Hoxb1 Regulates Distinct Signaling Pathways in Neuromesodermal and Hindbrain Progenitors to Promote Cell Survival and Specification.
Hox genes play key roles in the anterior-posterior (AP) specification of all 3 germ layers during different developmental stages. It is only partially understood how they function in widely different developmental contexts, particularly with regards to extracellular signaling, and to what extent their function can be harnessed to guide cell specification in vitro. Here, we addressed the role of Hoxb1 in 2 distinct developmental contexts; in mouse embryonic stem cells (mES)-derived neuromesodermal progenitors (NMPs) and hindbrain neural progenitors. We found that Hoxb1 promotes NMP survival through the upregulation of Fgf8, Fgf17, and other components of Fgf signaling as well as the repression of components of the apoptotic pathway. Additionally, it upregulates other anterior Hox genes suggesting that it plays an active role in the early steps of AP specification. In neural progenitors, Hoxb1 synergizes with shh to repress anterior and dorsal neural markers, promote the expression of ventral neural markers and direct the specification of facial branchiomotorneuron (FBM)-like progenitors. Hoxb1 and shh synergize in regulating the expression of diverse signals and signaling molecules, including the Ret tyrosine kinase receptor. Finally, Hoxb1 synergizes with exogenous Glial cell line-derived neurotrophic factor (GDNF) to strengthen Ret expression and further promote the generation of FBM-like progenitors. Facial branchiomotorneuron-like progenitors survived for at least 6 months and differentiated into postmitotic neurons after orthotopic transplantation near the facial nucleus of adult mice. These results suggested that the patterning activity of Hox genes in combination with downstream signaling molecules can be harnessed for the generation of defined neural populations and transplantations with implications for neurodegenerative diseases.


pH-induced changes in mitotic and developmental patterns in sea urchin embryogenesis. II. Exposure of sperm.
pH decrease and increase were tested for their ability to affect the fertilizing capacity of sea urchin sperm, as well as to induce developmental defects and mitotic abnormalities in the embryos generated by pretreated sperm. Seawater (sw) at different pH values was obtained by mixing acidified (HCl) sw and alkalinized (KOH) sw. Thereafter sperm were exposed to different pHs for a defined time interval, or subjected to inactivation, while suspended in sw at defined pHs, as long as their fertilizing capacity was maintained. The study was carried out over the pH range 5-9; sperm showed optimal fertilizing capacity between pH 6 and 7. Below pH 6 and above pH 8 a drop in the fertilizing capacity was observed, whereas at normal sw pH (8.0-8.2) sperm showed intermediate values. pH decrease in sperm suspension induced a reproducible increase in developmental defects and mitotic abnormalities in the offspring of pretreated sperm. This effect displayed a dose-response relationship, which was most evident for pH ranging from 7 to 8. The effects of decreased pH were detected as well in terms of quantitative changes in mitotic activity, which decreased in embryos generated by sperm exposed to low pH (5-6). The results are consistent with the induction of genetic damage following exposure of sperm to low pHs. This observation suggests a genotoxic action of hydronium ions per se. Another possible explanation for the observed genotoxicity of decreased pH might be based on the pH-dependent activity of several genotoxins present in sw at trace levels.


Development of a method for the detection and confirmation of the alpha-2 agonist amitraz and its major metabolite in horse urine.
Amitraz (N'-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl)imino]methyl]-N-methyl-methanimidamide) is an alpha-2 adrenergic agonist used in veterinary medicine primarily as a scabicide- or acaricide-type insecticide. As an alpha-2 adrenergic agonist, it also has sedative/tranquilizing properties and is, therefore, listed as an Association of Racing Commissioners International Class 3 Foreign Substance, indicating its potential to influence the outcome of horse races. We identified the principal equine metabolite of amitraz as N-2,4-dimethylphenyl-N'-methylformamidine by electrospray ionization(+)-mass spectrometry and developed a gas chromatographic-mass spectrometric (GC-MS) method for its detection, quantitation, and confirmation in performance horse regulation. The GC-MS method involves derivatization with t-butyldimethylsilyl groups; selected ion monitoring (SIM) of m/z 205 (quantifier ion), 278, 261, and 219 (qualifier ions); and elaboration of a calibration curve based on ion area ratios involving simultaneous SIM acquisition of an internal standard m/z 208 quantifier ion based on an in-house synthesized d(6) deuterated metabolite. The limit of detection of the method is approximately 5 ng/mL in urine and is sufficiently sensitive to detect the peak urinary metabolite at 1 h post dose, following administration of amitraz at a 75-mg/horse intravenous dose.


Expression and activity of mitogen activated protein kinases in human colorectal carcinoma.
Mitogen activated protein kinases (MAPKs) play a central role in the regulation of both cell growth and differentiation. They are involved in signal transduction of oncogenes and growth factors. The role of MAPK in colonic carcinoma is unknown. To establish whether the expression and activity of p42/44 MAPKs are altered in colorectal tumours as compared with normal mucosa. The expression and activity of p42/p44 MAPK were investigated in 22 colorectal carcinomas, four adenomas, and the corresponding normal colorectal mucosa by the use of western blotting, immunoprecipitation, and in vitro kinase assays. After immunoprecipitation with an antibody specific for p42 MAPK, we found significant inactivation of p42 MAPK in colonic carcinomas as well as in adenomas, whereas most sample pairs showed only minor differences in p42 MAPK expression. Investigation of MAPK with an antibody capable of detecting both p42 and p44 MAPK showed a slight but significant decrease in p44 MAPK content in malignant tissues. With this antibody, only minor alterations in MAPK activity and no correlation with p42 MAPK activity were found. Inactivation of p42 MAPK could be associated with colonic carcinogenesis.


Effects of phaseic Acid and dihydrophaseic Acid on stomata and the photosynthetic apparatus.
Plant extracts containing phaseic acid (PA), as well as solutions of purified PA and dihydrophaseic acid (DPA) were applied to leaves, isolated mesophyll cells, and isolated epidermal strips. In Commelina communis, stomatal closure began 4 minutes after the addition of either 20 micromolar (+/-)-abscisic acid or 10 micromolar PA. Stomata closed less rapidly after treatment with 10 micromolar PA than after treatment with 10 micromolar (+/-)-abscisic acid in Amaranthus powelli, Hordeum vulgare, Xanthium strumarium, and Zea mays and did not respond at all to PA in Vicia faba. DPA (10 micromolar) did not cause stomatal closure in any species.Plant extracts containing PA reduced photosynthesis, as reported by Kriedemann et al. (Aust J Plant Physiol 2: 553-567, 1975). Subsequent experiments with PA purified by crystallization and with residues of solvents employed in the extraction of PA proved that it was not PA that impaired photosynthetic O(2) evolution or CO(2) uptake but unidentified contaminants of the allegedly pure solvents.


Investigation of Balance Function Using Dynamic Posturography under Electrical-Acoustic Stimulation in Cochlear Implant Recipients.
Introduction. The purpose of the present study is to investigate the effect of electrical-acoustic stimulation on vestibular function in CI patients by using the EquiTest and to help answer the question of whether electrically stimulating the inner ear using a cochlear implant influences the balance system in any way. Material and Methods. A test population (n = 50) was selected at random from among the cochlear implant recipients. Dynamic posturography (using the EquiTest) was performed with the device switched off an switched on. Results. In summary, it can be said that an activated cochlear implant affects the function of the vestibular system and may, to an extent, even lead to a stabilization of balance function under the static conditions of dynamic posturography, but nevertheless also to a significant destabilization. Significant improvements in vestibular function were seen mainly in equilibrium scores under conditions 4 and 5, the composite equilibrium score, and the vestibular components as revealed by sensory analysis. Conclusions. Only under the static conditions are significantly poorer scores achieved when stimulation is applied. It may be that the explanation for any symptoms of dizziness lies precisely in the fact that they occur in supposedly noncritical situations, since, when the cochlear implant makes increased demands on the balance system, induced disturbances can be centrally suppressed.


Evaluating Factors That Influence Patient Satisfaction in Otolaryngology Clinics.
To identify factors that influence patient satisfaction during outpatient visits in various settings of otolaryngology clinics in an academic medical center. Retrospective review. Academic medical center. We reviewed Press Ganey patient satisfaction survey responses for new, outpatient visits between January 1, 2014 and December 31, 2018. Self-reported race was identified using electronic medical records. Multivariate binary logistic regression analyses were used to identify continuous and categorical variables associated with patient satisfaction. There were 3998 unique new patient visits with completed surveys. Multivariate analysis revealed that responses for patients <18 years old are less likely to be satisfied with their care compared to patients ≥18 years old (OR 0.66; P < .001). For each 10-minute increase in wait time, patients were 43.4% less likely report satisfaction (P < .001). African American patients were also less likely to report satisfaction (OR 0.22; P = .043) while Native Hawaiian and Pacific Islanders were over 3 times more likely to be satisfied (OR 3.6; P = .013). Additionally, Medicare patients and those who were seen at community satellite clinics compared to the main University Hospital had increased odds of achieving satisfactory care (OR 1.3; P = .005 and OR 1.3; P = .002, respectively). Wait time, clinic location, patient race, insurance provider, and age were all shown to significantly influence patient-reported satisfaction. Understanding how these variables influence patient satisfaction will hopefully lead to processes that improve patient satisfaction. Level 3.


Association between alcohol intake and measures of incident CKD: An analysis of nationwide health screening data.
To evaluate the association between alcohol intake and incident chronic kidney disease measures as well as the sex differences in this association, we analyzed health screening data of 14,190,878 adults who underwent health screening ≥3 times and had glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and normal proteinuria at baseline. eGFR was calculated with the Chronic Kidney Disease Epidemiology Collaboration equation. Proteinuria was defined as ≥1+ dipstick proteinuria and low eGFR as <60 mL/min/1.73 m2. The risk of incident proteinuria and low eGFR was analyzed with an extended Cox model with alcohol intake level as a time-varying determinant and the annual change of eGFR with generalized linear model. A J-shape association of alcohol intake with the incident proteinuria was observed in men (adjusted hazard ratio [aHR], 0.961, 95% confidence interval [CI], 0.953-0.970 in men drinking alcohol <10 g/day; aHR 1.139, 95% CI, 1.123-1.154 in men drinking alcohol ≥40 g/day, compared with non-drinking men), and a positive association was seen in women (aHR, 1.034, 95% CI, 1.023-1.044 in women drinking alcohol <10 g/day; aHR, 1.094, 95% CI, 1.034-1.158 in women drinking alcohol ≥40 g/day, compared with non-drinking women). In both sexes, an inverse association of alcohol intake with the annual eGFR decline and incident low eGFR was observed. This study observed a beneficial effect of moderate alcohol intake on incident proteinuria in men and a protective effect of alcohol intake of any amount on the annual eGFR decline and incident low eGFR in both sexes. The long-term implications of these observations need to be elucidated with future studies.


Identification of methylation profile of HOX genes in extrahepatic cholangiocarcinoma.
To identify methylation profile and novel tumor marker of extrahepatic cholangiocarcinoma (CCA) with high throughout microarray. Differential methylation profile was compared between normal bile duct epithelial cell lines and CCA cell lines by methyl-DNA immunoprecipitation (MeDIP) microarray. Bisulfite-polymerase chain reaction (BSP) was performed to identify the methylated allels of target genes. Expression of target genes was investigated before and after the treatment with DNA demethylating agent. Expression of candidate genes was also evaluated by immunofluorescence in 30 specimens of CCA tissues and 9 normal bile duct tissues. Methylation profile of CCA was identified with MeDIP microarray in the respects of different gene functions and signaling pathways. Interestingly, 97 genes with hypermethylated CpG islands in the promoter region were homeobox genes. The top 5 hypermethylated homeobox genes validated by BSP were HOXA2 (94.29%), HOXA5 (95.38%), HOXA11 (91.67%), HOXB4 (90.56%) and HOXD13 (94.38%). Expression of these genes was reactivated with 5'-aza-2'-deoxycytidine. Significant expression differences were found between normal bile duct and extrahepatic CCA tissues (66.67%-100% vs 3.33%-10%). HOXA2, HOXA5, HOXA11, HOXB4 and HOXD13 may work as differential epigenetic biomarkers between malignant and benign biliary tissues.


Effects of low animal protein or high-fiber diets on urine composition in calcium nephrolithiasis.
The purpose of this article is to evaluate the impact of low protein and high fiber intakes on risk factors of stone recurrence in idiopathic calcium stone formers (ICSFs). Ninety-six ICSFs were randomly assigned a low animal protein diet (< 10% of total energy), a high-fiber diet (> 25 g/day), or a usual diet (control group); all patients were recommended to increase their fluid intake. Their daily urine compositions were analyzed at baseline and at four months. Compliance with dietary recommendations was checked by validated food frequency questionnaires. Compliance with total and animal protein intakes was assessed by 24-hour urea and sulfate outputs, respectively. The nutritional intervention (oral instructions, written leaflet, phoning) and food assessment were carried out by a research dietitian. At baseline, diets and the daily urine composition did not differ between the three groups. At four months, while diets differed significantly, the 24-hour output of calcium and oxalate did not differ significantly within and between groups after adjustment for potential confounders (age, sex, and personal and family history of calcium stones) and baseline values. However, as many as 12 out of 31 ICSFs (95% CI, 22 to 58%) assigned to a low animal protein diet achieved a reduction in the urine urea excretion rate of more than 50 mmol/day and also exhibited a significant decrease in urinary calcium excretion that averaged 1.8 mmol/day. A significant correlation between urea and calcium outputs was observed only among patients with hypercalciuria. These results show that only ICSFs who markedly decrease their animal protein intake, especially those with hypercalciuria, can expect to benefit from dietary recommendations.


Platelets and protease-activated receptor-4 contribute to acetaminophen-induced liver injury in mice.
Acetaminophen (APAP)-induced liver injury in humans is associated with robust coagulation cascade activation and thrombocytopenia. However, it is not known whether coagulation-driven platelet activation participates in APAP hepatotoxicity. Here, we found that APAP overdose in mice caused liver damage accompanied by significant thrombocytopenia and accumulation of platelets in the liver. These changes were attenuated by administration of the direct thrombin inhibitor lepirudin. Platelet depletion with an anti-CD41 antibody also significantly reduced APAP-mediated liver injury and thrombin generation, indicated by the concentration of thrombin-antithrombin (TAT) complexes in plasma. Compared with APAP-treated wild-type mice, biomarkers of hepatocellular and endothelial damage, plasma TAT concentration, and hepatic platelet accumulation were reduced in mice lacking protease-activated receptor (PAR)-4, which mediates thrombin signaling in mouse platelets. However, selective hematopoietic cell PAR-4 deficiency did not affect APAP-induced liver injury or plasma TAT levels. These results suggest that interconnections between coagulation and hepatic platelet accumulation promote APAP-induced liver injury, independent of platelet PAR-4 signaling. Moreover, the results highlight a potential contribution of nonhematopoietic cell PAR-4 signaling to APAP hepatotoxicity.


Examining Health Care Mobility of Transgender Veterans Across the Veterans Health Administration.
Purpose: Transgender veterans are overrepresented in the Veterans Health Administration (VHA) compared with in the general population. Utilization of multiple different health care systems, or health care mobility, can affect care coordination and potentially affect outcomes, either positively or negatively. This study examines whether transgender veterans are more or less health care mobile than nontransgender veterans and compares the patterns of geographic mobility in these groups. Methods: Using an established cohort (n = 5,414,109), we identified 2890 transgender veterans from VHA electronic health records from 2000 to 2012. We compared transgender and nontransgender veterans on sociodemographic, clinical, and health care system-level measures and conducted conditional logistic regression models of mobility. Results: Transgender veterans were more likely to be younger, White, homeless, have depressive disorders, post-traumatic stress disorder (PTSD), and hepatitis C. Transgender veterans were more likely to have been health care mobile (9.9%) than nontransgender veterans (5.2%) (unadjusted odds ratio = 2.02, 95% confidence interval = 1.73-2.36). In a multivariable model, transgender status, being separated/divorced, receiving care in less-complex facilities, and diagnoses of depression, PTSD, or hepatitis C were associated with more mobility, whereas older age was associated with less mobility. For the top three health care systems utilized, a larger proportion of transgender veterans visited a second health care system in a different state (56.2%) than nontransgender veterans (37.5%). Conclusions: Transgender veterans were more likely to be health care mobile and more likely to travel out of state for health care services. They were also more likely to have complex chronic health conditions that require multidisciplinary care.


Fluorescent PNA probes as hybridization labels for biological RNA.
Fluorescent labeling of biological RNA is complicated by the narrow range of nucleoside triphosphates that can be used for biological synthesis (i.e., transcription) as well as the inability to site-specifically incorporate them into long RNA transcripts. Noncovalent strategies for labeling RNA rely on attaching fluorescent dyes to hybridization probes which deliver the dye to a specific region of the RNA through Watson-Crick base pairing. This report demonstrates the use of high-affinity peptide nucleic acid (PNA) probes in labeling mRNA transcripts with thiazole orange donor and Alexa-594 acceptor fluorophores. The PNA probes were targeted to sequences flanking splice sites in a pre-mRNA such that before splicing the PNAs were separated by >300 nucleotides (nts) whereas after splicing the separation decreased to <or=12 nts. The decreased separation led to enhanced Förster resonance energy transfer (FRET) for the spliced RNA. Bulk solution and single-molecule fluorescence experiments gave consistent results.


Six-dimensional and seven-dimensional quantum dynamics study of the OH + CH4 → H2O + CH3 reaction.
The reaction dynamics of hydroxyl radical with methane has been investigated using time-dependent wave packet approach within reduced six- and seven-dimensional models. Initial state-selected total reaction probabilities and integral cross sections for the hydrogen abstraction reaction have been computed on the empirical potential energy surface developed by Espinosa-García et al. [J. Chem. Phys. 112, 5731 (2000)]. Excitations of the CH stretching mode and/or the CH3 umbrella mode enhance the reaction. They are, however, both less efficient than translational energy in promoting the reaction, at least at low collision energies. Also, we studied the accuracy of two approximations: centrifugal sudden (CS) and J-shifting (JS), in the calculations of the integral cross sections by a comparison to coupled-channel (CC) calculations. The integral cross sections obtained indicated that the CS approximation works well over the whole energy range studied, and the JS approximation gives accurate cross sections at low collision energies, while noticeably overestimates them at relatively high collision energies. In addition, the OH radical acts as a good spectator as it has a negligible effect on the reaction.


Experiencing discrimination mediates the relationship between victimization and social withdrawal in patients suffering from a severe mental illness: A cross-sectional study.
Psychiatric patients are often victims of crime and discrimination and are often socially withdrawn. This has negative consequences for their health and recovery. We examined whether such discrimination mediates the association between victimization and social withdrawal, and whether these associations differ between men and women. We also determined the prevalence of social withdrawal and the discrimination experienced by patients suffering from a severe mental illness. This study is embedded in the Victimization in Psychiatric Patients study. Information on discrimination, social withdrawal and victimization was obtained using structured self-report questionnaires (N = 949). We reported the 12-month prevalence of these phenomena and used path analysis to estimate the direct path between personal and property victimization and social withdrawal, and the indirect path through the discrimination experienced. The impact of gender was assessed by testing interaction terms. Social withdrawal was reported by 20.6% (95%CI 18.1-23.2) of participants, and being discriminated against in the past 12 months by 75.3% (95%CI: 72.6-78.0%). While crime victimization had no direct effects on social withdrawal, personal crime victimization (B = 0.47; 95%CI 0.25-0.72; p < 0.001) and property crime victimization (B = 0.65; 95%CI 0.42-0.93; p < 0.001) had significant indirect effects on social withdrawal, which were mediated by the discrimination experienced. In men we found a direct negative effect of property crime on social withdrawal (B = -0.68; 95%CI: -1.21to -0.11, p = 0.014). We conclude that personal and property victimization, for both men and women, was associated with higher levels of social withdrawal, and this was fully mediated by the discrimination experienced.


Beware of your Cre-Ation: lacZ expression impairs neuronal integrity and hippocampus-dependent memory.
Expression of the lacZ-sequence is a widely used reporter-tool to assess the transgenic and/or transfection efficacy of a target gene in mice. Once activated, lacZ is permanently expressed. However, protein accumulation is one of the hallmarks of neurodegenerative diseases. Furthermore, the protein product of the bacterial lacZ gene is ß-galactosidase, an analog to the mammalian senescence-associated ß-galactosidase, a molecular marker for aging. Therefore we studied the behavioral, structural and molecular consequences of lacZ expression in distinct neuronal sub-populations. lacZ expression in cortical glutamatergic neurons resulted in severe impairments in hippocampus-dependent memory accompanied by marked structural alterations throughout the CNS. In contrast, GFP expression or the expression of the ChR2/YFP fusion product in the same cell populations did not result in either cognitive or structural deficits. GABAergic lacZ expression caused significantly decreased hyper-arousal and mild cognitive deficits. Attenuated structural and behavioral consequences of lacZ expression could also be induced in adulthood, and lacZ transfection in neuronal cell cultures significantly decreased their viability. Our findings provide a strong caveat against the use of lacZ reporter mice for phenotyping studies and point to a particular sensitivity of the hippocampus formation to detrimental consequences of lacZ expression. © 2016 Wiley Periodicals, Inc.


Characterization of the interaction of cryptophycin 1 with tubulin: binding in the Vinca domain, competitive inhibition of dolastatin 10 binding, and an unusual aggregation reaction.
The antimitotic depsipeptide cryptophycin 1 (CP1) was compared to the antimitotic peptide dolastatin 10 (D10) as an antiproliferative agent and in its interactions with purified tubulin. The potent activity of CP1 as an inhibitor of cell growth was confirmed. The agent had an IC50 of 20 pM against L1210 murine leukemia cells versus 0.5 nM for D10. Both drugs were comparable as inhibitors of the glutamate-induced assembly of purified tubulin, with D10 being slightly more potent. CP1, like D10, was a noncompetitive inhibitor of the binding of [3H]vinblastine to tubulin (apparent Ki, 3.9 microM); and the depsipeptide was a competitive inhibitor of the binding of [3H]D10 to tubulin (apparent Ki, 2.1 microM). CP1 was less potent than D10 as an inhibitor of nucleotide exchange on tubulin, but the two drugs were equivalent in stabilizing the colchicine binding activity of tubulin. CP1, like D10, caused the formation of extensive structured aggregates of tubulin when present in stoichiometric amounts relative to the protein. Whereas at lower concentrations the drugs were equivalent in causing formation of small oligomers detected by gel permeation high-performance liquid chromatography, there were notable differences in the aggregation reactions induced by the two drugs. The electron micrographic appearance of the D10-induced aggregate differed substantially from that of the CP1-induced aggregate. With D10, but not CP1, aggregate morphology was greatly altered in the presence of microtubule-associated proteins. Finally, although CP1 caused the formation of massive aggregates, as did D10, there was little turbidity change with the depsipeptide as opposed to the peptide.


Fluoxetine and norfluoxetine plasma concentrations during relapse-prevention treatment.
Virtually no attention has been given to the relationship between antidepressant plasma drug concentrations and relapse-prevention during maintenance therapy. The purpose of this study was to investigate the relationship between steady-state plasma drug concentrations and outcome during relapse-prevention therapy with fluoxetine. The patients studied had responded to acute fluoxetine treatment for major depression (defined by DSM-III-R). Patients who met criteria for remission after 10-12 weeks of open-label acute fluoxetine therapy (N=395 of 839 patients), were randomly assigned to one of four treatment arms (50 weeks of fluoxetine, 38 weeks of fluoxetine followed by 12 weeks of placebo, 14 weeks of fluoxetine followed by 36 weeks of placebo and 50 weeks of placebo). Plasma fluoxetine and norfluoxetine concentrations were measured (1) after 4 and 8 weeks of open-label treatment and (2) at the beginning and after 14 weeks of double-blind, relapse-prevention therapy. Mean drug plasma levels were stable throughout the study. There was no significant difference in steady state plasma levels for the patients who relapsed compared to those who completed fluoxetine therapy without relapsing after 14, 38 or 50 weeks of fluoxetine relapse-prevention treatment. In addition, time-to-relapse was not related to steady-state drug plasma levels. Finally, after dividing patients into two groups based on their drug plasma levels, no significant differences were seen in the cumulative proportions of patients staying well during relapse-prevention therapy. Plasma concentrations of fluoxetine and/or its metabolite norfluoxetine, are not correlated with relapse in patients treated with a fixed dose of 20 mg/day fluoxetine. Fluoxetine plasma levels cannot be used to guide relapse-prevention treatment.


Ethyl 4-(9H-carbazol-9-yl)benzoate: fivefold superstructure with ten crystallographically independent molecules refined from a twinned crystal.
The photophysical properties of organic fluorophores are sensitive to the local sterics of the surrounding environment. Restriction of torsional motion in aggregates and crystals can give rise to enhanced emissive behavior. N-Aryl-substituted carbazoles serve an essential role as ubiquitous host matrices for organic light-emitting diodes, due to their large band gaps and high triplet energies, and so studies connecting photophysical behaviors with detailed crystallographic structural information are important. To elucidate the structural changes involved in the excited-state charge-transfer processes of N-aryl-substituted carbazoles with ester withdrawing groups, ethyl 4-(9H-carbazol-9-yl) benzoate, C21H17NO2, was synthesized. The compound crystallizes with ten independent molecules in the asymmetric unit that pack together through moderate C-H...π interactions between carbazole units (2.5-2.9 Å) and π-stacks of benzoate groups (3.8-3.9 Å) between neighboring molecules. Four of the ten independent molecules show disorder by rotation of the ethyl carboxylate groups, with major occupancy rates between 0.931 (3) and 0.840 (3). The attached benzoate groups are also disordered, with identical occupancies, to compensate for the altered steric profile of the misaligned ethyl ester groups. For two molecules, the disorder extends to the entire carbazole units as well. Torsion angles between the nonplanar carbazole and benzoate groups range from θ = 44.8 to 57.2°, while those between the benzoate planes and the carboxylate COO atoms vary from α = 6.4 to 15.7°. The crystal is twinned by pseudomerohedry. The superstructure can be reduced to a hypothetical averaged parent structure in the space group Pbcn with Z' = 1, displaying fourfold disorder. Variable-temperature data collection shows that there is no phase transition between the disordered supercell and the hypothetical parent structure; supercell reflections persist up to 350 K. We propose that the disorder and variation in torsion angles result from frustrated close-packing and necessitate a unit cell with a high Z' number.


Limited Clinical Significance of Splenectomy and Splenic Hilar Lymph Node Dissection for Type 4 Gastric Cancer.
Type 4 gastric cancer (GC) has a very poor prognosis even after curative resection, and the survival benefit of splenectomy for splenic hilar lymph node (LN; #10) dissection in type 4 GC remains equivocal. This study aimed to clarify the clinical significance of splenectomy for #10 dissection in patients with type 4 GC. The data of a total of 56 patients with type 4 GC who underwent total gastrectomy with splenectomy were retrospectively analyzed. Postoperative morbidity, state of LN metastasis, survival outcomes, and therapeutic value index (TVI) of each LN station were evaluated. TVI was calculated by multiplying the incidence of LN metastasis at each nodal station and the 5-year overall survival (OS) of patients who had metastasis to each node. Overall, the postoperative morbidity rate was 28.6%, and the incidence of #10 metastasis in the patients was 28.6%. The 5-year OS rate for all patients was 29.9%, and most patients developed peritoneal recurrence. Moreover, the 5-year OS rates with and without #10 metastasis were 6.7% and 39.1% (median survival time, 20.4 vs. 46.0 months; P=0.006). The TVI of #10 was as low as 1.92. The clinical significance of splenectomy in the dissection of #10 for type 4 GC is limited and splenectomy for splenic hilar dissection alone should be omitted.


Dynamics Combined With Hill Model for Functional Electrical Stimulation Ankle Angle Prediction.
Musculoskeletal models play an essential role in ankle rehabilitation research. The majority of the existing models have established the relationship between EMG and joint torque. However, EMG signal acquisition requires higher clinical conditions, such as sensitivity to external circumstances, motion artifacts and electrode position. To solve the nonlinear and time-varying nature of joint movement, a Functional Electrical Stimulation (FES) model was proposed in this study to simulate the whole process of ankle dorsiflexion. The model is combined with muscle contraction dynamics based on Hill model and ankle inverse dynamics to connect FES parameters, torques, and ankle angles. In addition, the extended Kalman filter (EKF) algorithm was applied to identify the unknown parameters of the model. Model validation experiment was performed by acquiring the actual data of healthy volunteers. Results showed that the root mean square error (RMSE) and normalized root mean square error (NRMSE) of this model were 11.93%±0.53% and 1.39°±0.26°, respectively, which means it can effectively predict the output variation of ankle joint angle while changing electrical stimulation parameters. Therefore, the proposed mode is essential for developing closed-loop feedback control of electrical stimulation and has the potential to help patients to conduct rehabilitation training.


Comparison of intracranial pressure prediction in hydrocephalus patients among linear, non-linear, and machine learning regression models in Thailand.
Hydrocephalus (HCP) is one of the most significant concerns in neurosurgical patients because it can cause increased intracranial pressure (ICP), resulting in mortality and morbidity. To date, machine learning (ML) has been helpful in predicting continuous outcomes. The primary objective of the present study was to identify the factors correlated with ICP, while the secondary objective was to compare the predictive performances among linear, non-linear, and ML regression models for ICP prediction. A total of 412 patients with various types of HCP who had undergone ventriculostomy was retrospectively included in the present study, and intraoperative ICP was recorded following ventricular catheter insertion. Several clinical factors and imaging parameters were analyzed for the relationship with ICP by linear correlation. The predictive performance of ICP was compared among linear, non-linear, and ML regression models. Optic nerve sheath diameter (ONSD) had a moderately positive correlation with ICP (r=0.530, P<0.001), while several ventricular indexes were not statistically significant in correlation with ICP. For prediction of ICP, random forest (RF) and extreme gradient boosting (XGBoost) algorithms had low mean absolute error and root mean square error values and high R2 values compared to linear and non-linear regression when the predictive model included ONSD and ventricular indexes. The XGBoost and RF algorithms are advantageous for predicting preoperative ICP and establishing prognoses for HCP patients. Furthermore, ML-based prediction could be used as a non-invasive method.


Metal-catalyzed asymmetric conjugate addition reaction: formation of quaternary stereocenters.
All-carbon quaternary stereocenters are ubiquitous motifs in biological products and pharmaceutical agents. However, due to sterical reasons, these centers are not always easily accessible. The metal-catalyzed conjugate addition reaction to trisubstituted conjugated substrates presents a viable methodology to create quaternary centers. In this article, different ways of activating the conjugate system towards nucleophilic addition will be described. An overview will be given on the different types of quaternary centers that are accessible through the conjugate addition reaction.


Non-genetic inheritance via the male germline in mammals.
Numerous studies in humans and in animal models have demonstrated that exposure to adverse environmental conditions in early life results in long-term structural and functional changes in an organism, increasing the risk of cardiometabolic, neurobehavioural and reproductive disorders in later life. Such effects are not limited to the first generation offspring but may be transmitted to a second or a number of subsequent generations, through non-genomic mechanisms. While the transmission of 'programmed' effects through the maternal line could occur as a consequence of multiple influences, for example, altered maternal physiology, the inheritance of effects through the male line is more difficult to explain and there is much interest in a potential role for transgenerational epigenetic inheritance. In this review, we will discuss the mechanisms by which induced effects may be transmitted through the paternal lineage, with a particular focus on the role of epigenetic inheritance. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.


Intra-Helical Salt Bridge Contribution to Membrane Protein Insertion.
Salt bridges between negatively (D, E) and positively charged (K, R, H) amino acids play an important role in protein stabilization. This has a more prevalent effect in membrane proteins where polar amino acids are exposed to a hydrophobic environment. In transmembrane (TM) helices the presence of charged residues can hinder the insertion of the helices into the membrane. It is possible that the formation of salt bridges could decrease the cost of membrane integration. However, the presence of intra-helical salt bridges in TM domains and their effect on insertion has not been properly studied yet. In this work, we show that potentially salt-bridge forming pairs are statistically over-represented in TM-helices. We then selected some candidates to experimentally determine the contribution of these electrostatic interactions to the translocon-assisted membrane insertion process. Using both in vitro and whole cell systems, we confirm the presence of intra-helical salt bridges in TM segments during biogenesis and determined that they contribute ∼0.5 kcal/mol to the apparent free energy of membrane insertion (ΔGapp). Our observations suggest that salt bridge interactions can be stabilized during translocon-mediated insertion and thus could be relevant to consider for the future development of membrane protein prediction software.


Placement effects of inertial measurement units on contact identification in wheelchair racing.
Inertial measurement units (IMUs) provide a practical solution for attaining key performance data for wheelchair sports. The effects of IMU placement position on the identification of propulsion characteristics are unknown. The aim of this study was to determine the variability in the reliability of cycle time measurements (time between hand contacts) across IMU locations on the chair frame (axle housings), and wheels (axle, push rim, outer rim), on both the left and right sides (n = 8). Contacts were defined by spikes in the resultant acceleration data, corresponding to impact between the hands and push rim, and verified against motion capture. Five elite wheelchair racing athletes propelled at racing speeds on a treadmill. Excellent inter-rater Intraclass Correlation Coefficient values indicated high reliability and repeatability for both motion capture and IMU signal analysis approaches (R = 0.997, p < 0.001 and R = 0.990, p < 0.001, respectively). The best results were (as determined by the best between method agreement) were observed for IMUs located on the frame. Detection reliability was positively associated with signal-to-noise ratio of the acceleration data. The IMU assessment approach facilitates an automated processing capability, which is an improvement to the currently used video analysis.


Ab initio simulations of water splitting on hematite.
In recent years, hematite has attracted great interest as a photocatalyst for water splitting, but many questions remain unanswered about the mechanisms and the main limiting factors. For this reason, density functional theory has been used to understand the optical, electronic and chemical properties of this material at an atomistic level. Bulk doping can be used to reduce the band gap, and to increase photoabsorption and charge mobility. Charge transport takes place through adiabatic polaron hopping. The stable (0 0 0 1) surface has a stoichiometric termination when exposed to oxygen, it becomes hydroxylated in water, and it has an oxygen-rich termination under illumination in a photoelectrochemical setup. On the oxygen-rich termination, surface states are present that might act as recombination centres for electrons and holes. On the contrary, on the hydroxylated termination surface states appear only on reaction intermediates. The intrinsic surface states disappear in the presence of an overlayer of gallium oxide. The reaction of water oxidation is assumed to proceed by four proton-coupled electron transfers and it is shown to involve a nucleophilic attack with the formation of an OOH group. Calculated overpotentials are in the range of 0.5-0.6 V. Open questions and future research directions are briefly discussed.


Hyaluronic acid and chondroitin sulfate unsaturated disaccharides analysis by high-performance liquid chromatography and fluorimetric detection with dansylhydrazine.
A system capable of resolving all the known unsaturated nonsulfated, mono- and disulfated disaccharides derived from chondroitin sulfate samples, dermatan sulfate, and hyaluronic acid after their derivatization with dansylhydrazine and separation by HPLC and fluorimetric detection is reported. This method was found superior to others in that unsaturated disaccharides can be separated with good resolution in about 50 min in an isocratic solvent with a sensitivity greater than about 50 pmol (approx 20-30 ng) and linearity from 50 to 500 pmol. The system was applied to the analysis of various chondroitin sulfate samples, including highly sulfated species and dermatan sulfate, and also to a defructosylated polysaccharide with a chondroitin backbone purified from Escherichia coli U1-41. Excellent agreement was obtained with traditional compositional analysis performed by anion-exchange HPLC separation and UV absorption at 230 nm.


Effect of iRoot Fast Set root repair material on the proliferation, migration and differentiation of human dental pulp stem cells in vitro.
The present study investigated the effect of iRoot Fast Set root repair material (iRoot FS) on the proliferation, migration and differentiation of human dental pulp stem cells (hDPSCs). The hDPSCs were treated with eluates of iRoot FS at concentrations of 0.2 and 2 mg/mL, referred to as FS0.2 and FS2, respectively, and Biodentine (BD; Septodont, Saint Maur des Faussés, France) eluates at the corresponding concentrations as positive controls. A CCK8 assay was performed to determine cell proliferation. Wound healing and transwell assays were conducted to examine cell migration. Osteogenic differentiation was evaluated based on alkaline phosphatase activity, Alizarin Red S staining and quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) to analyze the mRNA expression of differentiation gene markers. Cell proliferation was higher in the FS and BD groups than in the blank controls at 3 and 7 days. Moreover, FS0.2 enhanced cell migration and significantly promoted the osteogenic differentiation of hDPSCs. These findings suggested that iRoot FS is a bioactive material that promotes the proliferation, migration and osteogenic differentiation of hDPSCs.


Portal vein reconstruction with interposition of cryopreserved aortic graft: A case report and literature review.
Pancreatic cancer is one of the most aggressive malignancies with poor rates of survival especially in the event radical procedures are not feasible. However, improvements in surgical techniques have led to the successful association of vascular resection followed by reconstruction without a significant increase in the rates of postoperative complications. In the present article, we present the case of a 49-year-old patient diagnosed with pancreatic head cancer invading the portal vein. After discussing with the patient the risks and the benefits of the surgical procedure, the patient was submitted to pancreatoduodenectomy en bloc with portal vein resection while the continuity of the portal vein was reestablished by using a cadaveric graft originating from the abdominal aorta. The postoperative outcome was uneventful. In conclusion, in selected cases, arterial cadaveric grafts may be used in order to establish the continuity of the portal vein with good results. However, it should be emphasized that these are demanding procedures which should be carefully analyzed before deciding upon the opportunity for performing them.


The effect of cardiac rehabilitation at 4 weeks postoperatively on quality of life in patients treated with totally thoracoscopic ablation.
There is a lack of evidence on the effect of exercise-based cardiac rehabilitation (EBCR) in patients treated with total thoracoscopic ablation (TTA) for atrial fibrillation (AF). Our study investigated the efficacy and safety of postoperative exercise intervention in patients recovering from TTA. Twenty-four patients participated in the study, and were divided into the two groups, exercise group (EG) (n=12) and control group (n= 12). Patients in EG performed the exercise intervention including the aerobic and resistance exercise program twice a week for 8 weeks, which was used as a hospital-based cardiac rehabilitation for the out-patient. A cardiopulmonary exercise test was administered to evaluate aerobic exercise capacity, and qualitative aspect of patient's life was assessed using the Short Form 36 questionnaires to compare pre and postoperative wellness of patient's life. Although there was an increase of VO2peak (peak oxygen uptake) after exercise intervention, no significant improvement was found (P=0.055). Two of 4 physical health scores (role-physical, P=0.013 and general health, P=0.05) and three of four mental health scores (vitality, P=0.027, social function, P=0.016, and mental health, P=0.003) were significantly improved after 8 weeks of EBCR. Each summarized scale in the physical (P=0.022) and mental (P= 0.004) survey section was also significantly improved in postoperative assessment compared to the preoperative one. In this context, we concluded that EBCR initiated at the time point of 4th week after TTA operation can guarantee the secure postoperative physical activity, and the 8 weeks of EBCR can effectively improve the quality of life in AF Patients.


Graphene-multilayer graphene nanocomposites as highly efficient thermal interface materials.
We found that the optimized mixture of graphene and multilayer graphene, produced by the high-yield inexpensive liquid-phase-exfoliation technique, can lead to an extremely strong enhancement of the cross-plane thermal conductivity K of the composite. The "laser flash" measurements revealed a record-high enhancement of K by 2300% in the graphene-based polymer at the filler loading fraction f = 10 vol %. It was determined that the relatively high concentration of the single-layer and bilayer graphene flakes (~10-15%) present simultaneously with the thicker multilayers of large lateral size (~1 μm) were essential for the observed unusual K enhancement. The thermal conductivity of the commercial thermal grease was increased from an initial value of ~5.8 W/mK to K = 14 W/mK at the small loading f = 2%, which preserved all mechanical properties of the hybrid. Our modeling results suggest that graphene-multilayer graphene nanocomposite used as the thermal interface material outperforms those with carbon nanotubes or metal nanoparticles owing to graphene's aspect ratio and lower Kapitza resistance at the graphene-matrix interface.


Knowledge and practices of obtaining informed consent for medical procedures among specialist physicians: questionnaire study in 6 Croatian hospitals.
AIM. To assess physicians' knowledge and practices for obtaining patients' informed consent to medical procedures. METHODS. An anonymous and voluntary survey of knowledge and practices for obtaining informed consent was conducted among 470 physicians (63% response rate) working in 6 hospitals: 93 specialists in anesthesiology, 166 in internal medicine, and 211 in surgery. RESULTS. Only 54% physicians were acquainted with the fact that the procedure for obtaining consent was regulated by the law. Internists and surgeons were better informed than anesthesiologists (P=0.024). More than a half of respondents (66%) were familiar with the fact that a law on patient rights was passed in Croatia; there were no differences among different specialties (P=0.638). Only 38% of the physicians were fully informed about the procedure of obtaining consent. Internists and surgeons provided detailed information to the patient in 33% of the cases and anesthesiologists in 16% of the cases (P<0.050). Internists reported spending more time on informing the patient than anesthesiologists and surgeons (P<0.001). There were no differences in knowledge and practices for obtaining informed consent between physicians working in university and those working in community hospitals (P> or =0.05 for all questions). CONCLUSION. Physicians in Croatia have no formal education on informed consent and implement the informed consent process in a rather formal manner, regardless of the type of hospital or medical specialty. Systemic approach at education and training at the national level is needed to improve the informed consent process.


No impact of HIV-1 protease minority resistant variants on the virological response to a first-line PI-based regimen containing darunavir or atazanavir.
To evaluate, in a clinical cohort of HIV-1-infected patients, the prevalence of PI minority resistant variants (MRV) at ART baseline and their impact on the virological response to a first-line PI-based regimen. In an observational single-centre cohort, we assessed all ART-naive patients initiating a first-line regimen including two NRTI and one boosted PI, darunavir/ritonavir or atazanavir/ritonavir, between January 2012 and March 2015. Ultra-deep sequencing of the pol gene was performed using Illumina® technology. Protease mutations were identified using the WHO transmitted drug resistance list and major PI resistance mutations (IAS-USA drug resistance mutations list). Ninety-four and 16 patients initiating a darunavir/ritonavir-based regimen and an atazanavir/ritonavir-based regimen, respectively, were assessed. Twenty-eight percent of the patients were HIV-1 subtype B, 39% CRF02_AG and 33% other non-B subtypes. Thirteen patients (13.8%) in the darunavir group and three patients (18.8%) in the atazanavir group experienced a virological failure (VF). Overall, 13 (11.8%) subjects had PI MRV at baseline in the median proportion of 1.3% (IQR = 1.1-1.7). The most prevalent PI MRV were G73C (n = 5) and M46I (n = 3). The proportion of patients harbouring baseline PI MRV was similar between those with virological success (10.6%) and those experiencing VF (18.8%) (P = 0.40). No difference was observed in the rate of PI MRV by viral subtype (P = 0.51) or by PI drug (P = 0.40). This study showed a prevalence of 11.8% of PI MRV among 110 ART-naive subjects, without significant impact on the virological response to a first-line PI-based regimen containing darunavir or atazanavir.


Trainee and Faculty Perceptions of Remote PACS Workstations and Next Steps in a Large US Academic Medical Institution.
Remote workstations were rapidly deployed in our academic radiology practice in late March 2020 in response to the COVID-19 pandemic. Although well-received by faculty, there were concerns for the impact on resident education. Surveys of the radiology trainees and faculty were conducted online seven- and thirteen-months following workstation deployment as a part of a quality improvement project to assess the impact on radiology education and faculty wellness, as well as assess the desired trajectory of remote work in an academic setting. The majority of trainees (52%) reported the implementation had negatively impacted resident education, greatest among lower level residents (p < .001). This perception did not change despite interventions and perceived improvement in teleconferencing. Greater than 75% of radiologists with remote workstations reported improved wellness and lower stress levels compared to the onsite radiologists. The majority of all respondents voted to continue or expand remote work following the COVID-19 pandemic in both surveys. Onsite teaching is important for the education of residents, particularly for lower-level residents. However, the adoption of a hybrid model in an academic setting may prove beneficial for faculty wellness and recruitment of the next generation.


Strategies for empowering women's voices in the medical culture.
Power and knowledge are closely connected, and this is no less true for the medical profession than it is for any other sphere of life. Knowledge is constructed by voice. Unfortunately, women's voices are often silent in the factory where medical knowledge is produced. Medicalization and ignoring are symptoms of the medical oppression of women's voices. Empowerment of women's voices at various levels within the medical culture is essential for influence and social reconstruction. In this regard, a research project on alternative approaches to physician-patient communication as well as research methods is presented. Knowledge constructed from women's voices will be neglected by medical power unless it can hold up to systematic investigative procedures. Sensitive and sensible research from women's voices requires methodology that preserves women's messages and transforms them into medical knowledge. Such efforts may ultimately lead toward construction of a feminine medical epistemology--a medical knowledge that reflects women's reality.


Factors Associated With Neonatal Pneumonia and its Mortality in India: A Systematic Review and Meta-Analysis.
Neonatal pneumonia remains a significant contributor to infant mortality in India and responsible for increased prevalence of infant deaths globally. To identify risk factors associated with neonatal pneumonia and its mortality in India. A systematic review was conducted including both analytic study designs and descriptive study designs, which reported a quantitative analysis of factors associated with all the three types of pneumonia among neonates. The search was conducted from August to December, 2016 on the following databases; CINAHL, EMBASE, Ovid MEDLINE, PubMed, ProQuest, SCOPUS, Web of Science, WHO IMSEAR and IndMED. The search was restricted to Indian setting. The population of interest was neonates. The outcome measures included risk factors for incidences and mortality predictors of neonatal pneumonia. These could be related to neonate, maternal and pregnancy, caregiver, family, environment, healthcare system, iatrogenic and others. A total of three studies were included. For risk factors, two studies on ventilator-associated pneumonia were included with 194 neonates; whereas for mortality predictors, only one study with 150 neonates diagnosed with pneumonia was included. 11 risk factors were identified from two studies: duration of mechanical ventilation, postnatal age, birth weight, prematurity, sex of the neonate, length of stay in NICU, primary diagnosis, gestational age, number of re-intubation, birth asphyxia, and use of nasogastric tube. Meta-analysis with random-effects model was possible only for prematurity (<37 week) and very low birth weight (<1500 g) and very low birth weight was found to be significant (OR 5.61; 95% CI 1.76, 17.90). A single study was included on predictors of mortality. Mean alveolar arterial oxygen gradient (AaDO2) >250 mm Hg was found to be the single most significant predictor of mortality due to pneumonia in neonates. The study found scant evidence from India on risk factors of neonatal pneumonia other than ventilator-associated pneumonia.


Diagnosis and treatment of atherosclerotic renal artery stenosis (ARAS).
Atherosclerotic renal artery stenosis (ARAS) is an increasingly common cause of secondary hypertension and progressive chronic renal failure. Recent studies provide valuable information about the pathophysiology, natural history, diagnosis and treatment of ARAS. The pathophysiology of ARAS is more complex than experimental models using clipped renal arteries because the renal artery narrowing is gradual, may be bilateral, may affect smaller intra-renal arteries and other co-existing nephropathies are often present. Patients with ARAS have high mortality due to associated co-morbidity and progression of renal failure may be less common than previously thought. Magnetic resonance arteriography offers great promise for diagnosing of ARAS as it is non-invasive and can provide data on kidney function. In patients with ARAS, the co-existence of atherosclerotic disease in other vascular beds means that aspirin, blood pressure reduction, advice to stop smoking and lipid lowering therapy are likely to be associated with reduced vascular events. The effect of these approaches on the progression of ARAS is unclear but likely to be beneficial. Re-vascularisation of occluded renal arteries is an attractive option for treatment of ARAS but data from the few randomised controlled studies that have been published do not support its widespread application. Arterial stenting has a higher technical success rate than angioplasty while surgical revascularisation does not appear to improve outcome compared with angioplasty. Recent studies examining functional and histological features of kidneys supplied by atherosclerotic stenosed renal arteries may explain why revascularisation is not always beneficial. The results of on-going studies may identify sub-groups of patients with ARAS who gain a clear benefit from re-vascularisation. In the meantime it seems reasonable to attempt re-vascularisation in the following circumstances: severe hypertension resistant to medical therapy, rapidly progressive renal failure with no obvious cause other than ARAS and recurrent flash pulmonary oedema.


Anti-tuberculosis immunity induced in mice by vaccination with Mycobacterium smegmatis over-expressing Antigen 85B is due to the increased influx of IFNgamma-positive CD4 T cells into the lungs.
BCG vaccine is unsafe for use in patients with AIDS. Mycobacterium smegmatis (Msm), an avirulent species unlike virulent Mycobacterium tuberculosis (H37Rv, Mtb) has been used as a carrier vaccine with ambiguous results due to the elicitation of poor immune responses to antigens in mice. In this study, we over-expressed the immunodominant antigen 85B in M. smegmatis (Msm-OEAg85B) and compared the immunogenicity of Msm-OEAg85B with that of wild-type Msm. Mice which were vaccinated with either Msm or Msm-OEAg85B and challenged 2 weeks later with Mtb. Vaccine-induced protection and lung T cell responses were evaluated post vaccination and post challenge. Unlike wild-type Msm that elicited minimal T cell responses in mice, MsmOE-Ag85B induced enhanced CD4+IFNgamma+ T cell responses that leveled off over 2 weeks. After virulent challenge at 2 weeks, Mtb grew progressively in the lungs of naive mice and mice vaccinated with wild-type Msm, but showed reduced growth (<0.6 log(10)) and therefore protection in Msm-OEAg85B-vaccinated mice. Lungs of Msm-OEAg85B-vaccinated mice showed increased numbers of CD4+IFNgamma+ T cells suggesting that the reduced bacterial growth was likely due to the enhanced T cell response in lungs. Since wild-type Msm was unable to protect but Msm-OEAg85B was, we suggest that Msm can be genetically manipulated to over-express selected Mtb antigens, thereby paving the way for safer vaccines that can be used in immunodeficient patients.


A Semidian Rhythm in the Flowering Response of Pharbitis nil to Far-Red Light: II. The Involvement of Phytochrome.
The semidian ( approximately 12 h) periodicity in the effect of far-red (FR) interruptions of the light period preceding inductive darkness on flowering in Pharbitis nil appears to be mediated by phytochrome: (a) promotion by interruptions 2 hours before inductive darkness (-2 hours) and inhibition at -8 hours are greater the higher the proportion of FR/R+FR during the interruption; (b) brief FR exposures followed by darkness are even more effective than FR throughout; (c) the effect of brief FR is reversed by subsequent R; (d) R interruptions of an FR background are most promotive at -8 hours, when FR is most inhibitory. Promotive FR interruptions at -2 or -14 hours shorten the critical dark period whereas inhibitory FR interruptions at -8 hours lengthen it. We conclude that the semidian rhythm is controlled by a ;timing pool' of phytochrome FR absorbing form (Pfr) which disappears rapidly in darkness: four different estimates from our experiments indicate that Pfr was reduced to the level set by FR within 20 to 45 minutes in darkness. However, flowering may also be influenced by a ;metabolic pool' of Pfr with a delayed loss in darkness, the time of which can be advanced or retarded by shifting the semidian rhythm.


Formation of a normal epidermis supported by increased stability of keratins 5 and 14 in keratin 10 null mice.
The expression of distinct keratin pairs during epidermal differentiation is assumed to fulfill specific and essential cytoskeletal functions. This is supported by a great variety of genodermatoses exhibiting tissue fragility because of keratin mutations. Here, we show that the loss of K10, the most prominent epidermal protein, allowed the formation of a normal epidermis in neonatal mice without signs of fragility or wound-healing response. However, there were profound changes in the composition of suprabasal keratin filaments. K5/14 persisted suprabasally at elevated protein levels, whereas their mRNAs remained restricted to the basal keratinocytes. This indicated a novel mechanism regulating keratin turnover. Moreover, the amount of K1 was reduced. In the absence of its natural partner we observed the formation of a minor amount of novel K1/14/15 filaments as revealed by immunogold electron microscopy. We suggest that these changes maintained epidermal integrity. Furthermore, suprabasal keratinocytes contained larger keratohyalin granules similar to our previous K10T mice. A comparison of profilaggrin processing in K10T and K10(-/-) mice revealed an accumulation of filaggrin precursors in the former but not in the latter, suggesting a requirement of intact keratin filaments for the processing. The mild phenotype of K10(-/-) mice suggests that there is a considerable redundancy in the keratin gene family.


[In vivo antitumor effects of polyethylene glycol--modified recombinant human interleukin-2 on mouse uterine cervical carcinoma].
Polyethylene glycol (PEG-8000) -modified recombinant human interleukin-2 (PEG-rIL-2) is a cytokine with prolonged circulatory half-life. In this paper, the antitumor effects of PEG-rIL-2 against mouse uterine cervical carcinoma (U14) transplanted intraperitoneally or subcutaneously is reported. PEG-rIL-2 at different doses was administered intratumorally. The results showed that PEG-rIL-2 (4,500 IU, i.p., QD x 5) prolonged survival time of mice bearing ascites tumor as compared to rIL-2 (P < 0.01), but PEG-rIL-2 at lower doses was without therapeutic effect. In addition, compared to rIL-2, PEG-rIL-2 at different doses (1,500-13,500 IU, QD x 5) caused significant dose-dependent growth inhibition of solid tumor (P < 0.01) when the treatment started on lay 4 after subcutaneous inoculation of tumor.


Resinous perforation-repair materials inhibit the growth, attachment, and proliferation of human gingival fibroblasts.
The choice of repair material is one of the important factors in the prognosis of the endodontically treated tooth with a perforation defect. The cytotoxicity of perforation-repair materials must be investigated to ensure a safe biological response. The aim of this in vitro study was to evaluate the effect of resin-modified, glass-ionomer cement, compomer, and resin on human-gingival fibroblasts. Human gingival fibroblasts from crown lengthening surgery were cultured by using an explant technique with the consent of the patient. Cytotoxicity was judged by using an assay of tetrazolium bromide reduction. The results showed that resin-modified, glass-ionomer cement Fuji II LC, compomer Compoglass, and resin SpectrumTPH (TPH) were cytotoxic to primary human gingival fibroblast cultures by inhibiting cell growth and proliferation. TPH alone had an effect on cell attachment. It was found that TPH was the most cytotoxic repair material among those tested in all cultures. The toxicity decreased in the order of TPH>FLC>CG.


Tibiofibula Transposition in High-Energy Fractures.
We report two cases of failed attempts at closed reduction of high-energy tibial fractures with an associated fibula fracture. The first case was a 39-year-old male involved in high-speed motorbike collision, while the second was a 14-year-old male who injured his leg following a fall of three metres. Emergency medical services at the scenes of the accidents reported a 90-degree valgus deformity of the injured limb and both limbs were realigned on scene and stabilized. Adequate alignment of the tibia could not be achieved by manipulation under sedation or anaesthesia. Open reduction and exposure of the fracture sites revealed that the distal fibula fragment was "transposed" and entrapped in the medulla of the proximal tibial fragment. Reduction required simulation of the mechanism of injury in order to disengage the fragments and allow reduction. Tibiofibula transposition is a rare complication of high-energy lower limb fractures which has not previously been reported and may prevent adequate closed reduction. Impaction of the distal fibula within the tibial medulla occurs as the limb is realigned by paramedic staff before transfer to hospital. We recommend that when this complication is identified the patient is transferred to the operating room for open reduction and stabilization of the fracture.


Long-term follow-up of therapeutic efficacy of everolimus-eluting bioresorbable vascular scaffold in comparison to everolimus-eluting stent in treatment of chronic total occlusion guided by intracoronary imaging.
We hypothesized that 1st generation everolimus-eluting bioresorbable vascular scaffold (BVS) stent associated with less complication and less restenosis rate than everolimus-eluting stent (EES) in chronic total occlusion (CTO) recanalization guided by intracoronary imaging. Therefore, we aimed to assess the safety and performance of BVS stent in CTO revascularization in comparison to EES guided by intracoronary imaging. Our prospective comparative cross-sectional study was conducted on 60 CTO patients divided into two groups according to type of stent revascularization: group I (EES group): 40 (66.7%) patients and group II (BVS group): 20 (33.3%) patients. All patients were subjected to history taking, electrocardiogram (ECG), echocardiography, laboratory investigation, stress thallium study to assess viability before revascularization. Revascularization of viable CTO lesion guided by intracoronary imaging using optical coherence tomography (OCT). Then, long-term follow-up over 1 year clinically and by multi-slice CT coronary angiography (MSCT). Our clinical and angiographic endpoints were to detect any clinical or angiographic complications during the follow-up period. At 6 months angiographic follow-up, BVS group had not inferior angiographic parameters but without statistically significant difference (p = 0.566). At 12 months follow-up, there was no difference at end points between the two groups (p = 0.476). No differences were found at angiographic or clinical follow-up between BVS and EES. This study shows that 1st generation everolimus-eluting BVS is non-inferior to EES for CTO revascularization. Further studies are needed to clearly state which new smaller footprint BVS, faster reabsorption, magnesium-based less thrombogenicity, and advanced mechanical properties is under development. We cannot dismiss the efficacy and safety of new BVS technology. ZU-IRB#2498/3-12-2016 Registered 3 December 2016, email: firstname.lastname@example.com.


Caregiver experiences of racism and child healthcare utilisation: cross-sectional analysis from New Zealand.
Children's exposure to racism via caregiver experience (vicarious racism) is associated with poorer health and development. However, the relationship with child healthcare utilisation is unknown. We aimed to investigate (1) the prevalence of vicarious racism by child ethnicity; (2) the association between caregiver experiences of racism and child healthcare utilisation; and (3) the contribution of caregiver socioeconomic position and psychological distress to this association. Cross-sectional analysis of two instances of the New Zealand Health Survey (2006/2007: n=4535 child-primary caregiver dyads; 2011/2012: n=4420 dyads). Children's unmet need for healthcare, reporting no usual medical centre and caregiver-reported dissatisfaction with their child's medical centre. The prevalence of reporting 'any' experience of racism was higher among caregivers of indigenous Māori and Asian children (30.0% for both groups in 2006/2007) compared with European/Other children (14.4% in 2006/2007). Vicarious racism was independently associated with unmet need for child's healthcare (OR=2.30, 95% CI 1.65 to 3.20) and dissatisfaction with their child's medical centre (OR=2.00, 95% CI 1.26 to 3.16). Importantly, there was a dose-response relationship between the number of reported experiences of racism and child healthcare utilisation (eg, unmet need: 1 report of racism, OR=1.89, 95% CI 1.34 to 2.67; 2+ reports of racism, OR=3.06, 95% CI 1.27 to 7.37). Adjustment for caregiver psychological distress attenuated the association between caregiver experiences of racism and child healthcare utilisation. Vicarious racism is a serious health problem in New Zealand disproportionately affecting Māori and Asian children and significantly impacting children's healthcare utilisation. Tackling racism may be an important means of improving inequities in child healthcare utilisation.


Affective and cognitive decision-making in adolescents.
Adolescents demonstrate impaired decision-making in emotionally arousing situations, yet they appear to exhibit relatively mature decision-making skills in predominantly cognitive, low-arousal situations. In this study we compared adolescents' (13-15 years) performance on matched affective and cognitive decision-making tasks, in order to determine (1) their performance level on each task and (2) whether performance on the cognitive task was associated with performance on the affective task. Both tasks required a comparison of choice dimensions characterized by frequency of loss, amount of loss, and constant gain. Results indicated that in the affective task, adolescents performed sub-optimally by considering only the frequency of loss, whereas in the cognitive task adolescents used relatively mature decision rules by considering two or all three choice dimensions. Performance on the affective task was not related to performance on the cognitive task. These results are discussed in light of neural developmental trajectories observed in adolescence.


Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3.
The c-Jun NH(2)-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) is activated in response to the treatment of cells with inflammatory cytokines and by exposure to environmental stress. JNK activation is mediated by a protein kinase cascade composed of a MAPK kinase and a MAPK kinase kinase. Here we describe the molecular cloning of a putative molecular scaffold protein, JIP3, that binds the protein kinase components of a JNK signaling module and facilitates JNK activation in cultured cells. JIP3 is expressed in the brain and at lower levels in the heart and other tissues. Immunofluorescence analysis demonstrated that JIP3 was present in the cytoplasm and accumulated in the growth cones of developing neurites. JIP3 is a member of a novel class of putative MAPK scaffold proteins that may regulate signal transduction by the JNK pathway.


Preharvest Spray Hexanal Formulation Enhances Postharvest Quality in 'Honeycrisp' Apples by Regulating Phospholipase D and Calcium Sensor Proteins Genes.
'Honeycrisp' (Malus domestica Borkh.), a premium applecultivar, is highly susceptible to bitter pit and decline in quality during long-term storage. In order to enhance the quality, an aqueous composition containing hexanal was applied as a preharvest spray. The effects of hexanal were assessed on the treated fruit and compared with HarvistaTM (a sprayable 1-Methylcyclopropene based commercial formulation) applied and control fruit under both cold (2.5 °C; four months) and cold after room temperature storage (20 °C; 14 days) conditions. Color, firmness, and total soluble solids (TSS) did not show a significant change in response to any treatment at harvest, while abscisic acid (ABA) significantly reduced and tryptophan increased in response to hexanal, compared to HarvistaTM and control. The treatment effects on quality traits were observed during storage. Both hexanal and HarvistaTM sprayed apples had higher TSS under both cold and room temperature storage. In addition, both sprays enhanced firmness at room temperature storage. However, the effects of sprays on other quality traits showed a different pattern. Apples sprayed with hexanal had lower phospholipase D enzyme (PLD) activity, lower incidence of bitter pit, and decreased expression of MdPLDα1 compared to HarvistaTM and control. On the other hand, HarvistaTM treated fruit produced lower ethylene. Both sprays decreased the expression of MdPLDα4, MdCaM2, MdCaM4 and MdCML18 genes. Generally, PLD alpha has a direct role in promoting fruit senescence, whereas the calcium senor proteins (CaM/CMLs) may involve in fruit ripening process via calcium and ethylene interactions. Therefore, improved postharvest qualities, including the lower incidence of bitter pit in hexanal treated 'Honeycrisp', may be associated with lower membrane damage due to lower PLD enzyme activity and decreased expression of MdPLDα1 and MdPLDα4 genes throughout the storage period.


Synthesis and application of a new cleavable linker for "click"-based affinity chromatography.
A new chemically-cleavable linker has been synthesised for the affinity-independent elution of biomolecules by classical affinity chromatography. This azo-based linker is shown to couple efficiently with "click" derivatised ligands such as biotin propargyl amide through a copper(I)-catalysed Huisgen 1,3-dipolar cycloaddition reaction. Binding to Affi-Gel matrices displaying ligands coupled to the new linker is both efficient and selective. The captured material may be readily released from the resin upon treatment with sodium dithionite. These mild elution conditions have allowed for the efficient isolation of the affinity partner from complex protein mixtures such as those found in fetal bovine serum.


Proverb comprehension in youth: the role of concreteness and familiarity.
This study examined factors that were posited to play an important role in the development of proverb comprehension in school-age children and adolescents, namely, the concreteness and the familiarity of the expressions. Normally achieving students enrolled in Grades 5, 8, and 11 (n = 180) were administered a written forced-choice task that contained eight instances of four different types of proverbs: concrete-familiar ("A rolling stone gathers no moss"); concrete-unfamiliar ("A caged bird longs for the clouds"); abstract-familiar ("Two wrongs don't make a right"); and abstract-unfamiliar ("Of idleness comes no goodness"). Performance on the task steadily improved as a function of increasing grade level and, as predicted, the expressions proved to be differentially challenging: Concrete proverbs were easier to understand than abstract proverbs, and familiar proverbs were easier to understand than unfamiliar proverbs. The results concerning concreteness support the "metasemantic" hypothesis, the view that comprehension develops through active analysis of the words contained in proverbs. The results concerning familiarity support the "language experience" hypothesis, the view that comprehension develops through meaningful exposure to proverbs.


Elevated Hapln2 Expression Contributes to Protein Aggregation and Neurodegeneration in an Animal Model of Parkinson's Disease.
Parkinson's disease (PD), the second most common age-associated progressive neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SN). The pathogenesis of PD and the mechanisms underlying the degeneration of DA neurons are still not fully understood. Our previous quantitative proteomics study revealed that hyaluronan and proteoglycan binding link protein 2 (Hapln2) is one of differentially expressed proteins in the substantia nigra tissues from PD patients and healthy control subjects. However, the potential role of Hapln2 in PD pathogenesis remains elusive. In the present study, we characterized the expression pattern of Hapln2. In situ hybridization revealed that Hapln2 mRNA was widely expressed in adult rat brain with high abundance in the substantia nigra. Immunoblotting showed that expression levels of Hapln2 were markedly upregulated in the substantia nigra of either human subjects with Parkinson's disease compared with healthy control. Likewise, there were profound increases in Hapln2 expression in neurotoxin 6-hydroxydopamine-treated rat. Overexpression of Hapln2 in vitro increased vulnerability of MES23.5 cells, a dopaminergic cell line, to 6-hydroxydopamine. Moreover, Hapln2 overexpression led to the formation of cytoplasmic aggregates which were co-localized with ubiquitin and E3 ligases including Parkin, Gp78, and Hrd1 in vitro. Endogenous α-synuclein was also localized in Hapln2-containing aggregates and ablation of Hapln2 led to a marked decrease of α-synuclein in insoluble fraction compared with control. Thus, Hapln2 is identified as a novel factor contributing to neurodegeneration in PD. Our data provides new insights into the cellular mechanism underlying the pathogenesis in PD.


Roles of a tetrahydroborate ligand in a facile route to ruthenium(II) ethyl hydride complexes, and a kinetic study of ethane reductive elimination.
The tetrahydroborate ligand in [Ru(eta(2)-BH(4))(CO)H(PMe(2)Ph)(2)], 1, allows conversion under very mild conditions to [Ru(CO)(Et)H(PMe(2)Ph)(3)], 7, by way of [Ru(eta(2)-BH(4))(CO)Et(PMe(2)Ph)(2)], 4. Deprotection of the hydride ligand in 7(by BH(3) abstraction) occurs only in the final step, thus preventing premature ethane elimination. A deviation from the route from 4 to 7 yields [Ru(eta(2)-BH(4))(COEt)(PMe(2)Ph)(3)], 6, but does not prevent ultimate conversion to 7. Modification of the treatment of 4 yields an isomer of 7, 10. Both isomers eliminate ethane at temperatures above 250 K: the immediate product of elimination, thought to be [Ru(CO)(PMe(2)Ph)(3)], 11, can be trapped as [Ru(CO)(PMe(2)Ph)(4)], 12, [Ru(CO)H(2)(PMe(2)Ph)(3)], 3a, or [Ru(CO)(C[triple bond]CCMe(3))H(PMe(2)Ph)(3)], 13. The elimination is a simple first-order process with negative DeltaS(++) and (for 7) a normal kinetic isotope effect (k(H)/k(D)= 2.5 at 287.9 K). These results, coupled with labelling studies, rule out a rapid equilibrium with a [sigma]-ethane intermediate prior to ethane loss.


Effects of combination therapy with rosuvastatin and fenofibric acid in patients with mixed dyslipidemia and high-sensitivity C-reactive protein (≥ 2 mg/L). email@example.com.
Elevated levels of high-sensitivity C-reactive protein (hsCRP) correlate with an increased risk for cardiovascular events. Combination therapy with a statin and a fibrate may be more effective than statin monotherapy for reducing hsCRP, especially in patients with mixed dyslipidemia. To characterize the treatment effects of rosuvastatin and fenofibric acid combination therapy compared with individual monotherapies in mixed dyslipidemic patients with baseline hsCRP ≥2 mg/L versus <2 mg/L and to determine the effects of long-term treatment with rosuvastatin and fenofibric acid combination therapy on hsCRP and other lipids for patients with hsCRP ≥2 mg/L after treatment with rosuvastatin monotherapy. Data for the post hoc analysis were derived from two 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; rosuvastatin 5, 10, 20, or 40 mg; or rosuvastatin 5, 10, or 20 mg and fenofibric acid 135 mg in the controlled studies; and with rosuvastatin 20 mg and fenofibric acid 135 mg in the extension study. In this analysis, 65% (1416/2182) of patients had pretreatment baseline hsCRP ≥2 mg/L. Among all treatment groups, larger decreases in hsCRP were observed in patients with greater baseline hsCRP; however, improvements in other lipids/apolipoprotein were comparable between the baseline hsCRP categories. Among patients with high hsCRP (≥2 mg/L) remaining after 12 weeks of rosuvastatin 10, 20, or 40 mg monotherapy, hsCRP was reduced by ∼36% after switching to rosuvastatin 20 mg and fenofibric acid 135 mg for up to 52 weeks, and ∼36% of patients shifted from hsCRP ≥2 mg/L to <2 mg/L. Combination therapy with rosuvastatin and fenofibric acid may be effective for improving the inflammatory biomarker, hsCRP as well as other lipid abnormalities in patients with mixed dyslipidemia and high hsCRP.


2,4,6-Trichlorophenol mediated increases in extracellular peroxidase activity in three species of Lemnaceae.
Chlorinated phenols, or chlorophenols, are persistent priority pollutants that are widespread in the environment. Class III peroxidases are well-characterised plant enzymes that can catalyse the oxidative dechlorination of chlorophenols. Expression of these enzymes by plants is commonly associated with plant stress, therefore limiting scope for phytoremediation. In this study, we have quantitatively compared peroxidase activity and phytotoxicity as a function of 2,4,6-trichlorophenol (TCP) concentration in three species of Lemnaceae; Lemna minor, Lemna gibba and Landoltia punctata. Effects of TCP on the growth rates of the three species differed considerably with L. punctata being the most tolerant species. TCP also affected photosynthetic parameters, causing a decrease in open photosystem II reaction centres (qP) and, in L. punctata only, a decrease in non-photochemical quenching (qN). In parallel, TCP exposure resulted in increased peroxidase activity in all three species. Peroxidase activity in L. minor and L. gibba displayed an inverse relationship with biomass accumulation, i.e. the more growth reduction the more peroxidase activity. In contrast, induction of peroxidase activity in L. punctata was bi-phasic, with a TCP-induced activity peak at concentrations that had no major effect on growth, and further induction under phytotoxic concentrations. The mechanism by which L. punctata recognises and responds to low concentrations of an anthropogenic compound, in the absence of wide-ranging stress, remains enigmatic. However, we conclude that this "window" of peroxidase production in the absence of major growth inhibition offers potential for the development of sustainable, peroxidise-mediated phytoremediation systems.


Sr[C2(COO)2]: the first anhydrous salt of acetylenedicarboxylic acid.
Single crystals of Sr[C(2)(COO)(2)] were formed at the phase boundary of an aqueous silica gel that contained acetylenedicarboxylic acid and an aqueous solution of SrCl(2). The crystal structure (I4(1)/amd, Z=4) shows a diamond-like topology, with the strontium ions in an eightfold co-ordination by the oxygen atoms of six carboxylate ligands with two of them co-ordinating in a chelating-type bidentate mode. As each oxygen atom of the carboxylate groups is involved in both a chelating-type bidentate and unidentate co-ordination and, therefore, bridging two strontium atoms, a three-dimensional framework results. Sr[C(2)(COO)(2)] exhibits a surprising thermal stability. In air decomposition starts at about 720 K and in an argon atmosphere around 750 K. This decomposition is accompanied by a mass loss of approximately 12 %, which is probably due to the loss of one CO molecule. The resulting residue is amorphous to X-rays. A small negative thermal expansion is found between 30 and 280 K, whereas between room temperature and 573 K almost no thermal expansion is observed. Single-crystal investigations at different temperatures show a strong "guitar string" vibration of the oxygen atom perpendicular to the contacts to the strontium atoms; this could be responsible for the thermal expansion behaviour.


Molecular approaches to lung cancer evaluation.
The stagnation of therapeutic results in lung cancer over the last decade(s) is a matter of great concern, also due to the constantly increasing incidence of the disease. Among the reasons for this failing therapeutic progress is the lack of understanding of the molecular mechanisms underlying the disease. Presently molecular biology techniques contribute to the deciphering of these mechanisms. This review article gives an overview of the actual situation. The genetic changes leading to malignancy are successively considered at the DNA, RNA and protein levels. Alterations at the DNA level represent the bulk of the available data, being related to p53 mutations, alterations in the beta-tubulin gene, microsatellite alterations, methods for identifying individual and isolated aberrant cells, identification of epigenetic mechanisms such as methylation of the promoter region of tumor suppressor genes; alterations in pre-neoplastic lesions are also evoked. In all cases, the techniques are described and results presented. RNA based methods are critically considered, and the yeast functional assay described. Protein based methods are also considered. The use of cDNA microarrays opens new perspectives and brings the simultaneous identification of numerous DNA alterations at a grip, with hopefully significant improvements in treatment results and increased efficiency for early detection and prevention.


[Idiopathic pulmonary fibrosis. A case report].
A case of idiopathic pulmonary fibrosis is presented. The difficulty of a differential diagnosis with other interstitial lung diseases and the necessity of a right and complete diagnostic pathway are underlined.


Combining graph neural networks and spatio-temporal disease models to improve the prediction of weekly COVID-19 cases in Germany.
During 2020, the infection rate of COVID-19 has been investigated by many scholars from different research fields. In this context, reliable and interpretable forecasts of disease incidents are a vital tool for policymakers to manage healthcare resources. In this context, several experts have called for the necessity to account for human mobility to explain the spread of COVID-19. Existing approaches often apply standard models of the respective research field, frequently restricting modeling possibilities. For instance, most statistical or epidemiological models cannot directly incorporate unstructured data sources, including relational data that may encode human mobility. In contrast, machine learning approaches may yield better predictions by exploiting these data structures yet lack intuitive interpretability as they are often categorized as black-box models. We propose a combination of both research directions and present a multimodal learning framework that amalgamates statistical regression and machine learning models for predicting local COVID-19 cases in Germany. Results and implications: the novel approach introduced enables the use of a richer collection of data types, including mobility flows and colocation probabilities, and yields the lowest mean squared error scores throughout the observational period in the reported benchmark study. The results corroborate that during most of the observational period more dispersed meeting patterns and a lower percentage of people staying put are associated with higher infection rates. Moreover, the analysis underpins the necessity of including mobility data and showcases the flexibility and interpretability of the proposed approach.


Imagination of body rotation can induce eye movements.
Several studies have shown that spatiotemporal aspects of motion are stored and can be retrieved with the use of vestibular and somatosensory cues. The purpose of this study was to examine whether intentional imagination of body rotation can induce oculomotor activity similar to the typical vestibulo-ocular reflex (VOR). Normal subjects without known vestibular and/or oculometric abnormalities were instructed to imagine a sensation of accelerating body rotation in the horizontal plane (rightward or leftward) while sitting in darkness with closed eyes, using only vestibular and somatosensory cues and not imaginary visual cues. Eye movements were recorded during the imagery session and also during a full, routine electronystagmography (ENG) test. All subjects selected for this study showed normal results in the ENG test, and none of them had gaze-evoked or end-point nystagmus. In response to imaginary rotations, horizontal eye movements were found in 91/121 recordings (75%) in 10 subjects. A typical pattern of nystagmus (0.3-3 Hz, 3-30 degrees /s maximal speed of slow component) was recorded in 53% of mental rightward rotations and 49% of leftward rotations. The fast component was always in the direction of the imaginary rotation (similar to a normal VOR). Other types of eye movement comprised either contralateral eye drift ( approximately 17% of trials) or macro square waves. In 25% of the recordings no definite eye movements could be detected during the mental maneuvers. These mentally induced eye movements seem to be due to a cortical process which can affect the normal input to the brainstem nuclei. A possible mechanism is discussed. This phenomenon may serve as an objective measurement of mental activity, may be used for testing the cognitive resources of patients and can probably be used for enhancing the rehabilitation process after acute vestibular insult.


Lack of dose response by dietary n-3 fatty acids at a constant ratio of n-3 to n-6 fatty acids in suppressing eicosanoid biosynthesis from arachidonic acid.
This study evaluated whether it is the ratio of n-3 to n-6 fatty acids or the absolute amount of n-3 fatty acids in diets that determines the degree of inhibition of eicosanoid biosynthesis from arachidonic acid (AA). Rats were fed diets containing different doses of linolenic acid or menhaden oil for 3 mo. Constant ratios of n-3 to n-6 fatty acids were maintained by concomitant increases in safflower oil as the n-6 fatty acid source. Results showed that AA concentrations in liver, platelet, and lung phospholipids and concentrations of eicosanoids synthesized in tissues were significantly (P less than 0.05) suppressed both by linolenic acid and menhaden oil; however, there was a lack of a dose response within groups fed different amounts of the same dietary fat. These results indicate that the ratio of n-3 to n-6 fatty acids in the diets, rather than the absolute amount of n-3 fatty acids, is the determining factor in inhibiting eicosanoid biosynthesis from AA.


Preclinical and clinical research on inflammation after intracerebral hemorrhage.
Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise.


Reduction of caveolin 1 gene expression in lung carcinoma cell lines.
Caveolae are plasma membrane microdomains that have been implicated in organizing and concentrating certain signaling molecules. Caveolins, constitute the main structural proteins of caveolae. Caveolae are abundant in terminally differentiated cell types. However, caveolin-1 is down-regulated in transformed cells and may have a potential tumor suppressor activity. In the lung, caveolae are present in the endothelium, smooth muscle cells, fibroblasts as well as in type I pneumocytes. The presence of caveolae and caveolin expression in the bronchial epithelium, although probable, has not been investigated in human. We were interested to see if the bronchial epithelia express caveolins and if this expression was modified in cancer cells. We thus tested for caveolin-1 and -2 expression several bronchial epithelial primary cell lines as well as eight lung cancer cell lines and one larynx tumor cell line. Both caveolin-1 and -2 are expressed in all normal bronchial cell lines. With the exception of Calu-1 cell line, all cancer cell lines showed very low or no expression of caveolin-1 while caveolin-2 expression was similar to the one observed in normal bronchial epithelial cells.


Acute obstruction of an endotracheal tube: a case report.
This report describes a case of sudden ventilatory failure, originally diagnosed as bronchospasm, in a child during general anesthesia. A blood clot impaction in the nasotracheal tube was detected using flexible fiberoptic bronchoscopy. The clot was successfully treated as a result of its passage. We hope this report will stress to dental anesthesiologists the intraoperative importance of fiberoptic bronchoscopy not only as an intubation-aiding device but also as a diagnostic and therapeutic tool.


Evidence of two isomers of phosphatidylinositol in plant tissue.
The structure of phosphatidylinositol in barley (Hordeum vulgare) aleurone layers was investigated by chemical degradation. In vivo myo-[2-(3)H]inositol-labeled phosphatidylinositol was first converted to glycerophosphoinositol and, subsequently, after removal of the glycerol moiety, to inositol monophosphate. Here, we present data that show that, in addition to the commonly occurring 1,2-diacylglycero-3-(d-myo-inositol-1-phosphate), barley aleurone cells contain a novel second isomer of phosphatidylinositol that differs in structure of the head group.


Significant increase of CKS1B amplification from monoclonal gammopathy of undetermined significance to multiple myeloma and plasma cell leukaemia as demonstrated by interphase fluorescence in situ hybridisation.
The genetic events that lead to tumour progression in plasma cell dyscrasia are not well understood. Interphase cytoplasmic fluorescence in situ hybridisation was used to investigate the CKS1B amplification status (at 1q21) in clonal plasma cells from 123 patients: 23 monoclonal gammopathy of undetermined significance (MGUS), 75 multiple myeloma (MM) and 26 plasma cell leukaemia (PCL). While CKS1B amplification was absent in MGUS patients, such amplification (3-8 copies) was detected in 36% of newly diagnosed MM, 52% relapsed MM and 62% PCL (P < 0.001). Our results suggest that CKS1B amplification is associated with transformation from MGUS to MM and progression to PCL.


Freely relaxing polymers remember how they were straightened.
The relaxation of initially straight semiflexible polymers has been discussed mainly with respect to the longest relaxation time. The biologically relevant nonequilibrium dynamics on shorter times is comparatively poorly understood, partly because "initially straight" can be realized in manifold ways. Combining Brownian dynamics simulations and systematic theory, we demonstrate how different experimental preparations give rise to specific short-time and universal long-time dynamics. We also discuss boundary effects and the onset of the stretch-coil transition.


High-efficiency (>20%) planar carbon-based perovskite solar cells through device configuration engineering.
Carbon-based perovskite solar cells (C-PSCs) have attracted widespread research interest because of their excellent stability. However, the power conversion efficiency (PCE) of C-PSCs, especially planar C-PSCs, lags far behind the certified efficiency (25.5%) of metal-based PSCs. The simple architecture of planar C-PSCs imparts stringent requirements for device configuration. In this study, we fabricated high-performance planar C-PSCs through device configuration engineering in terms of the perovskite active layer and carbon electrode. Through the combination of component and additive engineering, the crystallization and absorption profiles of perovskite active layer have been improved, which afforded sufficient photogenerated carriers and decreased nonradiative recombination. Furthermore, the mechanical and physical properties of carbon electrode were evaluated comprehensively to regulate the back-interface contact. Based on the compromise of the flexibility and conductivity of carbon film, an excellent back-interface contact has been formed, which promoted fast interface charge transfer, thereby decreasing interface recombination and improving carrier collection efficiency. Finally, the as-prepared devices achieved a remarkable PCE of up to 20.04%, which is a record-high value for planar C-PSCs. Furthermore, the as-prepared devices exhibited excellent long-term stability. After storage for 1000 h at room temperature and 25% relative humidity without encapsulation, the as-prepared device retained 94% of its initial performance.