Physical and Mechanical Properties of Rapeseed Straw Concrete.
This paper investigates an innovative building material based on rapeseed concrete. This material is a non-load-bearing insulating concrete, which is intended for use in the construction of wood-frame walls thanks to its thermophysical properties. It is composed of particles of rapeseed straw, lime, and cement. First, this work proposes to characterize rapeseed straw aggregates according to the place of cultivation, the year of harvest, and the size of the straw strands. For this purpose, straws of three different origins and different years of harvest were chosen. Aggregate sizes of 10 mm and 20 mm in length were selected. In a second step, this study focuses on the effect of the type of rapeseed straw aggregates on the mechanical resistance and thermal conductivity of bio-based concrete. The results obtained showed that the influence of the different parameters on the compressive strength was stronger than that on the thermal conductivity. On the one hand, rapeseed concrete made with 10 mm straw exhibited a lower thermal conductivity, averaging at 0.073 W.m-1.K-1. On the other hand, concrete manufactured with the 20 mm size aggregates demonstrated a higher mechanical strength, which remained relatively low and closer to 0.22 MPa. Finally, 20 mm-long aggregates offered the best compromise between mechanical and thermal resistance.


Primary HIV infection: molecular approaches in diagnosis and monitoring.
The aim of this study was to evaluate, in patients with primary HIV infection (PHI), the modification of HIV molecular parameters (HIV, RNA, and DNA) induced by highly active antiretroviral therapy (HAART) in peripheral blood mononuclear cells (PBMC) and in lymphoid tissue (LNMC). Nineteen patients with primary HIV infection, 4 women and 15 men with an average age of 35 years (range 27-62), were included in this study. Ten patients received 4 drugs: zidovudine plus lamivudine plus saquinavir plus ritonavir, 7 patients received 3 drugs: zidovudine plus lamivudine plus saquinavir and 2 patients received a different combination of 3 drugs: zidovudine plus lamivudine plus indinavir. As control group we included 8 patients who had been enrolled in a placebo-controlled trial of zidovudine between 1991 and 1995: four received placebo and 4 were treated with zidovudine alone. Peripheral blood samples and lymphoid tissue obtained by echo-driven fine needle biopsies were drawn to monitor molecular HIV parameters. A quantitative in house PCR method in the HIV gag region was used to monitor viral DNA burden and the NASBA system for viremia. A certain heterogeneity in the baseline values of HIV, DNA, and RNA was observed. Early HAART determined a rapid recovery of the CD4 cell number with normalisation of the CD4/CD8 ratio in most patients. HIV-RNA levels dropped to undetectable levels after a few months of therapy and HIV-DNA was consistently reduced although it never reached undetectable levels. Lymph-node biopsies were well tolerated due to the non-invasive sampling, however an optimisation of the method is needed to improve cell recovery. In the valuable samples the amount of HIV DNA recovered is comparable to that from peripheral blood samples, both at baseline and at follow-up.


[The use of the new bacterial biopreparation Acilact in the combined treatment of periodontitis].
Acilact, a bacterial biopreparation representing a complex of live lyophilized acidophilic lactobacteria, was used in combined therapy of 45 patients with periodontitis of mild and medium severity. The drag was applied locally and per os. Clinical parameters improved after therapy; gram-positive cocci and bacilli predominated in local microflora; natural antibacterial resistance of the body improved. This method of therapy is new in principle and pathogenetically grounded. It results in correction of autoflora of the oral cavity and periodontal pouches, and, possibly, of the gastrointestinal tract. Acilact is well tolerated by the patients and induces no side effects, there are no contraindications against its administration.


Out-of-hospital cardiac arrest related to exercise in the general population: Incidence, survival and bystander response.
Regular exercise is known to prevent cardiovascular disorders, but it may also trigger acute cardiac events. This study examined the incidence, prognosis, and outcomes of out-of-hospital cardiac arrest (OHCA) related to exercise in the general population of Denmark. This retrospective cohort study examined all the OHCAs in the Danish Cardiac Arrest Registry from 2016 to 2019. OHCA related to exercise was identified in a nationwide electronic database and coupled to the patient register. Descriptive statistics were used in combination with a multivariate logistic regression model to assess predefined factors. A total of 20,470 OHCAs were identified, of which 459 (2.2%) were related to exercise. Most were male (75.3%), with a median age of 61 years. Further, 95% of exercise-related OHCA received bystander cardiopulmonary resuscitation, compared to 77.4% in non-exercise-related OHCA (p < 0.001), and 38.3% received defibrillation by bystanders versus 7.5% in the non-exercise group (p < 0.001). Exercise-related OHCAs had a 30-day survival rate of 57.7% compared to 12.6% in the non-exercise group, yielding an adjusted odds ratio of 5.56. The 30-day survival rate of exercise-related subjects aged 15-35 years was 80.0%, compared to 25.0% in the non-exercise group. When comparing sports categories, team sports were associated with the greatest chance of survival (odds ratio of 18.5 versus a non-exercise odds ratio of 0.09). Exercise-related OHCA has a low incidence and is related to a significantly better prognosis when compared to non-exercise OHCA. Furthermore, many patients experiencing exercise-related OHCA received defibrillation and cardiopulmonary resuscitation by bystanders. These findings could help plan and execute campaigns and education.


Comparison of Transcutaneous and Percutaneous Implantable Hearing Devices for the Management of Congenital Aural Atresia: A Systematic Review and Meta-Analysis.
To compare audiometric outcomes, complications, and revisions required for percutaneous (pBCD) versus transcutaneous (tBCD) implantable bone-conduction devices for the treatment of hearing loss associated with congenital aural atresia (CAA).Databases Reviewed.PubMed, Scopus, CINAHL. A systematic review was performed searching for English language articles from inception to December 14, 2022. Studies reporting audiometric outcomes or complications for either pBCDs or tBCDs for the treatment of CAA were selected for inclusion. A meta-analysis of single means and meta-analysis of proportions with comparison (Δ) of weighted proportions was conducted. A total of 56 articles with 756 patients were selected for inclusion. One hundred ninety patients were implanted with pBCDs, whereas the remaining 566 were implanted with tBCDs. Mean pure-tone audiometry improvement in the pBCD group (39.1 ± 1.1 dB) was significantly higher than in the tBCD group (34.6 ± 1.6 dB; Δ4.5 dB; 95% confidence interval, 4.2-4.7 dB; p < 0.0001). The average improvement in speech reception threshold was 38.6 ± 2.5 dB in the percutaneous group as compared with 32.7 ± 1.6 dB in the transcutaneous group (Δ5.9 dB [5.3-6.5 dB], p < 0.0001). Overall complication rates for patients implanted with pBCDs and tBCDs were 29.0% (15.7-44.4%) and 9.4% (6.5%-13.0%), respectively (Δ19.6% [12.0-27.7%], p < 0.0001). Patients with CAA implanted with pBCDs had significantly better audiometric outcomes than those implanted with tBCDs. However, complication rates were significantly higher among the pBCD group.


Multiple functions of Nm23-H1 are regulated by oxido-reduction system.
Nucleoside diphosphate kinase (NDPK, Nm23), a housekeeping enzyme, is known to be a multifunctional protein, acting as a metastasis suppressor, transactivation activity on c-myc, and regulating endocytosis. The cellular mechanisms regulating Nm23 functions are poorly understood. In this study, we identified the modifications and interacting proteins of Nm23-H1 in response to oxidative stress. We found that Cys109 in Nm23-H1 is oxidized to various oxidation states including intra- and inter-disulfide crosslinks, glutathionylation, and sulfonic acid formation in response to H(2)O(2) treatment both in vivo and in vitro. The cross-linking sites and modifications of oxidized Nm23-H1 were identified by peptide sequencing using UPLC-ESI-q-TOF tandem MS. Glutathionylation and oxidation of Cys109 inhibited the NDPK enzymatic activity of Nm23-H1. We also found that thioredoxin reductase 1 (TrxR1) is an interacting protein of Nm23-H1, and it binds specifically to oxidized Nm23-H1. Oxidized Nm23 is a substrate of NADPH-TrxR1-thioredoxin shuttle system, and the disulfide crosslinking is reversibly reduced and the enzymatic activity is recovered by this system. Oxidation of Cys109 in Nm23-H1 inhibited its metastatic suppressor activity as well as the enzymatic activities. The mutant, Nm23-H1 C109A, retained both the enzymatic and metastasis suppressor activities under oxidative stress. This suggests that key enzymatic and metastasis suppressor functions of Nm23-H1 are regulated by oxido-reduction of its Cys109.


Influence of Concurrent Heroin and Cocaine Abuse on the Adrenergic and Serotonergic Systems in Mana.
Drugs of abuse interfere with the adrenergic activity at the periphery and the study of their effects In Vivo at this level may contribute to understand the central mechanisms of action. Free and sulfoconjugated catecholamines and serotonin (5-hydroxytryptamine, 5-HT) were measured by high-performance liquid chromatography with electrochemical detection (HPLC-ECD); plasma dopamine (DA)-b-hydroxylase (DBH) activity was determined by a HPLC technique. When compared with healthy subjects (n = 49), the results in drug addicts (n = 48) revealed: a) Significant increases in plasma DA (free and sulfoconjugated), epinephrine (Epi)- and norepinephrine (NE)-sulfate levels; b) no significant differences in the levels of plasma free NE or Epi, serum and platelet 5-HT. Concerning DBH activity, there was a tendency for an increase. In conclusion, since catecholamines are rapidly inactivated during blood circulation, the measurement of their sulfates may better reflect catecholamine turnover. The differences found may be interpreted as a reflection of the activation of adrenergic neurotransmission, principally as a consequence of catecholamine uptake blockade by cocaine. Finally, in our conditions the abuse of cocaine plus heroin does not significantly interfere with 5-HT uptake by platelets.


Meta-analysis of structural integrity of white matter and functional connectivity in developmental stuttering.
Developmental stuttering is a speech disfluency disorder characterized by repetitions, prolongations, and blocks of speech. While a number of neuroimaging studies have identified alterations in localized brain activation during speaking in persons with stuttering (PWS), it is unclear whether neuroimaging evidence converges on alterations in structural integrity of white matter and functional connectivity (FC) among multiple regions involved in supporting fluent speech. In the present study, we conducted coordinate-based meta-analyses according to the PRISMA guidelines for available publications that studied fractional anisotropy (FA) using tract-based spatial statistics (TBSS) for structural integrity and the seed-based voxel-wise FC analyses. The search retrieved 11 publications for the TBSS FA studies, 29 seed-based FC datasets from 6 publications for the resting-state, and 29 datasets from 6 publications for the task-based studies. The meta-analysis of TBSS FA revealed that PWS exhibited FA reductions in the middle and posterior segments of the left superior longitudinal fasciculus. Furthermore, the analysis of resting-state FC demonstrated that PWS had reduced FC in the right supplementary motor area and inferior parietal cortex, whereas an increase in FC was observed in the left cerebellum crus I. Conversely, we observed increased FC for task-based FC in regions implicated in speech production or sequential movements, including the anterior cingulate cortex, posterior insula, and bilateral cerebellum crus I in PWS. Functional network characterization of the altered FCs revealed that the sets of reduced resting-state and increased task-based FCs were largely distinct, but the somatomotor and striatum/thalamus networks were foci of alterations in both conditions. These observations indicate that developmental stuttering is characterized by structural and functional alterations in multiple brain networks that support speech fluency or sequential motor processes, including cortico-cortical and subcortical connections.


Synaptic Targeting of Double-Projecting Ventral CA1 Hippocampal Neurons to the Medial Prefrontal Cortex and Basal Amygdala.
The acquisition and retrieval of contextual fear memory requires coordinated neural activity in the hippocampus, medial prefrontal cortex (mPFC), and amygdala. The contextual information encoded in the hippocampus is conveyed to the mPFC and amygdala for contextual fear conditioning. Previous studies have suggested that a CA1 neuronal population in the ventral hippocampus (VH) projects to both the mPFC and amygdala and is recruited in context-dependent control of conditioned fear. However, how double-projecting ventral CA1 hippocampal (vCA1) neurons modulate the activity of the mPFC and amygdala at the synaptic level has not been determined previously. Here, we show that the optogenetic silencing of the VH prevented the recall of contextual fear memory in mice, indicating its role in contextual fear expression. In dual retrograde viral tracing and c-Fos immunostaining experiments, we found that a proportion of vCA1 neurons projected to both the mPFC and amygdala and were recruited preferentially during context exposure, suggesting their role in encoding context representations. Moreover, optogenetic stimulation of axon collaterals of double-projecting vCA1 neurons induced monosynaptic excitatory responses in both the mPFC and basal amygdala, indicating that they could convey contextual information through the VH-mPFC and VH-amygdala pathways. The activation of double-projecting vCA1 neurons also induced action potential firings in the mPFC neurons that project to the amygdala, suggesting that they can also activate the VH-mPFC-amygdala pathway. With these synaptic mechanisms, double-projecting vCA1 neurons could induce synchronized neural activity in the mPFC and amygdala and convey contextual information efficiently to the basal amygdala for contextual fear conditioning.SIGNIFICANCE STATEMENT This work demonstrates that ventral CA1 hippocampal (vCA1) neurons projecting to both the medial prefrontal cortex (mPFC) and amygdala are activated preferentially when contextual information is processed in the ventral hippocampus, which is required for contextual fear expression. Our electrophysiological experiments reveal that the activation of double-projecting vCA1 neurons induces excitatory synaptic activity in both the mPFC and amygdala. These results suggest that double-projecting vCA1 neurons could contribute to contextual fear responses by inducing synchronized activity in the mPFC and amygdala and conveying contextual information to the basal amygdala more efficiently than vCA1 neurons projecting to either the mPFC or amygdala alone. These findings provide important insights into the mechanisms of the acquisition and retrieval of contextual fear memory.


Genomic Evaluation of Primiparous High-Producing Dairy Cows: Inbreeding Effects on Genotypic and Phenotypic Production-Reproductive Traits.
The main objective of this study was to analyze the effects of the inbreeding degree in high-producing primiparous dairy cows genotypically and phenotypically evaluated and its impacts on production and reproductive parameters. Eighty Holstein-Friesian primiparous cows (age: ~26 months; ~450 kg body weight) were previously genomically analyzed to determine the Inbreeding Index (II) and were divided into two groups: low inbreeding group (LI: <2.5; n = 40) and high inbreeding group (HI: ≥2.5 and ≤5.0; n = 40). Genomic determinations of production and reproductive parameters (14 in total), together with analyses of production (12) and reproductive (11) phenotypic parameters (23 in total) were carried out. Statistically significant differences were obtained between groups concerning the genomic parameters of Milk Production at 305 d and Protein Production at 305 d and the reproductive parameter Daughter Calving Ease, the first two being higher in cows of the HI group and the third lower in the LI group (p < 0.05). For the production phenotypic parameters, statistically significant differences were observed between both groups in the Total Fat, Total Protein, and Urea parameters, the first two being higher in the LI group (p < 0.05). Also, significant differences were observed in several reproductive phenotypic parameters, such as Number of Services per Conception, Calving to Conception Interval, Days Open Post Service, and Current Inter-Partum Period, all of which negatively influenced the HI group (p < 0.05). In addition, correlation analyses were performed between production and reproductive genomic parameters separately and in each consanguinity group. The results showed multiple positive and negative correlations between the production and reproductive parameters independently of the group analyzed, being these correlations more remarkable for the reproductive parameters in the LI group and the production parameters in the HI group (p < 0.05). In conclusion, the degree of inbreeding significantly influenced the results, affecting different genomic and phenotypic production and reproductive parameters in high-producing primiparous cows. The determination of the II in first-calf heifers is crucial to evaluate the negative effects associated with homozygosity avoiding an increase in inbreeding depression on production and reproductive traits.


Targeting the growth factors and angiogenesis pathways: small molecules in solid tumors.
Research over the last decades has provided us with a better understanding of the biology of solid tumors. In some solid tumor malignancies single molecular events leading to malignant transformation have been identified, whilst in others multiple pathways seem to play a role simultaneously. The delineation of such pathways has led to the identification of therapeutic targets. Multiple compounds are available now to treat those molecular aberrations. With the wider use of newer biologic therapies, the understanding of biologic characteristics predicting a clinical response has broadened. This review focuses on the clinical management of gastrointestinal stromal tumors as well as hepatocellular, non small cell lung, renal cell and breast cancer with small molecule tyrosine kinase inhibitors, integrating some of the clinical advances with monoclonal antibody therapies in solid tumor malignancies. It highlights recent advances in relevant biomarkers to predict efficacy of biologic therapies and elaborates on their relevance in the clinical management of patients with solid tumor malignancies.


Characterization of Klebsiella pneumoniae isolated from patients suspected of pulmonary or bubonic plague during the Madagascar epidemic in 2017.
Klebsiella pneumoniae can lead to a wide range of diseases including pneumonia, bloodstream and urinary tract infections. During a short period of a pulmonary plague epidemic in October 2017 in Madagascar, 12 K. pneumoniae isolates were identified in ten sputum and two buboes aspirate samples. These isolates were from 12 patients suspected of plague, without epidemiological relationships, but were negative for Yersinia pestis in culture. Data were collected from the plague national surveillance system. The isolates were characterized by antimicrobial susceptibility testing and whole-genome sequencing. Real-time PCR was performed to confirm the presence of K. pneumoniae DNA in buboes. All isolates were identified as K. pneumoniae sensu stricto. Five isolates were extended-spectrum β-lactamases producers; eleven different sequence types were identified. Five isolates belonged to known hypervirulent sequence types. Our results demonstrate community-acquired pneumonia caused by K. pneumoniae isolates in patients suspected of plague stressing the importance of bed-side differential diagnosis.


Supercurrent Detection of Topologically Trivial Zero-Energy States in Nanowire Junctions.
We report the emergence of zero-energy states in the trivial phase of a short nanowire junction with a strong spin-orbit coupling and magnetic field, formed by strong coupling between the nanowire and two superconductors. The zero-energy states appear in the junction when the superconductors induce a large energy shift in the nanowire, such that the junction naturally forms a quantum dot, a process that is highly tunable by the superconductor width. Most importantly, we demonstrate that the zero-energy states produce a π shift in the phase-biased supercurrent, which can be used as a simple tool for their unambiguous detection, ruling out any Majorana-like interpretation.


Determination of spatial distribution of melamine-cyanuric acid crystals in rat kidney tissue by histology and imaging matrix-assisted laser desorption/ionization quadrupole time-of-flight mass spectrometry.
After the outbreak of acute renal failure associated with melamine-contaminated pet food, many attempts have been made to uncover the mechanism underlying the renal toxicity caused by melamine and melamine-related compounds. Using rat models, we investigated the renal crystal formation following the ingestion of a melamine-cyanuric acid mixture (M+CA, 1:1) to gain insight into the M+CA-induced renal toxicity. M+CA did not induce toxicity in precision-cut kidney slices, suggesting that M+CA does not have a direct nephrotoxicity. On the contrary, oral administration of M+CA for 3 days induced nephrotoxicity as determined by increased serum blood urea nitrogen and creatinine, reduced creatinine clearance, and enlarged kidneys in the animals treated with 50 mg/kg M+CA (melamine, 25 mg/kg, and cyanuric acid, 25 mg/kg; 2 of 10 animals) and 100 mg/kg M+CA (9 of 9 animals). While urine crystals were found in all animals treated with M+CA (25-100 mg/kg), histological examination revealed that renal crystals could be observed only in the kidneys of animals showing signs of nephrotoxicity. Remarkably, at 50 mg/kg M+CA, crystals were observed mainly in the medulla region of the kidney, while at 100 mg/kg, crystals were disseminated throughout the cortex and medulla regions. To further investigate the crystal formation by M+CA, matrix-assisted laser desorption/ionization quadrupole time-of-flight (MALDI-Q-TOF) imaging mass spectrometry detecting melamine distribution through monitoring the product ion (m/z 85, M + H) from melamine (m/z 127, M + H) was developed to directly obtain the image of melamine distribution in the kidney. The distribution image of melamine in kidney tissue confirmed that dense points of melamine were located only in the medulla region at 50 mg/kg M+CA, while at 100 mg/kg, they were disseminated widely from the cortex to medulla. These results demonstrated that M+CA ingestion could lead to crystal formation in kidney tubules along the osmotic gradient and that renal crystal formation is closely linked with M+CA-induced nephrotoxicity.


Veterans' access to and use of Medicare and Veterans Affairs health care.
We examined the impact of access to care characteristics on health care use patterns among those veterans dually eligible for Medicare and Veterans Affairs (VA) services. We used a retrospective, cross-sectional design to identify veterans who were eligible to use VA and Medicare health care in calendar year 1999. We analyzed national VA utilization and Medicare claims data. We used descriptive and multivariable generalized ordered logit analyses to examine how patient, geographic, and environmental factors affect the percent reliance on VA and Medicare inpatient and outpatient services. Of the 1.47 million veterans in our study population with outpatient use, 18% were VA-only users, 36% were Medicare-only users, and 46% were both VA and Medicare users. Among veterans with inpatient use, 24% were VA only, 69% were Medicare only, and 6% were both VA and Medicare users. Multivariable analysis revealed that veterans who were black or had a higher VA priority were most likely to rely on the VA. Patient with higher risk scores were most likely to rely on a combination of VA and Medicare health care. Patients who lived farther from VA hospitals were less likely to rely on VA health care, particularly for inpatient care. Patients living in urban areas with more health care resources were less likely to rely on VA health care. VA health care provides an important safety net for vulnerable populations. Targeted approaches that carefully consider the simultaneous impacts of VA and Medicare policy changes on minority and high-risk populations are essential to ensure veterans have access to needed health care.


Chronic exposure to electronic cigarettes results in impaired cardiovascular function in mice.
Proponents for electronic cigarettes (E-cigs) claim that they are a safe alternative to tobacco-based cigarettes; however, little is known about the long-term effects of exposure to E-cig vapor on vascular function. The purpose of this study was to determine the cardiovascular consequences of chronic E-cig exposure. Female mice (C57BL/6 background strain) were randomly assigned to chronic daily exposure to E-cig vapor, standard (3R4F reference) cigarette smoke, or filtered air ( n = 15/group). Respective whole body exposures consisted of four 1-h-exposure time blocks, separated by 30-min intervals of fresh air breaks, resulting in intermittent daily exposure for a total of 4 h/day, 5 days/wk for 8 mo. Noninvasive ultrasonography was used to assess cardiac function and aortic arterial stiffness (AS), measured as pulse wave velocity, at three times points (before, during, and after chronic exposure). Upon completion of the 8-mo exposure, ex vivo wire tension myography and force transduction were used to measure changes in thoracic aortic tension in response to vasoactive-inducing compounds. AS increased 2.5- and 2.8-fold in E-cig- and 3R4F-exposed mice, respectively, compared with air-exposed control mice ( P < 0.05). The maximal aortic relaxation to methacholine was 24% and 33% lower in E-cig- and 3R4F-exposed mice, respectively, than in controls ( P < 0.05). No differences were noted in sodium nitroprusside dilation between the groups. 3R4F exposure altered cardiac function by reducing fractional shortening and ejection fraction after 8 mo ( P < 0.05). A similar, although not statistically significant, tendency was also observed with E-cig exposure ( P < 0.10). Histological and respiratory function data support emphysema-associated changes in 3R4F-exposed, but not E-cig-exposed, mice. Chronic exposure to E-cig vapor accelerates AS, significantly impairs aortic endothelial function, and may lead to impaired cardiac function. The clinical implication from this study is that chronic use of E-cigs, even at relatively low exposure levels, induces cardiovascular dysfunction. NEW & NOTEWORTHY Electronic cigarettes (E-cigs) are marketed as safe, but there has been insufficient long-term exposure to humans to justify these claims. This is the first study to report the long-term in vivo vascular consequences of 8 mo of exposure to E-cig vapor in mice (equivalent to ~25 yr of exposure in humans). We report that E-cig exposure increases arterial stiffness and impairs normal vascular reactivity responses, similar to other risk factors, including cigarette smoking, which contribute to the development of cardiovascular disease.


In vitro digestion profile and calcium absorption studies of a sea cucumber ovum derived heptapeptide-calcium complex.
In this study, a novel calcium-binding heptapeptide (NDEELNK) that is released during the trypsin hydrolysis of sea cucumber ovum was identified by peptidomics. The calcium binding mode, in vitro digestion profile and calcium absorption of the NDEELNK-calcium complex were investigated. The NDEELNK peptide could spontaneously bind calcium with a 1 : 1 stoichiometry, and the calcium-binding site might involve the carboxyl oxygen and amino nitrogen atoms of two glutamic acid and one aspartic acid residues in the NDEELNK peptide. The NDEELNK-calcium complex underwent disaggregation and self-aggregation in a mesh of smaller size during simulated gastrointestinal digestion, clarified by dynamic light scattering and confocal laser-scanning microscopy. In addition, the NDEELNK-calcium complex could be conducive to calcium absorption across Caco-2 cell monolayers. The findings from this research suggest possible utilization of hydrolyzed peptides from sea cucumber ovum as dietary supplements to improve calcium absorption.


Spatial distributions and interstellar reaction processes.
Methyl formate presents a challenge for the conventional chemical mechanisms assumed to guide interstellar organic chemistry. Previous studies of potential formation pathways for methyl formate in interstellar clouds ruled out gas-phase chemistry as a major production route, and more recent chemical kinetics models indicate that it may form efficiently from radical-radical chemistry on ice surfaces. Yet, recent chemical imaging studies of methyl formate and molecules potentially related to its formation suggest that it may form through previously unexplored gas-phase chemistry. Motivated by these findings, two new gas-phase ion-molecule formation routes are proposed and characterized using electronic structure theory with conformational specificity. The proposed reactions, acid-catalyzed Fisher esterification and methyl cation transfer, both produce the less stable trans-conformational isomer of protonated methyl formate in relatively high abundance under the kinetically controlled conditions relevant to interstellar chemistry. Gas-phase neutral methyl formate can be produced from its protonated counterpart through either a dissociative electron recombination reaction or a proton transfer reaction to a molecule with larger proton affinity. Retention (or partial retention) of the conformation in these neutralization reactions would yield trans-methyl formate in an abundance that exceeds predictions under thermodynamic equilibrium at typical interstellar temperatures of ≤100 K. For this reason, this conformer may prove to be an excellent probe of gas-phase chemistry in interstellar clouds. Motivated by new theoretical predictions, the rotational spectrum of trans-methyl formate has been measured for the first time in the laboratory, and seven lines have now been detected in the interstellar medium using the publicly available PRIMOS survey from the NRAO Green Bank Telescope.


Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu] DOTA-TATE of neuroendocrine tumors refractory to conventional therapy: preliminary results.
Neuroendocrine tumors over-express somatostatin receptors and literature data have demonstrated the efficacy of the peptide receptor radionuclide therapy with somatostatin analogues labelled with high activities of b-emitting radioisotopes, such as (90)Y and (177)Lu. Yttrium-90 is a pure high energy b-emitter while (177)Lu is a b/g emitter of medium energy. We decided to evaluate an original tandem treatment based on administration of radiolabeled [DOTA(0),Tyr(3)]octreotate (DOTA-TATE) alternating (177)Lu and 90Y. Aim of this study was to evaluate the feasibility, the efficacy and the toxicity of this treatment in neuroendocrine tumors expressing somatostatin receptors relapsed or refractory to conventional therapies. Patients were treated with four therapeutic cycles alternating [(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). Dosimetric evaluation after administration of [(177)Lu]DOTA-TATE allows to calculate the absorbed doses in healthy organs. Blood samples were collected at 5 min, 1, 6, 24, 48, 72, 96 h and scintigraphy was performed once a day for four days after administration. Toxicity was evaluated considering hematological parameters and renal toxicity was evaluated also by the glomerular filtration rate (GFR). Efficacy related with RECIST criteria. Up to now 26 patients entered the study and 16 patients completed all cycles. Treatment was well tolerated with no adverse event registered. No damage to healthy organs was revealed in accordance with the calculated absorbed doses. We had a partial response in 10/15 patients evaluated three months after the fourth treatment. Up to now only a few patients participated in and concluded this study; preliminary results are encouraging and indicate the feasibility of the study.


Risk indicators of organic diseases in uninvestigated dyspepsia: a one-week survey in 246 Italian endoscopy units.
To evaluate the predictive value of demographic and clinical features and of the results of an office-based test for Helicobacter pylori antibodies, in the presence of organic dyspepsia. Over a 1-week period, 2206 consecutive patients first referred for endoscopy in 246 Italian centres were included. Demographic and clinical features, endoscopy findings, and histological diagnosis of H. pylori infection were recorded for all patients. IgG antibodies to H. pylori were determined in 2128 cases by a rapid, immunochromatographic method (Flex Sure HP, S.K.D., San Jose, CA). Endoscopic abnormalities were found in 939 patients (42.6%). Histologically assessed H. pylori infection was predictive for duodenal ulcer (odds ratio (OR), 6.79; 95% confidence interval (CI), 4.4-10.5). Being male (OR, 1.97; 95% CI, 1.7-2.3), older than 40 years (OR, 1.81; 95% CI, 1.5-2.2), a smoker (OR, 1.88; 95% CI, 1.6-2.3), and presenting nocturnal awakening (OR, 1.62; 95% CI, 1.3-2.0) were independently associated with secondary dyspepsia. Epigastric (OR, 1.50; 95% CI, 1.2-1.9) and retrosternal pain (OR, 1.39; 95% CI, 1.1 -1.8) severe enough to affect the usual activities were predictive of organic diseases. The results of the Flex Sure HP test correlated poorly with histological findings. Male gender, older age, cigarette smoking, a family history of peptic ulcer, symptoms severe enough to induce awakening, epigastric/retrosternal pain severe enough to influence the usual activities are all independently (although weakly) associated with organic dyspepsia. H. pylori infection is strongly associated with duodenal ulcer, but the rapid test we used was not sensitive enough to achieve clinical utility.


MRI and myelography in the diagnosis of lumbar canal stenosis and disc herniation. A comparative study.
We studied the diagnostic accuracy of magnetic resonance imaging (MRI) and the possibility of its substitution for myelography in 78 patients with lumbar canal stenosis and/or disc herniation, who had myelography and MRI examination. The diagnostic results of the two methods were compared respectively with those of operation, showing no statistical significance (coincidence rate 88.5% vs 92.3%, P greater than 0.05). We conclude that MRI could clearly reveal the pathological changes and anatomical relations of lumbar structures without invasive and radioactive damages, and that with the improvement of operative technique, better understanding of images, and reduction of cost, MRI is likely to replace myelography in the future.


Treatment of congenital osteopetrosis with high-dose calcitriol.
We administered high doses of calcitriol (up to 32 micrograms per day) to an infant with malignant osteopetrosis, in an attempt to stimulate bone resorption. The patient was placed on a low-calcium diet to prevent hypercalcemia. Measures of bone turnover increased during calcitriol therapy; hydroxyproline excretion rose from 140 to 1358 micrograms per milligram of creatinine per 24 hours, with parallel increases in the ratio of calcium to creatinine in the urine, urinary gamma-carboxyglutamic acid, serum osteocalcin, and serum alkaline phosphatase. A pretreatment bone-biopsy specimen contained no osteoclasts with ruffled borders, a feature of active osteoclasts. After 11 days of calcitriol, ruffled borders were noted. After three months, numerous osteoclasts with ruffled borders and associated bony disruption were evident. Before therapy, the patient's monocytes were incapable of in vitro bone resorption, but after calcitriol, their resorptive capacity was increased to 3.3 times control levels. These data demonstrate that calcitriol increased bone mineral and matrix turnover in our patient. However, during the three months of calcitriol therapy there was only slight clinical improvement in her severe disease. Early and sustained treatment with calcitriol may be useful in osteopetrosis.


[The development of Brazilian fish culture without water quality degradation].
The water pollution in fish culture needs research to know the relation between the intensive or extensive culture system and the effluent quality. This paper discuss the main characteristics of the effluent water quality in each culture system. The advantages and restrictions of some treatment system for each kind of effluent and a special cultivation procedure to keep more homogeneous the pollution level of the effluent are discussed.


Development of sodium channels during differentiation of chick skeletal muscle in culture. II. 22Na+ uptake and electrophysiological studies.
The development of the functional properties of the sodium channel of chick skeletal muscle grown in culture was studied using 22Na uptake and electrophysiological techniques. In accord with the biochemical data in the preceding paper (Baumgold, J., J. B. Parent, and I. Spector (1983) J. Neurosci. 3: 995-1003), the functional manifestations of sodium channel expression are initiated shortly after cell fusion. At this stage, the myotubes have barely detectable sodium-dependent action potentials (Vmax = 1 to 9 V/sec) and exhibit a very small amount of batrachotoxin (BTX)-stimulated 22Na+ uptake. However, when these cultures are treated with scorpion toxin (ScTX), the amplitude and rate of rise of the sodium action potential increase dramatically (Vmax = 35 to 50 V/sec) and the (BTX)-stimulated 22Na+ uptake is much larger, suggesting that ScTX unmasks channels that are already present but nonfunctional in these immature myotubes. The two different rates of development of the biochemical properties of the sodium channel described in the preceding paper are also reflected in the two separate rates of development of its functional properties. In the absence of ScTX, the amplitude and Vmax of the action potential develop at a slow rate similar to that of the [3H]saxitoxin binding, eventually reaching a Vmax of 158 V/sec by day 10; the BTX-stimulated 22Na+ uptake also rises gradually, reaching 12 nmol of 22Na+/culture/min by day 7.5. In contrast, in the presence of ScTX, the Vmax of the Na+ action potential increases more rapidly, reaching 158 V/sec by day 5 and 220 V/sec by day 10. The BTX-stimulated 22Na+ uptake also increases more rapidly in the presence of ScTX. This rapid rate of development is very similar to that for [125I]ScTX binding. These findings and those in the preceding paper suggest the existence of two types of Na+ channels: an immature, nonfunctional channel capable of binding [125I]ScTX alone, and a mature, functional channel capable of binding both [125I]ScTX and [3H]saxitoxin. They further suggest that the insertion of the immature form of the channel protein into the cell membrane shortly after cell fusion is the first event in the expression of the sodium channel. During development, the sodium channel undergoes a structural change which renders it functional. The possibility that both the appearance of functional sodium channels during development and the rapid induction of functional channels by ScTX in immature myotubes reflect a post-translational modification or aggregation of immature nonfunctional channels is discussed.


Strengthening national decision-making on immunization by building capacity for economic evaluation: Implementing ProVac in Europe.
For many years, low- and middle-income countries have made efforts to strengthen national decision-making on immunization. The Pan American Health Organization (PAHO) ProVac Initiative was established to help expedite the use of evidence-based decision-making around new vaccine introduction. This initiative provides training in user-friendly cost-effectiveness models and supports the development of country-led economic evaluations. Due to the success of the ProVac Initiative in the Americas, and following requests from countries from outside the Americas, the Bill & Melinda Gates Foundation funded a two-year pilot effort to expand the initiative to other world regions. Called the ProVac International Working Group (IWG), this endeavor took place in 2012 and 2013. It was coordinated by PAHO and carried out in collaboration with several international partners, including the Agence de Médecine Préventive (AMP), London School of Hygiene & Tropical Medicine (LSHTM), Program for Appropriate Technology in Health, Sabin Vaccine Institute, United States Centers for Disease Control and Prevention, and the World Health Organization (WHO). In the WHO European Region, technical support was provided by AMP, in close collaboration with the WHO Regional Office for Europe and other ProVac IWG partners. In 2012, AMP, the WHO Regional Office for Europe, and other partners held a training workshop in Dubrovnik, Croatia, for 31 participants from four countries of the WHO European Region. The aim was to train health professionals in standard methods of economic evaluation and to assess regional demand for economic studies to support decision-making on immunization. AMP and the other organizations also supported four national cost-effectiveness studies in the WHO European Region. The assistance included country visits and support over a period of six months, the establishment of multidisciplinary teams of experts, ongoing training on the TRIVAC decision-support model for new-vaccine economic analysis, review of local evidence, recommending key data inputs, and support in presenting results to national decision makers. National cost-effectiveness studies were conducted in four countries: Albania (rotavirus vaccine [RV]), Azerbaijan (pneumococcal conjugate vaccine [PCV]), Croatia (PCV), and Georgia (PCV). All four countries improved their estimates of the burden of disease preventable by the new vaccines. National advisory bodies and ministries of health obtained economic evidence that helped Albania and Croatia to make decisions on introducing the new vaccines. Azerbaijan and Georgia used economic evidence to confirm previously made preliminary decisions to introduce PCV and make corresponding financial commitments. The study helped Albania to obtain access to affordable prices for rotavirus vaccines through participation in the UNICEF procurement mechanism for middle-income countries. Croatia was able to define the PCV price that would make its introduction cost-effective, and can use this figure as a basis for price negotiations. Despite some challenges due to competing national priorities, tight budgets for immunization, and lack of available national data, the ProVac IWG helped to build capacity of national health professionals, support decision-making for the introduction of new vaccines, and promote utilization of economic evidence for making decisions on immunization. This type of strong collaboration among international partners and countries should be scaled up, given that many other countries in the WHO European Region have expressed interest in receiving assistance from the ProVac IWG.


Confession to Make: Inadvertent Confessions and Admissions in United Kingdom and United States Police Contexts.
Previous studies have addressed many different kinds of confessions in police investigations - real, false, coerced, fabricated - and highlighted both psychological and social mechanisms that underlie them. Here, we focus on inadvertent confessions and admissions, which occur when a suspect appears to be confessing without being fully aware of doing so, or when police officers believe they have a confession or admission of guilt when in fact this is not the case. The goal of the study is to explain when, how and why these confessions and admissions occur as well as how they are dealt with in two different jurisdictions, the United States and the United Kingdom. We use a discourse analysis approach because inadvertent confessions and admissions of guilt are the product of miscommunication - they happen because the speaker's meaning and the hearer's meaning are misaligned. The data consist of 50 interviews from the United Kingdom and 50 interrogations from the United States with both English-speaking and non-English speaking suspects. Our results demonstrate that inadvertent confessions can occur in both locales due to reliance on inference, which is inevitable since inference is the backbone of any human communication, as well as due to additional factors such as linguistic, cultural and procedural issues. We found that these phenomena are more frequent and less well controlled for in the United States context due to (a) no systematic checking of understanding, (b) adversarial questioning techniques and an absence of legal representation, and (c) lack of professional, high-quality interpreting. We discuss the implications of our findings for current efforts to improve access to justice, custodial procedures and language services, and we make recommendations for the implementation of our research in professional practice.


[Early diagnosis of orthostasis disturbances].
The observations were carried out in 51 healthy volunteers (26 men and 25 women) who underwent passive orthotest with the registration of thoracic impedance (TI). It was found that women had a higher index of TI both in rest and in dynamics of the performance of the orthostatic test than men. In 10 subjects the increase of TI in orthostasis was higher than 15% that can be supposed to be a criterion of the pathological drop of the venous return. The TI dynamics in performing the orthotest was quicker than changes in AP and the appearance of complains can be taken for a preclinical symptom of latent volume disturbances in the orthostatic regulation that has an important diagnostic value.


The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy.
Reperfusion following intra-arterial stroke therapy is associated with improved clinical outcomes. However, the degree of reperfusion needed to achieve successful outcomes is unknown. The purpose of this analysis was to determine whether the degree of reperfusion has an impact on final infarct volumes and clinical outcomes. A retrospective analysis identified 88 consecutive patients who underwent intra-arterial therapy for acute anterior circulation stroke. Reperfusion was graded by using the TICI scale into none (TICI 0 or 1), partial (TICI 2a), or near-complete (TICI 2b/3). Baseline characteristics were compared. For each of these groups, we compared discharge disposition and final infarct volumes. Near-complete, partial, and no reperfusion occurred in 44.3%, 26.1%, and 29.6% of patients, respectively. Baseline characteristics were similar across all 3 groups. The median NIHSS score was 15. Significant differences in discharge disposition were seen, with 41.0% of the TICI 2b/3 group discharged home versus 17.4% of TICI 2a and 7.7% of TICI 0/1. In-hospital mortality was 12.8% for TICI 2b/3 compared with 39.1% for TICI 2a and 34.6% for TICI 0/1. Patients with near-complete reperfusion were significantly more likely to have infarct volumes ≤70 mL (OR = 12.1; 95% CI, 2.7-54.2), compared with patients with partial reperfusion (OR = 2.2; 95% CI, 0.5-9.6). Significant differences exist in outcomes and infarct volumes between partial (TICI 2a) and near-complete (TICI 2b/3) reperfusion following intra-arterial stroke therapy. Further trials should separately report these groups to facilitate comparison among treatment paradigms.


[Diagnostic possibilities of ultrasonic scanning of the knee joints in osteoarthrosis].
To examine diagnostic potential of arthrosonography (ASG) in diagnosis of tendenitis in combination with synovitis in patients with gonarthrosis stage I-III by Kellgren's classification. A total of 40 patients with gonarthrosis exacerbation were examined with x-ray and ultrasound scanning (80 joints). ASG was made on Aloka-SSD-630 device using two-dimentional scanning in 4 longitudinal and 4 transverse positions. Clinical symptoms of synovitis were predominant in patients with gonarthrosis x-ray stage II (68.3%). In ASG synovitis was detected in 41 (51.25%) of 48 knee joints with clinical picture of synovitis. Ultrasound detected such synovitis signs as increased amount of water in the knee joint cavity and b. suprapatellaris, thickening of the synovial membrane more than 0.3 cm and changes in its structure. Six (7.5%) joints were affected with subclinical synovitis diagnosed only in ASG. Ultrasound visualized Baker's cyst in 5 patients and in 5 knee joints. Periarthritis was detected in 77.5% joints, in 46.25% joints it combined with synovitis, ASG provided differential diagnosis of synovitis with periarthritis. Thinning of the cartilage was detected in most of the joints both in synovitis and in its absence but it was more significant in synovitis (62.5 and 40%, respectively). ASG is an informative diagnostic method in periarthritis and synovitis, including subclinical, and give additional information for x-ray diagnosis in gonarthrosis stage I-III.


Analysis of muscle function in the lower limb after fracture of the diaphysis of the tibia in adults.
We examined the recovery of power in the muscles of the lower limb after fracture of the tibial diaphysis, using a Biodex dynamometer. Recovery in all muscle groups was rapid for 15 to 20 weeks following fracture after which it slowed. Two weeks after fracture the knee flexors and extensors have about 40% of normal power, which rises to 75% to 85% after one year. The dorsiflexors and plantar flexors of the ankle and the invertors and evertors of the subtalar joint are much weaker two weeks after injury, but at one year their mean power is more than that of the knee flexors and extensors. Our findings showed that age, the mode of injury, fracture morphology, the presence of an open wound and the Tscherne grade of closed fractures correlated with muscle power. It is age, however, which mainly determines muscle recovery after fracture of the tibial diaphysis.


Multistress resistance of Saccharomyces cerevisiae is generated by insertion of retrotransposon Ty into the 5' coding region of the adenylate cyclase gene.
Heat shock-resistant mutants, which were isolated by their ability to withstand lethal heat treatment, were characterized. Resistance was demonstrated to be a consequence of insertion of retrotransposon Ty into either the 5' coding or noncoding region, close to the putative initiation codon of the adenylate cyclase gene CYR1 (or CDC35). These heat shock-resistant mutants contained about threefold lower adenylate cyclase activity than wild-type strains. The mutants were also observed to be resistant to other stresses such as UV light and ethanol. These results demonstrate that multistress resistance, which may confer a survival advantage to yeast cells, can be generated by transposition of a Ty element into CYR1.


Gastric acid and pepsin hypersecretion in conscious rabbits.
In conscious, gastric fistula rabbits, gastric acid and pepsin secretion averaged 4.5 +/- 0.1 mmol/h (1.3 mmol.kg-1.h-1) and 4.9 +/- 0.3 IU/h (1.6 IU.kg-1.h-1), respectively; these values represent approximately 40-50% of maximal output. Basal serum gastrin concentrations averaged 24 +/- 4 pg/ml and did not correlate with basal acid secretion. Atropine and vagotomy incompletely inhibited basal acid secretion (by 84 and 50%, respectively) and completely inhibited 2-deoxy-D-glucose-stimulated gastric acid secretion. Atropine and vagotomy similarly inhibited basal pepsin secretion by 50 and 40%, respectively. Ranitidine decreased acid and pepsin secretion, but as with atropine, inhibition was not complete (73 and 37%, respectively). Although omeprazole did not affect pepsin secretion, omeprazole completely inhibited basal acid secretion and elevated postprandial intragastric pH above 5.0. Conscious, gastric fistula rabbits have the highest basal acid and pepsin output among species commonly studied. Both vagal-cholinergic pathways and histamine drive basal acid and pepsin secretion in the rabbit.


Acidianus, Sulfolobus and Metallosphaera surface layers: structure, composition and gene expression.
The cell walls of Sulfolobales species consist of proteinaceous S-layers assembled from two polypeptides, SlaA and SlaB. We isolated the large S-layer protein of Acidianus ambivalens and both S-layer subunits of Sulfolobus solfataricus and Metallosphaera sedula, respectively. The slaAB genes, lying adjacently in the chromosomes, are constitutively transcribed as bicistronic operons in A. ambivalens and S. solfataricus. A smaller slaA transcript appeared in Northern hybridizations of A. ambivalens RNA. PCRs experiments showed that 80-85% of the transcripts stop at an oligo-T terminator downstream of slaA while 15-20% are read through to a second terminator downstream of slaB. The bicistronic operons including promoter and terminator regions are conserved in the Sulfolobales. While no SlaA homologue is found outside the Sulfolobales, SlaB is distantly similar to S-layer proteins of other Crenarchaeota, e.g. the Staphylothermus marinus tetrabrachion. Molecular modelling suggests SlaBs to be composed of 2-3 consecutive beta sandwich domains, a coiled-coil domain of 15-17 nm in length and a C-terminal transmembrane helix. Electron microscopy shows crystalline protein arrays with triangular and hexagonal pores. We propose that the mushroom-shaped 'unit cells' of the Sulfolobales' S-layers consist of three SlaBs anchoring the complex in the membrane and six SlaAs forming the detergent-resistant outer sacculus.


Validity of selected physical activity questions in white Seventh-day Adventists and non-Adventists.
The validity and reliability of selected physical activity questions were assessed in both Seventh-day Adventist (N = 131) and non-Adventist (N = 101) study groups. Vigorous activity questions similar to those used by others and new questions that measured moderate and light activities were included. Validation was external, comparing questionnaire data with treadmill exercise time, resting heart rate, and body mass index (kg.m-2), and internal, comparing data with other similar questions. Both Adventist and non-Adventist males showed significant age-adjusted correlations between treadmill time and a "Run-Walk-Jog Index" (R = 0.28, R = 0.48, respectively). These correlations increased substantially when restricting analysis to exercise speeds exceeding 3 mph (R = 0.39, R = 0.71, respectively). Frequency of sweating and a vigorous physical activity index also correlated significantly with treadmill time in males. Correlations were generally weaker in females. Moderate- and light-intensity questions were not correlated with physical fitness. Internal correlations R = 0.50-0.78) between the above three vigorous activity questions were significant in all groups, and correlations (R = 0.14-0.60) for light and moderate activity questions were also documented. Test-retest reliability coefficients were high for vigorous activity questions (R = 0.48-0.85) and for one set of moderate activity questions (R = 0.43-0.75). No important differences in validity and reliability were found between Adventist and non-Adventists, but the validity of vigorous activity measures was generally weaker in females.


Passive Clearing and 3D Lightsheet Imaging of the Intact and Injured Spinal Cord in Mice.
The spinal cord contains a diverse array of sensory and motor circuits that are essential for normal function. Spinal cord injury (SCI) permanently disrupts neural circuits through initial mechanical damage, as well as a cascade of secondary injury events that further expand the spinal cord lesion, resulting in permanent paralysis. Tissue clearing and 3D imaging have recently emerged as promising techniques to improve our understanding of the complex neural circuitry of the spinal cord and the changes that result from damage due to SCI. However, the application of this technology for studying the intact and injured spinal cord remains limited. Here, we optimized the passive CLARITY technique (PACT) to obtain gentle and efficient clearing of the murine spinal cord without the need for specialized equipment. We demonstrate that PACT clearing enables 3D imaging of multiple fluorescent labels in the spinal cord to assess molecularly defined neuronal populations, acute inflammation, long-term tissue damage, and cell transplantation. Collectively, these procedures provide a framework for expanding the utility of tissue clearing to enhance the study of spinal cord neural circuits, as well as cellular- and tissue-level changes that occur following SCI.


Infection of PTFE mesh 15 years following pedicled TRAM flap breast reconstruction: mechanism and aetiology.
The pedicled transverse rectus abdominis myocutaneous (TRAM) flap procedure is still widely used for breast reconstruction. The repair of the flap harvest site in the transverse rectus abdominis muscle and sheath is often assisted by the use of prosthetic meshes. This decreases the risk of abdominal wall weakness and herniation but, being a foreign body, it also carries the risk of infection. In this report, we describe the case of a 63-year-old patient who, whilst receiving chemotherapy for metastatic breast cancer, presented with an infected polytetrafluoroethylene mesh 15 years after pedicled TRAM flap immediate breast reconstruction. This necessitated mesh removal to treat the infection. Following a thorough review of the English literature, this is the longest recorded presentation of an abdominal prosthetic mesh infection. The mechanism and aetiology of such a late complication are discussed.


Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world.
Pembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease. To analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the real world. Patients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study. Clinical staging of the patients was based on the 8th edition of the American Joint Committee on Cancer TNM staging system. The patients received different treatments based on clinical stage. In brief, patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery. For those who were not candidates for resection, radical concurrent chemoradiotherapy plus pembrolizumab was more preferable. Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab. Long-term survival outcomes such as overall survival (OS), progression-free survival, disease-free survival, long-term adverse effects (AEs), immune maintenance therapy and predictors of immune checkpoint inhibitors (ICIs) efficacy were evaluated. A total of 55 patients with advanced ESCC were enrolled in this retrospective, observational study. The median age was 61 years (range 44-74), with 47.3% (26/55) of the patients in stage IV and 45.5% of the patients had the tumor (25/55) located in the middle third of the esophagus. The median OS in all patients was not reached. The 12-mo OS rate among all patients was 78.8% and the 18-mo OS rate was 72.7%. 9 patients died due to tumor progression and 7 patients died due to treatment-related complications. The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome. Patients with complete response or partial response in all patients (P = 0.005) and in the chemoradiotherapy plus pembrolizumab group (P = 0.007) obtained a better prognosis than non-responders. A total of 20 patients (20/55, 36%) received immune maintenance therapy. Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-to-(leukocyte-neutrophil) ratio did not predict the efficacy of ICIs. Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC, with safe and manageable long-term AEs.


Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy.
Diabetic cardiomyopathy was first defined over four decades ago. It was observed in small post-mortem studies of diabetic patients who suffered from concomitant heart failure despite the absence of hypertension, coronary disease or other likely causal factors, as well as in large population studies such as the Framingham Heart Study. Subsequent studies continue to demonstrate an increased incidence of heart failure in the setting of diabetes independent of established risk factors, suggesting direct effects of diabetes on the myocardium. Impairments in glucose metabolism and handling receive the majority of the blame. The role of concomitant impairments in lipid handling, particularly at the level of the myocardium, has however received much less attention. Cardiac lipid accumulation commonly occurs in the setting of type 2 diabetes and has been suggested to play a direct causal role in the development of cardiomyopathy and heart failure in a process termed as cardiac lipotoxicity. Excess lipids promote numerous pathological processes linked to the development of cardiomyopathy, including mitochondrial dysfunction and inflammation. Although somewhat underappreciated, cardiac lipotoxicity also occurs in the setting of type 1 diabetes. This phenomenon is, however, largely understudied in comparison to hyperglycaemia, which has been widely studied in this context. The current review addresses the changes in lipid metabolism occurring in the type 1 diabetic heart and how they are implicated in disease progression. Furthermore, the pathological pathways linked to cardiac lipotoxicity are discussed. Finally, we consider novel approaches for modulating lipid metabolism as a cardioprotective mechanism against cardiomyopathy and heart failure.


Identification and characterization of five novel MAN2B1 mutations in Italian patients with alpha-mannosidosis.
Mutation analysis performed on six Italian families with alpha-mannosidosis type II allowed the identification of five new mutations in the MAN2B1 gene: c.157G>T, c.562C>T, c.599A>T, c.293dupA, c.2402G>A (p.E53X, p.R188X, p.H200L, p.Y99VfsX61, p.G801D). Protein residues G801 and H200 are conserved among the four mammalian alpha-mannosidases cloned to date: human, cattle, cat and mouse. In vitro expression studies demonstrated that both missense mutations expressed no residual alpha-mannosidase activity indicating that they are disease-causing mutations. Modelling into the three-dimensional structure revealed that the p.H200L could involve the catalytic mechanism, whereas p.G801D would affect the correct folding of the enzyme.


A protocol for the Development of Core Outcome Sets for Endodontic Treatment modalities (COSET): an international consensus process.
The outcome of endodontic treatment is generally assessed using a range of patient and clinician-centred, non-standardised clinical and radiographic outcome measures. This makes it difficult to synthesise evidence for systematic analysis of the literature and the development of clinical guidelines. Core outcome sets (COS) represent a standardised list of outcomes that should be measured and reported in all clinical studies in a particular field. Recently, clinical researchers and guideline developers have focussed on the need for the integration of a patient-reported COS with clinician-centred measures. This study aims to develop a COS that includes both patient-reported outcomes and clinician-centred measures for various endodontic treatment modalities to be used in clinical research and practice. To identify reported outcomes (including when and how they are measured), systematic reviews and their included clinical studies, which focus on the outcome of endodontic treatment and were published between 1990 and 2020 will be screened. The COSs will be defined by a consensus process involving key stakeholders using semi-structured interviews and an online Delphi methodology followed by an interactive virtual consensus meeting. A heterogeneous group of key 'stakeholders' including patients, general dental practitioners, endodontists, endodontic teachers, clinical researchers, students and policy-makers will be invited to participate. Patients will establish, via interactive interviews, which outcomes they value and feel should be included in a COS. In the Delphi process, other stakeholders will be asked to prioritise outcomes identified from the literature and patient interviews and will have the opportunity at the end of the first round to add outcomes that are not included, but which they consider relevant. Feedback will be provided in the second round, when participants will be asked to prioritise the list again. If consensus is reached, the remaining outcomes will be discussed at an online meeting and agreement established via defined consensus rules of outcome inclusion. If consensus is not reached after the second round, a third round will be conducted with feedback, followed by the online meeting. Following the identification of a COS, we will proceed to identify how and when these outcomes are measured. Using a rigorous methodology, the proposed consensus process aims to develop a COS for endodontic treatment that will be relevant to stakeholders. The results of the study will be shared with participants and COS users. To increase COS uptake, it will also be actively shared with clinical guideline developers, research funders and the editors of general dental and endodontology journals. COMET 1879. 21 May 2021.


Role of water in the physical stability of solid dosage formulations.
The interaction of moisture with pharmaceutical solids is highly crucial to an understanding of water-based processes, for example, manufacturing processes or prediction of solid dosage form stability and shelf life. Both the active pharmaceutical ingredient (API) and excipients in the formulation have different moisture sorption properties that can result in unexpected processing-induced phase transitions and they can affect solid-state phase transitions in the final dosage forms. The character of excipient effects on the stability of formulation. Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The aim of the present study was to investigate the water sorption properties of different excipients, model the sorption isotherms, examine the phase transitions, and identify differences of excipients in solid dosage form stability using dynamic vapor sorption analysis, near-infrared spectroscopy, and X-ray diffraction methods. The thermal processing was carried out with a variable temperature X-ray powder diffractometer to compare the dehydration behavior of wet excipients and evaluate solid-state properties during heating. These results showed that despite some limitations, moisture sorption isotherms of excipients are useful in predicting solid-state stability, interactions at early stages of formulation development, and effects of moisture on physicochemical properties of the final dosage forms.


Artemisinin: an alternative treatment for oral squamous cell carcinoma.
Artemisinin (AR) is a widely used antimalarial drug. Recently, additional uses for AR as an anticancer drug were discovered. Using TUNEL, immunohistochemistry (IHS) markers and flow cytometry techniques, we evaluated the effect of AR and 5-FU on HPV 16 immortalized and transformed human gingival epithelial (IHGK) cells. The results of TUNEL showed that AR-treated IHGK cells consisted of 82% positive cells, while 5-FU-treated cells consisted of 18% positive cells. The IHS markers demonstrated positive staining with Bax p53, CD40 and CD40L in AR-treated cells and negative staining with Bcl-2. 5-FU-treated cells demonstrated a profile similar to AR but with less intensity. Cell cycle by flow cytometry results showed that only 5-FU-treated cells demonstrated a significant S-phase rate increase to 45%. In conclusion, our results indicate that AR is cytotoxic to transformed oral epithelial cells through apoptosis, while 5-FU is cytotoxic primarily through cell toxicity.


Strategies for Constructing and Operating DNA Origami Linear Actuators.
Linear actuators are ubiquitous components at all scales of engineering. DNA nanotechnology offers a unique opportunity for bottom-up assembly at the molecular scale, providing nanoscale precision with multiple methods for constructing and operating devices. In this paper, DNA origami linear actuators with up to 200 nm travel, based on a rail threading a topologically locked slider, are demonstrated. Two strategies, one- and two-pot assembly, are demonstrated whereby the two components are folded from one or two DNA scaffold strands, respectively. In order to control the position of the slider on the rail, the rail and the inside of the slider are decorated with single-stranded oligonucleotides with distinct sequences. Two positioning strategies, based on diffusion and capture of signaling strands, are used to link the slider reversibly to determined positions on the rail with high yield and precision. These machine components provide a basis for applications in molecular machinery and nanoscale manufacture including programmed chemical synthesis.


FHIT loss of function in human primary breast cancer correlates with advanced stage of the disease.
The FHIT gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a tumor suppressor gene involved in different tumor types. We have assessed 29 human primary breast carcinomas for both the presence of abnormal FHIT transcripts and the Fhit protein levels as compared with the normal breast epithelium of the same patients. In addition, we have also examined a second retrospective series of 156 consecutive breast carcinomas for the expression of the Fhit protein. In nine (31%) cases of the first series, FHIT transcripts were either aberrant or absent as determined by reverse transcription-PCR, and Fhit protein levels in tumors were low or absent as determined immunohistochemically. In 11 other cases (38%), only normal FHIT transcripts were detected by PCR, paralleled by the reduction or absence of Fhit protein. In the remaining nine cases (31%), the presence of the normal FHIT transcript corresponded to protein levels that were similar in tumor and normal breast epithelia. Thus, alterations in FHIT transcripts were detected in 31% of the patients, but reduction or absence of Fhit protein occurred in 69% of the breast carcinoma samples examined. These data suggest that alteration in Fhit expression in breast carcinomas is a frequent event. Analysis of correlation between Fhit expression and pathological, clinical, and biological parameters in these 29 tumors and in a second retrospective series of 156 consecutive primary breast carcinomas indicated that a decrease or an absence of Fhit protein expression is associated with high proliferation and large tumor size.


Responses of Neurons in the Medullary Lateral Tegmental Field and Nucleus Tractus Solitarius to Vestibular Stimuli in Conscious Felines.
Considerable evidence shows that the vestibular system contributes to adjusting sympathetic nervous system activity to maintain adequate blood pressure during movement and changes in posture. However, only a few prior experiments entailed recordings in conscious animals from brainstem neurons presumed to convey baroreceptor and vestibular inputs to neurons in the rostral ventrolateral medulla (RVLM) that provide inputs to sympathetic preganglionic neurons in the spinal cord. In this study, recordings were made in conscious felines from neurons in the medullary lateral tegmental field (LTF) and nucleus tractus solitarius (NTS) identified as regulating sympathetic nervous system activity by exhibiting changes in firing rate related to the cardiac cycle, or cardiac-related activity (CRA). Approximately 38% of LTF and NTS neurons responded to static 40° head up tilts with a change in firing rate (increase for 60% of the neurons, decrease for 40%) of ~50%. However, few of these neurons responded to 10° sinusoidal rotations in the pitch plane, in contrast to prior findings in decerebrate animals that the firing rates of both NTS and LTF neurons are modulated by small-amplitude body rotations. Thus, as previously demonstrated for RVLM neurons, in conscious animals NTS and LTF neurons only respond to large rotations that lead to changes in sympathetic nervous system activity. The similar responses to head-up rotations of LTF and NTS neurons with those documented for RVLM neurons suggest that LTF and NTS neurons are components of the vestibulo-sympathetic reflex pathway. However, a difference between NTS/LTF and RVLM neurons was variability in CRA over time. This variability was significantly greater for RVLM neurons, raising the hypothesis that the responsiveness of these neurons to baroreceptor input is adjusted based on the animal's vigilance and alertness.


Lentivirus-Mediated VEGF Knockdown Suppresses Gastric Cancer Cell Proliferation and Tumor Growth in vitro and in vivo.
Gastric cancer has a high mortality rate worldwide. Although treatments, such as molecular-targeted therapy, have been introduced, the resulting long-term survival and prognosis remain unsatisfactory. Downregulation of the target genes using lentivirus-mediated short hairpin RNA (shRNA) can be an effective therapeutic strategy for patients with gastric cancer. Overexpressed vascular endothelial growth factor A (VEGF) in human gastric cancer cells can be an effective novel therapeutic target for human gastric cancer. Thus, this study aimed to evaluate the therapeutic effects of lentivirus-mediated knockdown of VEGF gene expression in human gastric cancer growth. Specific shRNA sequences targeting VEGF were designed to construct a lentiviral expression vector. After human gastric carcinoma cells (cell line NCI-N87) were infected with the lentiviral vector, the therapeutic effects of the lentivirus-mediated shRNA targeting VEGF were analyzed both in vitro and in vivo. Stable suppression of VEGF gene expression in NCI-N87 cells using shRNA (ShVEGF) showed significant inhibition of cell proliferation, clonogenicity, and cell motility. ShVEGF also showed increased G0/G1 cell cycle arrest and apoptosis. In addition, in vivo results from nude mice xenografted ShVEGF showed significant inhibition of tumor growth. Assessing the therapeutic effects of intratumoral injection of lentivirus-targeting VEGF (Virus_VEGF) revealed that it significantly inhibited tumor growth compared to that in the Virus_Scramble or saline injection control groups. The constructed ShVEGF showed significant inhibition of NCI-N87 gastric cancer cell growth both in vitro and in vivo. These experimental results suggest a novel therapeutic strategy for patients with gastric cancer using lentivirus-mediated shRNA targeting VEGF.


Energy and nutrient intake of young-old, old-old and very-old elderly in Germany.
Reliable information about the nutritional status of elderly people in Germany is lacking. To describe energy and nutrient intake of elderly people living in private households in Germany with special focus on age-related differences in the elderly. Descriptive nationwide cross-sectional study. Germany, 1998. : A random sample of 4020 elderly men and women living independently in private households stratified in three age groups (65-74, 75-84, 85+ y), of which 1550 participated and 1372 (789 female subjects) provided reliable 3-day estimated dietary records. The median daily energy intake was 2207 kcal (9.2 MJ) in men and 1994 kcal (8.3 MJ) in women without difference between the age groups. Protein intake amounted to 91 and 81 g/day, respectively, corresponding to 1.2 g/kg body weight per day. The median intake was well above the recommended amount for all nutrients except dietary fibre, calcium, vitamin D and folate, where 38, 35, 75 and 37% did not reach two-thirds of the recommended amount. An age-related decline was observed for calcium intake in male and for dietary fibre, water, calcium, magnesium, iron, vitamins A, E, C and thiamin intake in female participants; however, the overall picture was unaffected by these differences. Dietary intake in these independently living elderly, including the very-old, is adequate for most of the evaluated nutrients. Increased intake of foods rich in dietary fibre, calcium, vitamin D and folate as well as regular sunlight exposure is recommended in order to optimize nutrient supply in this population group. German Ministry of Health.


Animal models of chronic bronchitis and their relevance to studies of particle-induced disease.
Chronic bronchitis is a significant cause of morbidity and mortality. Chronic irritation of the conducting airways by inhaled substances, most importantly cigarette smoke, air pollution, and occupational exposures, is thought to be a key factor in the pathogenesis of chronic bronchitis. Microbial infections have been implicated in acute exacerbations of bronchitis and in its progression. Several animal models of chronic bronchitis have been developed. This review examines similarities and dissimilarities among commonly used animal models of bronchitis and the human disease. The most commonly used animal models of chronic bronchitis are those employing SO2, tobacco smoke, lipopolysaccharide (endotoxin), proteases, and secretagogues. Bronchiolitis induced by nickel and nitric acid have also been reported. Rats, hamsters, and dogs are the species most frequently used; sheep and monkeys have been used less frequently. These models vary in the extent or location of mucous-cell hyperplasia and metaplasia, airway inflammation, chronicity, ease of induction, and reproducibility. Frequently, the deficiencies in these models are attributable to anatomic differences between human and animal airways, differences in the severity or chronicity of inflammation or fibrosis, or lack of complete characterization of the responses and their time course in the animal model. These animal models may be useful for investigating how, and under what exposure conditions, ambient pollutants might exacerbate airway inflammation, mucus hypersecretion, and airflow limitation.


Homologous and heterologous protein import into mitochondria isolated from the green alga Chlamydomonas reinhardtii.
We have established a homologous system for studying mitochondrial protein import in Chlamydomonas reinhardtii, using C. reinhardtii precursor proteins and mitochondria isolated from C. reinhardtii. The precursors of the F1 alpha ATP synthase subunit and the Rieske FeS protein were imported into mitochondria with high efficiency, while the F1 beta subunit precursor was imported with much lower efficiency. The import of heterologous precursor proteins from higher plants was also less efficient. The precursor of the C. reinhardtii PsaF chloroplast protein was converted into a protease-protected form upon incubation with mitochondria. In vitro processing studies revealed that in contrast to the situation in higher plants, the processing of the precursors was catalysed by a soluble, matrix-located peptidase.


Anatomical Study on the Variations in the Branching Pattern of Internal Iliac Artery.
The internal iliac artery (IIA) arises from the common iliac artery at the level of the sacroiliac joint. It descends as trunk, divides into anterior and posterior divisions. From the anterior division it gives superior vesical, obturator, middle rectal, inferior vesical, inferior gluteal, and internal pudendal arteries. In females, inferior vesical artery is replaced by vaginal artery and gives an additional branch, uterine artery. The branches from the posterior division are ilio lumbar, lateral sacral, and superior gluteal arteries. An accidental hemorrhage and neurovascular injuries are common due to erroneous interpretation of variant arteries during surgical procedures. Hence the present study has been undertaken with reference to highlight its clinical and surgical significances. The study included 50 human bisected pelvises irrespective of their side and sex. Formalin-fixed specimens were selected and the branching patterns of IIA were studied. The level of origin, length, and the branching pattern of the IIA were examined and tabulated. The present study highlighted the variation seen in the origin, division branches of the IIA. The detailed knowledge of morphology is essential for successful ligation of the IIA during acute hemorrhage. This will guide the interventional radiologist in intra-arterial procedures during arterial embolization for hemorrhage, control of pelvic fractures, during selective catheterization of the intra-arterial chemotherapy, and embolization of the pelvic tumors.


Murine alpha-2-macroglobulin: localization on a subpopulation of macrophages.
We have previously shown that mouse peritoneal macrophages synthesize and secrete alpha-2-macroglobulin (alpha 2M) in culture. We have now examined whether alpha 2M delineates a subpopulation of murine macrophages. Mouse alpha 2M was purified from plasma by gel filtration and immunoabsorption to remove IgM. Purified alpha 2M was an active proteinase inhibitor, had a pI of 4.8, and a relative molecular mass (Mr) of 765 kD which dropped to 194 kD on reduction. Antisera raised against mouse alpha 2M were not cross-reactive with guinea pig or human alpha 2M, or with antigens in guinea pig, human, bovine or equine serum. One to 18 per cent of freshly isolated bone marrow, resident peritoneal or induced peritoneal macrophages displayed immunoreactive cytoplasmic and surface alpha 2M as detected by single cell immunoperoxidase assay or flow cytometry. alpha 2M was not detected in or on thymocytes or bone marrow lymphocytes. In culture, bone marrow-derived macrophages displayed peak levels of cytoplasmic alpha 2M on day 7 and two peaks of surface alpha 2M on days 2-3 and 5-7. The fact that alpha 2M can function as an anti-proteinase, can modulate lymphokine production and is present on inflammatory macrophages suggests a regulatory role for macrophages bearing and secreting this molecule at tissue sites of inflammation.


Molecular structure of the Dr adhesin: nucleotide sequence and mapping of receptor-binding domain by use of fusion constructs.
The Dr hemagglutinin of uropathogenic Escherichia coli mediates adherence to the upper urinary tract. E. coli strains which express this adhesin bind to the Dr blood group antigen and mediate mannose-resistant hemagglutination (MRHA). Chloramphenicol inhibits MRHA produced by the Dr hemagglutinin and may act as an analog for the tissue receptor at the adhesin-binding site. The nucleotide sequence of the Dr hemagglutinin fimbrial subunit was determined and found to have significant homology with that of F1845, a fimbrial adhesin associated with diarrhea, and with the afimbrial adhesin AFA-I of uropathogenic E. coli. Chimeric adhesin determinants consisting of the Dr structural subunit and F1845 accessory genes or of the F1845 structural subunit and Dr accessory genes were constructed. The Dr and F1845 determinants were shown to have a close structural relationship, with functional differences concentrated in the fimbrial subunit. Oligonucleotide-directed site-specific mutagenesis was used to facilitate construction of a hybrid adhesin subunit gene containing the amino terminus of F1845 fused to the carboxy terminus of the Dr structural gene. The resulting construct confers chloramphenicol-resistant hemagglutination when introduced into an E. coli strain expressing the cloned Dr hemagglutinin. The chloramphenicol sensitivity or resistant phenotype of MRHA produced by this family of adhesins is determined solely by the fimbrial subunit gene. Domains responsible for the chloramphenicol sensitivity of Dr-mediated MRHA reside within the amino-terminal portion of the fimbrial subunit.


Advances in ultrasensitive mass spectrometry of organic molecules.
Ultrasensitive mass spectrometric analysis of organic molecules is important for various branches of chemistry, and other fields including physics, earth and environmental sciences, archaeology, biomedicine, and materials science. It finds applications--as an enabling tool--in systems biology, biological imaging, clinical analysis, and forensics. Although there are a number of technical obstacles associated with the analysis of samples by mass spectrometry at ultratrace level (for example analyte losses during sample preparation, insufficient sensitivity, ion suppression), several noteworthy developments have been made over the years. They include: sensitive ion sources, loss-free interfaces, ion optics components, efficient mass analyzers and detectors, as well as "smart" sample preparation strategies. Some of the mass spectrometric methods published to date can achieve sensitivity which is by several orders of magnitude higher than that of alternative approaches. Femto- and attomole level limits of detection are nowadays common, while zepto- and yoctomole level limits of detection have also been reported. We envision that the ultrasensitive mass spectrometric assays will soon contribute to new discoveries in bioscience and other areas.


MRI findings of Persistent Mullerian Duct Syndrome: A Rare Case Report.
Embryologically mullerian duct derivatives lead to formation of female genitalia and wolffian duct derivatives to male genitalia. Presence of mullerian duct derivatives in a chromosomally normal male (XY) leads to male pseudohermaphroditism and is referred to as Persistent Mullerian Duct Syndrome (PMDS). A young male patient with bilateral cryptorchidism presented to our hospital who was subsequently imaged. There are many case reports of persistent mullerian duct syndrome but they focus mainly on surgical aspects. In this article, MRI features of persistent müllerian duct syndrome are presented.


Scaffolds and Cell-Based Tissue Engineering for Blood Vessel Therapy.
The increasing morbidity of cardiovascular diseases in modern society has made it crucial to develop a small-caliber blood vessel. In the absence of appropriate autologous vascular grafts, an alternative prosthesis must be constructed for cardiovascular disease patients. The aim of this article is to describe the advances in making cell-seeded cardiovascular prostheses. It also discusses the combinations of types of scaffolds and cells, especially autologous stem cells, which are suitable for application in tissue-engineered vessels with the favorable properties of mechanical strength, antithrombogenicity, biocompliance, anti-inflammation, fatigue resistance and long-term durability. This article highlights the advancements in cellular tissue-engineered vessels in recent years.


Improving a Gold Standard: Treating Human Relevance Judgments of MEDLINE Document Pairs.
Given prior human judgments of the condition of an object it is possible to use these judgments to make a maximal likelihood estimate of what future human judgments of the condition of that object will be. However, if one has a reasonably large collection of similar objects and the prior human judgments of a number of judges regarding the condition of each object in the collection, then it is possible to make predictions of future human judgments for the whole collection that are superior to the simple maximal likelihood estimate for each object in isolation. This is possible because the multiple judgments over the collection allow an analysis to determine the relative value of a judge as compared with the other judges in the group and this value can be used to augment or diminish a particular judge's influence in predicting future judgments. Here we study and compare five different methods for making such improved predictions and show that each is superior to simple maximal likelihood estimates.


Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair.
Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of a multiprotein UV-DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site. Here, we show that PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote GG-NER. It forms a stable complex with XPC in the nucleoplasm under steady-state conditions before irradiation and rapidly escorts it to the damaged DNA after UV irradiation in a DDB2-independent manner. The catalytic activity of PARP1 is not required for the initial complex formation with XPC in the nucleoplasm but it enhances the recruitment of XPC to the DNA lesion site after irradiation. Using purified proteins, we also show that the PARP1-XPC complex facilitates the handover of XPC to the UV-lesion site in the presence of the UV-DDB ligase complex. Thus, the lesion search function of XPC in the genomic context is controlled by XPC itself, DDB2, and PARP1. Our results reveal a paradigm that the known interaction of many proteins with PARP1 under steady-state conditions could have functional significance for these proteins.


Branch point strength controls species-specific CAMK2B alternative splicing and regulates LTP.
Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific CAMK2B alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing novel mechanistic insight into cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9, we introduce a weaker, human branch point sequence into the mouse genome, resulting in strongly altered Camk2b splicing in the brains of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled CAMK2B alternative splicing with a fundamental function in learning and memory.


Clinical and healthcare improvement through My Health Record usage and education in general practice (CHIME-GP): a study protocol for a cluster-randomised controlled trial.
There is an international interest in whether improved primary care can lead to a more rational use of health resources. There is evidence that educational interventions can lead to improvements in the quality of rational prescribing and test ordering. A new national platform for shared medical records in Australia, My Health Record (MHR), poses new opportunities and challenges for system-wide implementation. This trial (CHIME-GP) will investigate whether components of a multifaceted education intervention in an Australian general practice setting on rational prescribing and investigation ordering leads to reductions in health-service utilisation and costs in the context of the use of a national digital health record system. The trial will be undertaken in Australian general practices. The aim of the research is to evaluate the effectiveness of components of a web-based educational intervention for general practitioners, regarding rational use of medicines, pathology and imaging in the context of the use of the MHR system. Our target is to recruit 120 general practitioners from urban and regional regions across Australia. We will use a mixed methods approach incorporating a three-arm pragmatic cluster randomised parallel trial and a prospective qualitative inquiry. The effect of each education component in each arm will be assessed, using the other two arms as controls. The evaluation will synthesise the results embedding qualitative pre/post interviews in the quantitative results to investigate implementation of the intervention, clinical behaviour change and mechanisms such as attitudes, that may influence change. The primary outcome will be an economic analysis of the cost per 100 consultations of selected prescriptions, pathology and radiology test ordering in the 6 months following the intervention compared with 6 months prior to the intervention. Secondary outcome measures include the rates per 100 consultations of selected prescriptions, pathology and radiology test ordering 6 months pre- and post-intervention, and comparison of knowledge assessment tests pre- and post-intervention. The trial will produce robust health economic analyses on the evidence on educational intervention in reducing unnecessary prescribing, pathology and imaging ordering, in the context of MHR. In addition, the study will contribute to the evidence-base concerning the implementation of interventions to improve the quality of care in primary care practice. ClinicalTrials.gov ACTRN12620000010998 . Registered on 09 January 2020 with the Australian New Zealand Clinical Trials Registry.


SPT5 stabilizes RNA polymerase II, orchestrates transcription cycles, and maintains the enhancer landscape.
Transcription progression is governed by multitasking regulators including SPT5, an evolutionarily conserved factor implicated in virtually all transcriptional steps from enhancer activation to termination. Here we utilize a rapid degradation system and reveal crucial functions of SPT5 in maintaining cellular and chromatin RNA polymerase II (Pol II) levels. Rapid SPT5 depletion causes a pronounced reduction of paused Pol II at promoters and enhancers, distinct from negative elongation factor (NELF) degradation resulting in short-distance paused Pol II redistribution. Most genes exhibit downregulation, but not upregulation, accompanied by greatly impaired transcription activation, altered chromatin landscape at enhancers, and severe Pol II processivity defects at gene bodies. Phosphorylation of an SPT5 linker at serine 666 potentiates pause release and is antagonized by Integrator-PP2A (INTAC) targeting SPT5 and Pol II, while phosphorylation of the SPT5 C-terminal region links to 3' end termination. Our findings position SPT5 as an essential positive regulator of global transcription.


Science and religion: friends or foes?
There is a widespread assumption that science and religion are incompatible with each other; it may be acceptable for a scientist to practise religion, but--it is believed--this should be seen as despite, not because of his or her scientific profession and knowledge. Such an assumption is wrong. Examination of conflicts between science and religion (such as those about evolution) show that they always arise through misinterpretation or tenacious presuppositions. Unfortunately protagonists (both anti-religion and anti-science) receive more publicity than conciliators. This paper reviews some of the background and development of arguments over creation and evolution and shows that there is no need to choose between a rigorous scientific approach and an avowedly religious acknowledgement of God as creator and sustainer.


Hyperbolic Deep Neural Networks: A Survey.
Recently, hyperbolic deep neural networks (HDNNs) have been gaining momentum as the deep representations in the hyperbolic space provide high fidelity embeddings with few dimensions, especially for data possessing hierarchical structure. Such a hyperbolic neural architecture is quickly extended to different scientific fields, including natural language processing, single-cell RNA-sequence analysis, graph embedding, financial analysis, and computer vision. The promising results demonstrate its superior capability, significant compactness of the model, and a substantially better physical interpretability than its counterpart in the euclidean space. To stimulate future research, this paper presents a comprehensive review of the literature around the neural components in the construction of HDNN, as well as the generalization of the leading deep approaches to the hyperbolic space. It also presents current applications of various tasks, together with insightful observations and identifying open questions and promising future directions.