia of Macaca speciosa monkeys.


UV-C irradiation is highly effective in inactivating SARS-CoV-2 replication.
The potential virucidal effects of UV-C irradiation on SARS-CoV-2 were experimentally evaluated for different illumination doses and virus concentrations (1000, 5, 0.05 MOI). At a virus density comparable to that observed in SARS-CoV-2 infection, an UV-C dose of just 3.7 mJ/cm2 was sufficient to achieve a more than 3-log inactivation without any sign of viral replication. Moreover, a complete inactivation at all viral concentrations was observed with 16.9 mJ/cm2. These results could explain the epidemiological trends of COVID-19 and are important for the development of novel sterilizing methods to contain SARS-CoV-2 infection.


Low levels of serum urate are associated with a higher prevalence of depression in older adults: a nationwide cross-sectional study in Korea.
Soluble urate has been shown to serve as an antioxidant, especially in the central nervous system. Although there are intriguing data suggesting that low levels of serum urate are associated with worse outcomes in neurodegenerative diseases, its impact on mental health has not been adequately assessed. Thus, we aimed to investigate the association between serum urate and depression using a large, nationally representative sample. Information on participants' socio-demographic characteristics as well as physical and mental health conditions were retrieved from the Korea National Health and Nutrition Examination Survey (KNHANES) 2016 dataset. The Patient Health Questionnaire (PHQ)-9 was applied to identify depressive symptoms. Analyses were stratified by age: young adults (aged 19-39 years), middle-aged adults (aged 40-59 years), and older adults (aged 60 years and older). A total of 5332 participants were included. Serum urate concentrations were divided into sex-specific quartiles based on their distribution: ≤ 4.9 (Q1), 5.0-5.7 (Q2), 5.8-6.6 (Q3), and ≥ 6.7 (Q4) mg/dL in men and ≤ 3.7 (Q1), 3.8-4.3 (Q2), 4.4-4.9 (Q3), and ≥ 5.0 (Q4) mg/dL in women. There was a significant negative linear relationship between serum urate quartiles and PHQ-9 scores in older adults (p for trend = 0.020 in men and p for trend = 0.048 in women). Compared to high levels (Q3 and Q4) of serum urate, low levels (Q1 and Q2) were significantly associated with the overall burden of depression in older women (OR 1.78, 95% CI 1.21, 2.61) and clinically relevant depression in older men (OR 3.35, 95% CI 1.16, 9.70), even after adjustment. Based on the KNHANES data, low levels of serum urate are associated with a higher prevalence of depression in older adults. This may have clinical implications for mental health.


Quality of life from return to work and sports activities to sexual dysfunction after surgical treatment of acetabular fractures.
To evaluate the outcomes of patients treated for acetabular fractures in terms of Quality of Life (QoL), return to work, functional outcome, sports activities, and post-operative sexual dysfunction. The database of a level 1 trauma center was used to investigate the results of patients treated for acetabular fractures from 2010 to 2020. The minimum patient follow-up was 12 months. QoL was evaluated with the SF-12 questionnaire, return to work with the Workplace Activity Limitation Survey (WALS), functional outcomes and sports activities with Harris Hip Score (HHS) and Tegner activity scores, respectively, and the sexual function damage with a 0-10 NRS. Sixty-five patients (44 men, 21 women) were enrolled, mean age at surgery of 53.4 years (20-85 years). The HHS and Tegner scores were 79.0 ± 19.4 and 2.6 ± 1.5, respectively, and 18.5% of patients underwent THA after 21.3 ± 28.6 months. QoL evaluated with the SF-12 showed the worst results in terms of Bodily Pain and Role Physical; 35.4% of the patients who were working before the trauma lost their job, and one third was affected at sex functional level. Sex was found to influence significantly both Harris Hip Score (p < 0.05) and Tegner activity score (p < 0.05), with men reporting better scores. On the other hand, men presented a higher impact in terms of job loss and sexual dysfunction. Acetabular fractures affect patients' life as a whole, beyond the mere functional outcomes, often leading to a high rate of job loss and a significant probability of sexual functional worsening, especially for men. A significant number of patients also underwent THA at an early follow-up. Further efforts should aim at optimizing the surgical management, to improve functionality and the entire QoL sphere of patients affected by acetabular fractures.


Purification and partial characterization of a trypsin inhibitor from chick skeletal muscle.
A protein capable of inhibiting trypsin and a number of other serine proteases was purified from chicken skeletal muscle. It has an apparent molecular weight of 64,000 as determined by gel filtration. The inhibitor molecule binds trypsin at a molar ratio of 1:1 to form a stable complex, in which trypsin can be completely inhibited. In this complex, the inhibitor is extensively digested by trypsin but retains its inhibitory activity and tertiary structure by intramolecular disulfide bonds. In addition, its activity was found to markedly increase during development of embryonic muscle. The physiological role of this inhibitor, however, remains unknown.


A Colorimetric and Fluorescent Probe Based on Michael Acceptor Type Diketopyrrolopyrrole for Cyanide Detection.
A new probe 1 was synthesized by incorporating an α,β-unsaturated ketone to a diketopyrrolopyrrole fluorophore. The probe exhibited a selective and sensitive response to cyanide against other anions. Addition of CN- aqueous solution to 1 resulted in a rapid color change from pink to light yellow together with a blue shift from 518 to 421 nm, while other anions did not induce any significant color change. Furthermore, the Michael addition of cyanide to 1 elicited 98% fluorescence quenching at 608 nm, which constituted the fluorescence signature for cyanide detection. The detection limit was 0.67 μM using the fluorescence spectra changes, which was far lower than the WHO guideline of 1.9 μM. Moreover, 1-based test strips could successfully detect CN- solutions.


Assessment of Diffusion Tensor Imaging Parameters of Hepatic Parenchyma for Differentiation of Biliary Atresia from Alagille Syndrome.
To assess diffusion tensor imaging (DTI) parameters of the hepatic parenchyma for the differentiation of biliary atresia (BA) from Alagille syndrome (ALGS). This study included 32 infants with BA and 12 infants with ALGS groups who had undergone DTI. Fractional anisotropy (FA) and mean diffusivity (MD) of the liver were calculated twice by two separate readers and hepatic tissue was biopsied. Statistical analyses were performed to determine the mean values of the two groups. The optimum cut-off values for DTI differentiation of BA and ALGS were calculated by receiver operating characteristic (ROC) analysis. The mean hepatic MD of BA (1.56 ± 0.20 and 1.63 ± 0.2 × 10-3 mm²/s) was significantly lower than that of ALGS (1.84 ± 0.04 and 1.79 ± 0.03 × 10-3 mm²/s) for both readers (r = 0.8, p = 0.001). Hepatic MD values of 1.77 and 1.79 × 10-3 mm²/s as a threshold for differentiating BA from ALGS showed accuracies of 82 and 79% and area under the curves (AUCs) of 0.90 and 0.91 for both readers, respectively. The mean hepatic FA of BA (0.34 ± 0.04 and 0.36 ± 0.04) was significantly higher (p = 0.01, 0.02) than that of ALGS (0.30 ± 0.06 and 0.31 ± 0.05) for both readers (r = 0.80, p = 0.001). FA values of 0.30 and 0.28 as a threshold for differentiating BA from ALGS showed accuracies of 75% and 82% and AUCs of 0.69 and 0.68 for both readers, respectively. Hepatic DTI parameters are promising quantitative imaging parameters for the detection of hepatic parenchymal changes in BA and ALGS and may be an additional noninvasive imaging tool for the differentiation of BA from ALGS.


Identification of a novel adhesion molecule in human leukocytes by monoclonal antibody LB-2.
Monoclonal antibody LB-2 to a surface antigen on human B cells, lymphoblast, monocytes and vascular endothelial cells largely inhibited adhesion among Epstein Barr virus-immortalized normal B cells (EBV-B) and concanavalin A-stimulated blood mononuclear cells (Con A-BMC) before and after phorbol ester treatment. The antibody inhibited to a lesser extent phorbol ester-induced aggregation of monocytes, U937 cells and fresh BMC and had virtually no inhibitory effect on the adhesion among enriched T cells and granulocytes. A surface glycoprotein band of 84 kDa was obtained from EBV-B cells by immunoprecipitation and gel electrophoresis. Immunological and biochemical studies clearly distinguished this molecule from gp90 and associated glycoproteins which also mediate leukocyte adhesion.


BioPlexR and BioPlexPy: integrated data products for the analysis of human protein interactions.
The BioPlex project has created two proteome scale, cell-line-specific protein-protein interaction (PPI) networks: the first in 293T cells, including 120k interactions among 15k proteins; and the second in HCT116 cells, including 70k interactions between 10k proteins. Here, we describe programmatic access to the BioPlex PPI networks and integration with related resources from within R and Python. Besides PPI networks for 293T and HCT116 cells, this includes access to CORUM protein complex data, PFAM protein domain data, PDB protein structures, and transcriptome and proteome data for the two cell lines. The implemented functionality serves as a basis for integrative downstream analysis of BioPlex PPI data with domain-specific R and Python packages, including efficient execution of maximum scoring sub-network analysis, protein domain-domain association analysis, mapping of PPIs onto 3D protein structures and analysis of BioPlex PPIs at the interface of transcriptomic and proteomic data. The BioPlex R package is available from Bioconductor (bioconductor.org/packages/BioPlex), and the BioPlex Python package is available from PyPI (pypi.org/project/bioplexpy). Applications and downstream analyses are available from GitHub (github.com/ccb-hms/BioPlexAnalysis).


The Relationship Between Hypothyroidism and Cardiac Findings in Children With and Without Down Syndrome.
Down syndrome is a genetic syndrome characterized with various dysmorphisms and congenital malformations such as congenital heart diseases. We aimed to evaluate the relationship between Down syndrome, hypothyroidism, and cardiac ���ndings. Thyroid hormone pro���les and echocardiographic ���ndings were evaluated. Patients with hypothyroidism and Down syndrome were named group 1; patients with hypothyroidism without Down syndrome group 2 and group 3 was control. The echocardiographic parameters (interventricular septum and left ventricular systolic, diastolic posterior wall thickness, left ventricular end-diastolic diameter, ejection fraction) were indexed to body surface area. Left ventricular mass index and relative wall thickness were calculated. Patients with relative wall thickness equal to or below 0.42 were classi���ed as eccentric hypertrophy or normal geometry, while those over 0.42 as concentric remodeling or concentric hypertrophy. Thyroid stimulating hormone values of groups 1 and 2 were signi���cantly higher than those of group 3. There were no signi���cant di���erences for fT4 between the groups. Interventricular septum and left ventricular posterior wall end-diastolic and end-systolic thickness were signi���cantly higher in group 1 than groups 2 and 3. There was no statistically signi���cant di���erence in left ventricular mass index between groups 1 and 2. In terms of relative wall thickness, 16 out of 29 patients in group 1 were revealed as concentric remodeling, 12 as normal geometry, 1 patient as eccentric hypertrophy. In group 2, 6 patients were revealed as concentric remodeling, 14 as normal geometry. There was no statistically signi���cant di���erence of left ventricular end-diastolic thickness between 3 groups. Cardiac morphology and functions were signi���cantly a���ected by hypothyroidism in patients with Down syndrome. Hypertrophy in Down syndrome may be caused by the cellular changes in myocardium.


Prenatal exposure to organophosphate esters and neonatal thyroid-stimulating hormone levels: A birth cohort study in Wuhan, China.
Increasing animal studies have indicated that organophosphate esters (OPEs) have endocrine-disruptive potential. However, human epidemiological evidence is limited, especially in susceptible populations, such as pregnant women and neonates. The purpose of this present study was to examine the trimester-specific relationships of prenatal exposure to OPEs with neonatal thyroid-stimulating hormone (TSH). A total of 102 mother-newborn pairs were recruited from a birth cohort study between April 2015 and September 2016 in Wuhan, China. Eight OPE metabolites were detectable in urine samples from pregnant women across the different three trimesters. Neonatal TSH levels were measured using time-resolved immunofluorescence assay. The associations between maternal urinary OPE metabolites and neonatal TSH and the critical exposure windows of fetal vulnerability were estimated using multiple informant models. Seven OPE metabolites with detection frequency > 50% (52.9%-98.0%) were detected in repeated urine samples from different three trimesters, and the urinary OPE metabolites across pregnancy was of high variability (ICCs: 0.09-0.26). After adjusted for confounders (e.g., maternal age, prepregnancy BMI, passive smoking during pregnancy), some suggestive associations were observed between maternal urinary OPE metabolites and neonatal TSH in different trimesters. A doubling of second trimester di-o-cresyl phosphate & di-p-cresyl phosphate (DoCP & DpCP) was associated with a 7.82% increase in neonatal TSH level (95% CI: -0.70%, 17.06%, p-value = 0.07), a doubling of third trimester diphenyl phosphate (DPHP) was associated with a 4.71% decrease in neonatal TSH level (95% CI: -9.80%, 0.67%, p-value = 0.09), and a doubling of third trimester bis(2-butoxyethyl) phosphate (BBOEP) was associated with a 6.38% increase in neonatal TSH level (95% CI: -0.12%, 13.31%, p = 0.05). However, such associations did not differ materially across trimesters. When performing stratified analysis by infant sex, the associations were statistically significant and were sex-dependent.In females, maternal urinary DoCP & DpCP concentrations in each trimester were associated with increased neonatal TSH levels, and urinary DPHP concentration in the third trimester was associated with decreased neonatal TSH level. In males, maternal urinary BBOEP concentration in the first trimester was positively related to neonatal TSH level. This prospective study demonstrated that prenatal exposure to OPEs can lead to a sex-dependent change in neonatal TSH levels. Although the sex-selective effect was differed among various urinary OPE metabolites, more evidence was supported that OPE exposure was related to increased TSH levels for both males and females.


Dynamic decision making: human control of complex systems.
This paper reviews research on dynamic decision making, i.e., decision making under conditions which require a series of decisions, where the decisions are not independent, where the state of the world changes, both autonomously and as a consequence of the decision maker's actions, and where the decisions have to be made in real time. It is difficult to find useful normative theories for these kinds of decisions, and research thus has to focus on descriptive issues. A general approach, based on control theory, is proposed as a means to organize research in the area. An experimental paradigm for the study of dynamic decision making, that of computer simulated microworlds, is discussed, and two approaches using this paradigm are described: the individual differences approach, typical of German work in the tradition of research on complex problem solving, and the experimental approach. In studies following the former approach, the behaviour of groups differing in performance is compared, either with respect to strategies or with respect to performance on psychological tests. The results show that there are wide interindividual differences in performance, but no stable correlations between performance in microworlds and scores on traditional psychological tests have been found. Experimental research studying the effects of system characteristics, such as complexity and feedback delays, on dynamic decision making has shown that decision performance in dynamic tasks is strongly affected by feedback delays and whether or not the decisions have side effects. Although neither approach has led to any well-developed theory of dynamic decision making so far, the results nevertheless indicate that we are now able to produce highly reliable experimental results in the laboratory, results that agree with those found in field studies of dynamic decision making. This shows that an important first step towards a better understanding of these phenomena has been taken.


A Preliminary Investigation of Health and Work-Environment Factors on Presenteeism in the Workplace.
This study investigates the health and work-environment factors that are associated with presenteeism. A self-report survey that measured presenteeism, 13 health conditions (eg, stress and allergies), and nine work-environment factors (eg, job strain and leadership) was completed by 229 workers. The most common health condition was stress, while the most common work-environment factor was job strain. Allergies, asthma, and high blood pressure along with work-life imbalance, poor leadership, and a lack of development opportunities were associated with presenteeism. Finally, several inter-relationships between the health and work-environment factors were also reported. Interventions targeted at the points of intersection among the health conditions and work-environment factors could be a cost-effective way to improve employees' overall well-being at work, and thus reduce presenteeism.


Identification of DNA regions required for mitotic and meiotic functions within the centromere of Schizosaccharomyces pombe chromosome I.
We have determined the structural organization and functional roles of centromere-specific DNA sequence repeats in cen1, the centromere region from chromosome I of the fission yeast Schizosaccharomyces pombe. cen1 is composed of various classes of repeated sequences designated K', K"(dgl), L, and B', arranged in a 34-kb inverted repeat surrounding a 4- to 5-kb nonhomologous central core. Artificial chromosomes containing various portions of the cen1 region were constructed and assayed for mitotic and meiotic centromere function in S. pombe. Deleting K' and L from the distal portion of one arm of the inverted repeat had no effect on mitotic centromere function but resulted in greatly increased precocious sister chromatid separation in the first meiotic division. A centromere completely lacking K' and L, but containing the central core, one copy of B' and K" in one arm, and approximately 2.5 kb of the core-proximal portion of B' in the other arm, was also fully functional mitotically but again did not maintain sister chromatid attachment in meiosis I. However, deletion of K" from this minichromosome resulted in complete loss of centromere function. Thus, one copy of at least a portion of the K" (dgl) repeat is absolutely required but is not sufficient for S. pombe centromere function. The long centromeric inverted-repeat region must be relatively intact to maintain sister chromatid attachment in meiosis I.


Comprehensive two-dimensional gas chromatography-mass spectrometry combined with multivariate data analysis for pattern recognition in Ecuadorian spirits.
The current methodology used in quality control of Ecuadorian beverages such as Pájaro azúl, Puro and Pata de vaca is carried out by using conventional gas chromatography; however, it does not allow the fingerprinting of these Ecuadorian spirit beverages and their possible cases of adulteration. In order to overcome this drawback, comprehensive two-dimensional gas chromatography-mass spectrometry (GC × GC-MS) was combined with multivariate data analysis, revealing that compounds like citronellal, citronellol, geraniol, methyl anthranilate, (-)-trans-α-bergamotene, (-)-cis-α-bergamotene and D-limonene can be considered key elements for pattern recognition of these traditional beverages and product adulteration cases. Thus, the two-dimensional chromatographic fingerprints obtained by GC × GC-MS coupled with chemometric analysis, using Principal Component Analysis and Fisher-ratio can be considered as a potential strategy for adulteration recognition, and it may used as a quality assurance system for Ecuadorian traditional spirits.


Nocturnal dipping of heart rate is impaired in children with Down syndrome and sleep disordered breathing.
Children with Down syndrome (DS) are at increased risk for sleep disordered breathing (SDB), which can have adverse effects on the cardiovascular system. In adults with SDB, nocturnal dipping of heart rate (HR) and blood pressure (BP) is reduced, and this is associated with an increased risk of future cardiovascular events. We aimed to compare nocturnal dipping of HR and pulse transit time (PTT) (a surrogate inverse measure of BP change) in children with DS and SDB to those of typically developing (TD) children with and without SDB. 19 children with DS (3-18 years) were age and sex matched with 19 TD children without SDB (TD-) and with 19 TD children with matched severity of SDB (TD+). Nocturnal dipping was assessed as the percentage change in HR and PTT from wake before sleep onset to total sleep, N2, N3 and REM sleep across the night and to the first cycle of sleep. Children with DS exhibited reduced nocturnal dipping of HR during total sleep, N2, N3 and REM sleep and increased PTT (reduced BP dipping) in N2 sleep. Fewer children with DS exhibited a greater than 10% fall in HR between wake and N2 or REM sleep compared to TD+ children. Our findings demonstrate significantly reduced nocturnal dipping of HR in children with DS compared to TD children matched for SDB severity, suggesting SDB has a greater cardiovascular effect in these children. Further studies are required to fully understand the mechanisms involved and to assess if treatment of SDB improves nocturnal dipping.


Cl- currents activated by extracellular nucleotides in human bronchial cells.
The perforated-patch technique was used to study the response of human bronchial cells to extracellular nucleotides. ATP or UTP (100 microm) elicited a complex response consisting of a large transient membrane current increase followed by a relatively small sustained level. These two phases were characterized by different current kinetics. Throughout the transient phase (2-3 min) the membrane current (Ip) displayed slow activation and deactivation kinetics at depolarizing and hyperpolarizing potentials respectively. At steady-state (Is) the relaxation at hyperpolarizing potential disappeared whereas at positive membrane potentials the current became slightly deactivating. The Is amplitude was dependent on the extracellular Ca2+ concentration, being completely inhibited in Ca2+-free medium. Cell pre-incubation with the membrane-permeable chelating agent BAPTA/AM prevented completely the response to nucleotides, thus suggesting that both Ip and Is were dependent on intracellular Ca2+. The presence of a hypertonic medium during nucleotide stimulation abolished Is leaving Ip unchanged. On the contrary, niflumic acid, a blocker of Ca2+-activated Cl- channels, prevented completely Ip without reducing significantly Is. 1, 9-dideoxyforskolin fully inhibited Is but also reduced Ip. Replacement of extracellular Cl- with aspartate demonstrated that the currents activated by nucleotides were Cl- selective. Ip resulted five times more Cl- selective than Is with respect to aspartate. Taken together, our results indicate that ATP and UTP activate two types of Cl- currents through a Ca2+-dependent mechanism.


Application of time-resolved diffuse reflectance techniques in studies of reaction intermediates in suspensions of Bacillus subtilis.
Short lived reaction intermediates such as triplet states and free radicals can be detected in vivo using laser photolysis techniques with time-resolved diffuse reflectance detection. This novel approach is illustrated for bacterial suspensions of Bacillus subtilis.


Design and immunogenicity analysis of the combined vaccine against zoonotic hepatitis E and foot-and-mouth disease.
Design and immunogenicity assessment of the combined vaccine candidate against zoonotic hepatitis E virus (HEV) and foot-and-mouth disease virus (FMDV). Using the molecular cloning technology, we produced and purified 9 HEV ORF2-truncated proteins (HEV genotype 4). Then, we compared their thermal stability, antigenicity, and immunogenicity to select the best HEV immunogen. Next, we used the adjuvant Montanide ISA-206 to prepare different formulations of HEV vaccine alone, FMDV vaccine alone and HEV-FMDV combined vaccine. The formulations were injected into mice and the induced humoral immune responses were monitored up 12 weeks post-immunization. The HEV p222 protein could self-assemble into VLPs (∼34 nm) and showed higher stability and better antigenicity/immunogenicity than the other HEV antigens, thus it was selected as the best HEV immunogen. Mice immunization with the FMDV vaccine alone induced high FMDV-specific antibody titers in a dose-dependent manner; the HEV p222 protein also induced high levels of anti-HEV antibodies but in a dose-independent manner. The HEV-FMDV combination induced anti-FMDV antibody titers 7-16-fold higher than the titers induced by the FMDV vaccine alone, and HEV-specific antibody titers 2.4-fold higher than those induced by the HEV p222 antigen alone. Herein, we proposed a new approach for the control of zoonotic HEV infection through its control in its main host (pig). We also designed the first HEV-FMDV combined vaccine and the preliminary analyses revealed a synergistic effect on the immunogenicity of both HEV and FMDV antigens.


Serum GGT/ALT ratio predicts vascular invasion in HBV-related HCC.
The gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) ratio has been reported as an effective predictor of the severity of hepatitis and HCC. The purpose of this study was to determine the role of the GGT/ALT ratio in the prediction of vascular invasion and survival outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The risk factors for vascular invasion were determined by univariate/multivariate logistic analysis. The cut-off value of GGT/ALT in predicting vascular invasion was calculated using the receiver operating characteristic (ROC) curve. The prognostic value of GGT/ALT was examined by Cox analysis and Kaplan-Meier curves. Sensitivity analysis, such as subgroup analysis and propensity score matching (PSM), was performed to reduce potential confounding bias. A high GGT/ALT ratio was identified as an independent risk factor for vascular invasion (P = 0.03). The correlation analysis suggested that higher GGT/ALT was associated with more severe tumour burdens, including vascular invasion (P < 0.001), tumour volume > 5 cm (P < 0.001), poor pathological differentiation (P = 0.042), more severe BCLC (P < 0.001) and ALBI grade (P = 0.007). In the survival analysis, a high GGT/ALT ratio was associated with poor overall survival (OS) (HR: 1.38; 95% CI 1.03, 1.87; P < 0.0001) and disease-free survival (DFS) (HR: 1.32; 95% CI 1.03, 1.87; P < 0.0001). In the subgroup analysis, similar results were consistently observed across most subgroups. In PSM analysis, GGT/ALT remained independently associated with vascular invasion (OR, 186; 95% CI 1.23, 3.33). The GGT/ALT ratio was a potential effective factor in the prediction of vascular invasion and prognosis in patients with HBV-related HCC.


Short-term adverse events, length of stay, and readmission after iliac crest bone graft for spinal fusion.
Retrospective cohort study of 13,927 patients, 820 of whom received iliac crest bone graft (ICBG). To compare adverse events, length of stay (LOS), and readmission for patients receiving ICBG with those who did not using multivariate analysis to control for potentially confounding factors. The use of ICBG in spinal fusion has been associated with increased surgical time, LOS, and donor site morbidity. Development of expensive bone graft substitutes has been predicated on these issues. Data on the effect of bone graft harvest on LOS and readmission rate are sparse, and multivariate analysis has not been used to control for confounding factors. Prospectively collected data from the American College of Surgeons National Surgical Quality Improvement Project 2010-2012 database were retrospectively reviewed. This includes demographics, comorbidities, surgical data, and hospital and 30-day follow-up outcomes data including adverse events, LOS, and readmission. Only 5.9% of spinal fusions use ICBG. Bivariate logistic regression (used for categorical variables) found the ICBG cohort was more likely to have a postoperative blood transfusion (11.6% vs. 5.5%, P < 0.001). Bivariate linear regression (used for continuous variables) found the ICBG cohort to have an extended operative time (+36.0 min, P < 0.001) and extended LOS (+0.6 d, P < 0.001).Multivariate analyses controlling for comorbidities, demographics, and approach-determined postoperative blood transfusion (odds ratio, 1.5), extended operative time (+22.0 min, P < 0.001), and LOS (+0.2 d, P = 0.037) to be significantly associated with ICBG use.No other adverse event was significantly associated with ICBG use. Readmission rates were not significantly different. This study used a large national database cohort and identified increased postoperative blood transfusion, extended operative time, and increased LOS as short-term outcomes associated with ICBG on multivariate analysis. Other short-term morbidities were not significantly associated with ICBG. Readmission rates were not affected. 4.


Epidemiology of Orofacial clefts in Africa: Methodological challenges in ascertainment.
To carry out a systematic review of the birth prevalence of cleft lip with or without cleft palate (CLP) and cleft palate (CP) in Africa based on available published data. Using the Cochrane search strategy and the following keywords words "cleft palate", "prevalence", "incidence", "cleft lip" and "Africa" to screen Ovid Medline {1966 to March 2007), Cinahl {1982-March 2007}, Pub Med, Scopus, and Web-Google. All identified published, prospective and retrospective studies on the birth prevalence of CLP and CP in Africa were included. The dates, location, sources, number of births (live births, still births, number of cleft cases, prevalence rates, sex ratio, cleft types, and clefts with associated anomalies were extracted. Ascertainment of cases was through the hospitals. Overall there were 57 CL/P, 56 CL and 36 CP reported from all the studies. From seven studies combined, 21 males and 20 females had CL, 10 males and 22 females with CP and 26 males and 24 females with CL/P. There were 3 cases with CL/P, 2 with CP and 2 with CL from the three studies that reported clefts with associated anomalies. For an improved ascertainment of cleft cases, there is a need to set up a birth defects surveillance system in the form of a national birth registry. Future studies should then aim to include the entire population in geographically defined regions. Reliable data on incidence is an essential pre-requisite for studies into aetiology and prevention.


Successful Preoperative QUAD SHOT for Bulky Parotid Carcinoma: Potential Preoperative Ultra-Hypofractionated Radiotherapy for Conversion Surgery.
QUAD SHOT is an ultra-hypofractionated radiotherapy (RT) technique that prescribes 14.0-14.8 Gy over 2 days. Although this technique has already gained some status as an effective palliative treatment for inoperable head and neck cancer (HNC), its application in other situations has not been given much consideration. Herein, we report a case of a 62-year-old woman who received preoperative QUAD SHOT therapy for poorly differentiated parotid carcinoma. In this case, after two courses of QUAD SHOT plus a standard chemotherapy regimen with pembrolizumab, the patient's inoperable, bulky tumor shrank dramatically and became operable. Best of all, while adequate therapeutic effects were achieved, the patient's time commitment and physical exertion were limited. RT during this period consisted of only eight fractions over 4 days. According to previous reports, the response rate for QUAD SHOT is sufficiently high, and the rate of serious adverse events is quite low. This case asks the question of whether the indications for QUAD SHOT irradiation can be expanded as one of the preoperative interventions undertaken by HNC surgeons to achieve conversion surgery.


A Microsphere-Based Suspension Array for Blood Group Molecular Typing: An Update.
SUMMARY: BACKGROUND: In a previous publication we described a method for Jk(a)/Jk(b), Fy(a)/Fy(b), S/s, K/k, Kp(a)/Kp(b), Js(a)/Js(b), Co(a)/Co(b), and Lu(a)/Lu(b) genotyping based on a microsphere suspension array. Here, an improved version of the assay is presented. METHODS: TWO MULTIPLEX POLYMERASE CHAIN REACTIONS (PCR) WERE DEVELOPED: one for amplification of samples routinely tested and the other for those systems that are tested less frequently. Each biotinylated PCR product is hybridized in a single multiplex assay. A total of 2,020 samples were analyzed, and the genotypes were compared to the blood group phenotypes. RESULTS: There have been no discrepancies with the serology results other than null and/or weak phenotypes. CONCLUSION: In its present form, the method presented here has the capacity to genotype hundreds of a samples in few hours with a high concordance rate with serology.


In critically ill patients with COVID-19, IL-6 receptor antagonists reduced mortality vs. control at 180 d.
Writing Committee for the REMAP-CAP Investigators; Higgins AM, Berry LR, Lorenzi E, et al. Long-term (180-day) outcomes in critically ill patients with COVID-19 in the REMAP-CAP randomized clinical trial. JAMA. 2023;329:39-51. 36525245.


Using correlative light and electron microscopy to study zebrafish vascular morphogenesis.
Live imaging is extremely useful to characterize the dynamics of cellular events in vivo, yet it is limited in terms of spatial resolution. Correlative light and electron microscopy (CLEM) allows combining live confocal microscopy with electron microscopy (EM) for the characterization of biological samples at high temporal and spatial resolution. Here we describe a protocol allowing extracting endothelial cell ultrastructure after having imaged the same cell in its in vivo context through live confocal imaging during zebrafish embryonic development.


[Analysis of the parental origin of MECP2 mutations in patients with Rett syndrome].
To identify the parental origin of methyl-CpG-binding protein 2 (MECP2) gene mutations in Chinese patients with Rett syndrome. Single nucleotide polymorphisms (SNPs) in intron 3 of the MECP2 gene were analyzed by PCR and sequencing in 115 patients with Rett syndrome. Then sequencing of the SNP region was performed for the fathers of the patients who had at least one SNP, to determine which allele was from the father. Then allele-specific PCR was performed and the products were sequenced to see whether the allele from father or mother harbored the mutation. Seventy-six of the 115 patients had at least one SNP. Three hot SNPs were found in these patients. They were: IVS3+22C >G, IVS3+266C >T and IVS3+683C>T. Among the 76 cases, 73 had a paternal origin of MECP2 mutations, and the other 3 had a maternal origin. There were multiple types of MECP2 mutation of the paternal origin, including 4 frame shift, 2 deletion and 67 point (56C >T, 6C >G, 2A >G, 2G >T and 1A >T) mutations. The mutation types of the 3 patients with maternal origin included 2 frame shift and 1 point (C >T) mutation. In Chinese RTT patients, the MECP2 mutations are mostly of paternal origin.


Simultaneous shear and pressure sensor array for assessing pressure and shear at foot/ground interface.
Foot ulceration is a diabetic complication estimated to result in over $1 billion worth of medical expenses per year in the United States alone. This multifaceted problem involves the response of plantar soft tissue to both external forces applied to the epidermis and internal changes such as vascular supply and neuropathy. Increasing evidence indicates that a combination of elevated external forces (pressure and shear) and altered tissue properties is key to the etiology of foot ulcers. The overall goal of this research is to develop a platform-type hardware system that will allow a clinician to measure three-dimensional stress tensors (i.e. pressure and shear patterns) on the plantar surface and identify areas of concern. Experimental results have demonstrated that an optical approach can provide clear indication of both shear and pressure from 50 to 400 kPa with a frequency response of 100 Hz, a stress measurement accuracy of 100 Pa and a spatial resolution of 8.0mm. Initial evaluation of the system shows strong correlation between (i) applied shear and normal stress loads and (ii) the optical phase retardance computed for each stress axis of the polymer-based stress-sensing elements. These special sensing elements are designed to minimize the need for repeated calibration procedures-an issue that has plagued other attempts to develop multisensor shear and pressure systems.


A method for quantitative determination of average masses and concentrations of circulating immune complexes in human sera.
A method for rapid determination of average masses and concentrations of circulating immune complexes in human sera is suggested. It is based on the dissimilarity in solubilities of immune complexes with different masses in the presence of polyethyleneglycol. Light-scattering intensities are measured by a laser nephelometer after adding to the serum of PEG in two different concentrations. The experimental values of the average masses and concentrations are calculated using calibration curves. The calibration curves are plotted for model immune complexes with different average masses obtained by heat-aggregation of IgG at various concentrations. This technique has been employed for determination of the average masses and concentrations of circulating immune complexes in 17 patients suffering from systemic lupus erythematosus and in 8 control individuals.


A Review of Three Chinese Cases of Acromicric/Geleophysic Dysplasia with FBN1 Mutations.
This study aims to explore the clinical features and molecular diagnosis of FBN1-related acromelic dysplasia in Chinese patients. The clinical and genetic features of three FBN1-related acromicric dysplasia (AD)/geleophysic dysplasia (GD) Chinese patients from two families were reviewed, and comprehensive medical evaluations were performed. Targeted next-generation sequencing was used to detect genetic mutations associated with short statures, including FBN1. Sanger sequencing was used to determine the de novo mutation origin. Patient 1 presented with short stature, short and stubby hands and feet, mild facial dysmorphism, hepatomegaly, delayed bone age and beak-like femoral heads. Patient 2 and this patient's father merely presented with short stature, wide and short hands, and beak-like femoral heads. One novel mutation, c.5272G>T(p.D1758Y), and one known mutation, c.5183C>T(p.A1728V), were identified in these patients. The clinical features varied among these patients. The variant c.5272G>T(p.D1758Y) is a novel mutation.


A Case of Schwannoma of the Common Peroneal Nerve in the Knee.
Schwannomas are benign neurogenic tumors of peripheral nerves that originate from neural sheath. The aim of this case report is to bring to mind the schwannoma in the patient with knee pain. A 39-year-old woman presented with a complaint of knee pain of three months history. After surgical intervention, the patient's complaints completely disappeared in the post-operative period. This should come to mind in the differential diagnosis of knee pain.


Glomerular involvement in children with H syndrome.
H syndrome is a multisystem inflammatory disease caused by mutations in the SLC29A3 gene (OMIM #602782). The protein product, hENT3, is a nucleoside transporter essential for DNA salvage synthesis. Clinical manifestations are hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, short stature, skeletal deformities, and diabetes mellitus. Laboratory findings are consistent with inflammatory processes. Structural kidney anomalies have been described in 6% of patients. Three family members with genetically diagnosed H syndrome (c.1279G>A, p.Gly427Ser). Two of them presented with hypoalbuminemia and nephrotic range proteinuria. Kidney ultrasound was normal. Kidney biopsy performed in one patient presenting with generalized peripheral pitting edema revealed membranous nephropathy. Different treatments including ACE inhibitors, corticosteroids, and immunomodulatory agents failed to improve the clinical outcome. Generalized peripheral pitting edema and glomerulopathy broaden the clinical spectrum of H syndrome. Periodic bloodwork and urinalysis are recommended.


Vital registration and under-reporting of maternal mortality in Jamaica.
To identify why vital registration under-reports maternal deaths in Jamaica. A cross-sectional study was undertaken to identify all maternal deaths (during pregnancy or ≤42 days after pregnancy ended) occurring in 2008. Data sources included vital registration, hospital records, forensic pathology records, and an independent maternal mortality surveillance system. Potential cases were cross-referenced to registered live births and stillbirths, and hospital records to confirm pregnancy status, when the pregnancy ended, and registration. Medical certificates were inspected for certification, transcription, and coding errors. Maternal mortality ratios (MMRs) for registered and/or unregistered deaths were calculated. Of 50 maternal deaths identified, 10 (20%) were unregistered. Eight unregistered deaths were coroners' cases. Among 40 registered deaths, pregnancy was undocumented in 4 (10%). Among the other 36, 24 (67%) had been misclassified (59% direct and 89% indirect deaths). Therefore, only 12 (30%) registered maternal deaths had been coded as maternal deaths, yielding an MMR of 28.3 per 100 000 live births (95% confidence interval [CI] 12.3-48.3), which was 76% lower than the actual MMR of 117.8 (95% CI 85.2-150.4). Under-reporting of maternal deaths in Jamaica in 2008 was attributable to delayed registration of coroners' cases and misclassification. Timely registration of coroners' cases and training of nosologists to recognize and code maternal deaths is needed.


Rabbit endocervical epithelium: morphometric analysis of secretory cell populations.
In this report we quantitated ultrastructural changes in two cytologically distinct secretory cell populations from the rabbit endocervix. Type I and type II cells from estrous animals differ only in the presence of one or more empty cytoplasmic vacuoles in type II cells. Comparing type II cells from 5-day pseudopregnant (PSP) rabbits with type II cells from estrous controls, there is no increase (P greater than .05) in the average vacuole volume. When type I and type II cells from PSP animals are compared to cells from estrous controls, there is a decrease (P less than .01) in the average cell volume, a decrease (P less than .01) in the average nuclear volume, and a decrease (P less than .01) in the average granule volume. This reduction in the granule content of secretory endocervical cells was correlated with a dramatic decrease in protein glycosylation into the microsomal fraction. Serum estradiol concentrations for estrous (13.7 +/- 1.0 pg/ml) and PSP (18.1 +/- 1.5 pg/ml) animals were comparable. However, the 36-fold increase in serum progesterone concentrations for PSP (12.04 +/- 1.7 ng/ml) animals compared to estrous (0.33 +/- 0.1 ng/ml) animals may be responsible for the decrease in protein glycosylation.


Morphological alterations, activity, mRNA fold changes, and aging changes before and after orthodontic force application in young and adult human-derived periodontal ligament cells.
The response of periodontal ligament cells (PDLC) from adult subjects in comparison to those obtained from younger ones to mechanical forces has been a matter of interest recently because of induced senescent changes. This study evaluated and compared cell surface changes and activity, integrin beta 1, and β-actin mRNA fold changes as well as klotho protein secretion capabilities of PDLC from young and adult donors before and after subjecting to orthodontic forces. A total of 40 subjects with bimaxillary dentoalveolar protrusion requiring extraction of first premolars for orthodontic treatment were selected and divided into two groups. Force ranging from 80 to 90 g was applied to maxillary first premolars and extraction was carried out at two different time periods-pre-treatment (control group) and 28 days after force application (experimental group). Periodontal ligament was obtained, and cell surface changes and activity were observed with atomic force microscopy (AFM) and fluorescent tagging. mRNA fold change of integrin beta-1 and β-actin mRNA, as well as beta-galactosidase assay, was performed, and levels of klotho protein were evaluated. AFM nanoindentation and fluorescent tagging indicated increased surface morphological changes in younger cells compared to adult ones. We observed a decrease in integrin beta 1 but an increase in β-actin mRNA levels in PDLC obtained from younger subjects compared to adults, while an increase was observed in SA-β-GAL from adult cells. The level of klotho protein was lower in adult cells in comparison to younger ones. Large sample studies are required to find out a variation in aging characteristics between young and adult PDLC. The study observed significant differences between PDLC obtained from younger and adult subjects in response to orthodontic force application.


Resveratrol loaded oxidized mesoporous carbon nanoparticles: A promising tool to treat triple negative breast cancer.
Currently, breast cancer has become the most commonly diagnosed malignancy among females and triple negative breast cancer (TNBC) is a highly aggressive and metastatic subtype. The natural polyphenolic compound, resveratrol (3, 4', 5-trihydroxy-trans-stilbene, RES), has drawn great attention for its potential against TNBC. However, due to the poor aqueous solubility, the bioactivity of RES against TNBC is extremely hampered. In this study, oxidized mesoporous carbon nanoparticles (oMCNs) with size below 200 nm and excellent water dispersibility were synthesized using mild oxidation method and RES was successfully encapsulated into the pores of oMCNs with high drug loading efficiency (24.8% w/w). oMCNs exhibited good biocompatibility and excellent cellular uptake efficiency. Compared to pure RES, oMCNs-RES greatly improved the saturated solubility and in vitro release property. In vitro cytoxicity assay and apoptosis analysis showed that oMCNs-RES induced enhanced cytotoxic effect and pro-apoptosis effect mediated via the PARP and Caspase-3 protein cleavage in TNBC cell line, respectively. These results demonstrate oMCNs have the potential to deliver hydrophobic drugs and oMCNs-RES are promising in treating TNBC.


Participation of Macrogolstearate 400 lamellar phases in hydrophilic creams and vesicles.
In binary Macrogolstearate 400 (MS 400)/water systems, lamellar surfactant arrangements can be detected by polarized light and transmission electron microscopy. As demonstrated by X-ray diffraction and differential scanning calorimetry, the alkyl chains of the emulsifier are in the crystalline state. Ternary systems with liquid paraffin represent optically isotropic, homogeneous o/w creams for a wide composition range. Incorporation of up to 50 mol% cholesterol into the MS 400 lamellar structures leads to a gel-liquid crystalline phase separation within the bilayer, thus enabling the formation of spherical nonionic vesicles. The transition enthalpy of the samples decreases linearly with increasing cholesterol concentrations. The Macrogolstearate 400/cholesterol vesicles proved to be stable in hydrophilic cream systems. Cationic vesicles can be prepared using cetyltrimethylammonium bromide (CTAB) as a charge inducer. Low-CTAB portions are inhomogeneously distributed within the bilayer, as detected by DSC. The results also indicate a perturbation of the alkyl chains packing for the positively charged vesicles.


High throughput screening of native species for tailings eco-restoration using novel computer visualization for plant phenotyping.
Historical hard-rock mine activities have resulted in nearly half a million mining-impacted sites scattered around the US. Compared to conventional remediation, (aided) phytostabilization is generally cost-effective and ecologically productive approach, particularly for large-scale sites. Native species act to maintain higher local biodiversity, providing a foundation for natural ecological succession. Due to heterogeneity of mine waste, revegetation strategies are inconsistent in approach, and to avoid failure scenarios, greenhouse screening studies can identify candidate plants and amendment strategies before scaling up. This greenhouse study aimed to concurrently screen a variety of native species for their potential to revegetate Cu/Pb/Zn mine tailings and develop a high throughput and non-destructive approach utilizing computer vision and image-based phenotyping technologies to quantify plant responses. A total number of 34 species were screened in this study, which included: 5 trees, 8 grasses, and 21 forbs and legumes. Most of the species tested were Missouri native and prairie species. Plants were non-destructively imaged, and 15 shape and color phenotypic attributes were extracted utilizing computer vision techniques of PlantCV. Compared to reference soil, all species tested were negatively impacted by the tailings' characteristics, with lowest tolerance generally observed in tree species. However, significant improvement in plant growth and tolerance generally observed with biosolids addition with biomass surpassing reference soil for most legumes. Accumulation of Cu, Pb, and Zn was below Domestic Animal Toxicity Limits in most species. Statistically robust differences in species responses were observed using phenotypic data, such as area, height, width, color, and 9 other morphological attributes. Correlations with destructive data indicated that area displayed the greatest positive correlation with biomass and color the greatest negative correlation with shoot metals. Computer visualization greatly increased the phenotypic data and offers a breakthrough in rapid, high throughput data collection to project site-specific phytostabilization strategies to efficiently restore mine-impacted sites.


[Contribution of the cervical vertebral maturation (CVM) method to dentofacial orthopedics: update].
The successful orthopedic treatment of skeletal Class II malocclusions is closely related to the reasoned determination of the optimal time to initiate the treatment. This is why various methods have been proposed to assess skeletal maturation, such as a hand-wrist radiograph or the cervical vertebral maturation (CVM) method. The hand-wrist radiograph was up to now the most frequently used method to assess skeletal maturation. However, the clinical and biological limitations of this technique, as well as the need to perform an additional radiograph, were reasons to develop another method to explore the maturation stages of visible cervical vertebrae on a simple lateral cephalometric radiograph. The authors compare the 2 methods and prove the greater contribution of the CVM method compared to the hand-wrist radiograph.


Versatile photoelectrochemical and electrochemiluminescence biosensor based on 3D CdSe QDs-DNA nanonetwork-SnO2 nanoflower coupled with DNA walker amplification for HIV detection.
A novel 3D CdSe quantum dots (QDs)-DNA nanonetwork was assembled to sensitize the mesoporous SnO2 photoelectrochemical (PEC) substrate, which was coupled with a biped-DNA walker multiple amplification technique to design a versatile electrochemiluminescence (ECL) and PEC biosensor for dual detection of HIV. Firstly, the photosensitive CdSe QDs and SnO2 nanoflowers have well-matched band-edge energy level, thus their complex can promote effective transfer of the photogenerated carriers, and show better PEC and ECL property. Then, a novel 3D CdSe QDs-DNA nanonetwork was assembled and loaded with a large amount of QDs, which was used as multifunctional PEC and ECL probes. Moreover, the target-triggered biped DNA walker-cascade amplification method was introduced to generate a large amount of output DNA, which was used to link numerous 3D CdSe QDs-DNA nanonetwork probes to the electrode, generating greatly amplified signals for sensitive assay of HIV. The highly photosensitive 3D CdSe QDs-DNA reticulated nanomaterials have high stability and controllability, and display significantly improved PEC and ECL signals of the biosensor. This method opened a new photoelectric nanocomposite of QDs-sensitized SnO2 nanoflower, and developed a versatile biosensing strategy using the 3D CdSe QDS DNA sensitization probes for ultra-sensitive detection of biomolecules, which is important for the early diagnosis of diseases.


[Keratoprosthesis with Biological Haptic - The Düsseldorf-Offenburg-Experience with Osteo-Odonto- and Tibia-Keratoprosthesis].
In severe ocular surface disease with limbal stem cell deficiency associated with severe dry eye, penetrating keratoplasty is likely to fail. In these cases, and provided the posterior segment is normal, keratoprosthesis surgery (KPro) can achieve visual rehabilitation. In KPros with an autologous biological haptic, a bone-tooth-complex (osteo-odonto-keratoprothesis, OOKPro) or a piece of tibial cortex (tibia-keratoprosthesis, TKPro) is used to carry a PMMA cylinder. This construct can successfully be implanted even in severely dry eyes and in those with autoimmune disease, in which other KPro designs frequently fail. Herein we review the published anatomic long-term results of OOKPro and TKPro on our own patients. With a mean follow-up of 7.5 years (max. 20.6) for OOKPro and 4.5 years (max. 13.3) for TKPro patients, the retention rate was 91 and 86%, respectively. We are unaware of any other technique for artificial replacement of the cornea with equally positive long-term results as KPros with a biological haptic.


Repurposing the anthelmintic praziquantel to treat psoriasis.
The anthelmintic drug praziquantel has been used as a standard treatment for schistosomiasis for over 40 years. This study aimed to repurpose praziquantel to treat psoriasis. Psoriasis-like skin inflammation was induced in mice (C57 and Balb/C) by topical application of imiquimod or intradermal injection of recombinant IL-23. Praziquantel was either orally or topically administered during the psoriasis induction period. Mice treated with either oral or topical praziquantel exhibited markedly improved psoriasiform skin symptoms when compared with control mice, as judged by disease severity score, epidermal thickening, inflammatory cell infiltration and spleen size. Flow cytometric analysis of infiltrating immune cells from mouse skin displayed reduced infiltration of Th17 cells. In vitro experiments revealed that praziquantel inhibited STAT3 phosphorylation and RORγt expression in splenic CD4+ T-cells. Praziquantel also decreased STAT3 phosphorylation in HEK-A/F cells. Down-regulation of STAT3 phosphorylation in these cells accounts for the decreased number of Th17 cells and keratinocytes. These results provide the first preclinical evidence that praziquantel may effectively treat psoriasis, and suggest that praziquantel alleviates symptoms in mice by inhibiting STAT3 phosphorylation, thereby suppressing Th17 immune responses.


Methods for decreasing the statistical variance of stereological estimates.
Three methods are described for decreasing the statistical variance of stereological estimates. Method 1 uses profile boundaries and surface densities of nuclear membranes, measured in thin sections, to estimate the mean diameter, surface area, and numerical density of spherical and nonspherical nuclei. For the guinea pig pancreas (number(m) = 4), the standard deviations (s.d.) as a percent of the mean for the estimates of the diameters of the exocrine, duct, and endothelial cell nuclei were 1.5%, 3.3% and 1.4%. The estimate for the mean diameter of exocrine nuclei (6.4 +/- 0.1 micron) was based on a spherical model, whereas the estimates for the diameters of the nonspherical (and nonconvex) nuclei of the duct (6.4 +/- 0.2 micron) and endothelial (6.7 +/- 0.1 micron) cells were calculated from the numerical density of the exocrine cells and the relative frequencies of the three cell types (determined from serial reconstructions). In an average cubic centimeter, there were 6.17 X 10(8) +/- 0.32 X 10(8) (s.d. 5.1% of mean) exocrine cells, 1.64 X 10(8) +/- 0.18 X 10(8) (10.9%) duct cells, and 0.803 X 10(8) +/- 0.13 X 10(8) (16.6%) endothelial cells. In contrast to method 1, conventional stereological approaches were found to have standard deviations two- to eightfold larger. Method 2 uses a mean nuclear surface area and a ratio of surface densities to estimate the surface area of a membrane compartment in an average cell. A s.d. equal to 6.5% of the mean was found for the surface area of the outer mitochondrial membrane in an average exocrine cell (672 +/- 43.6 micron 2), which represented an almost fourfold reduction in the s.d. compared with an earlier estimate (Bolender, 1974). Method 3 relates the surface area of a membrane compartment to a standard number of cells. Referenced to 10(6) cells, for example, the surface area of the inner nuclear membrane of endothelial cells had a s.d. equal to 2.9% of the mean, whereas the surface density of the same membrane compartment-referenced to a cm3 of cells-had a s.d. at 19.1% of the mean. In this case, method 3 produced almost a sevenfold reduction in the standard deviation. Similar results were found for exocrine and duct cells. The results of the study indicate that the standard deviation of a stereological estimate can be reduced to a minimum by using a mean nuclear profile boundary to generate an estimate for a nuclear numerical density, which, in turn, can be combined with a surface density to obtain average cell information.


Overview of the Innervation of the Hip Joint.
The innervation of the hip joint has been investigated for over 200 years by anatomists and clinicians. Knowledge of the distribution and location of these nerves relative to anatomic landmarks visible with image guidance is important for optimizing nerve blocks and radiofrequency ablation procedures. In this article, the innervation of the anterior and posterior hip joint is reviewed, focusing on the source of articular branches, their course, termination, and relationship to anatomic landmarks. The innervation of the hip joint is multifaceted, with articular nerves originating from many sources in close proximity to and distant from the hip joint.