BCL3 encodes a nuclear protein which can alter the subcellular location of NF-kappa B proteins.
BCL3 is a candidate proto-oncogene involved in the recurring translocation t(14;19) found in some patients with chronic lymphocytic leukemia. BCL3 protein acts as an I kappa B in that it can specifically inhibit the DNA binding of NF-kappa B factors. Here, we demonstrate that BCL3 is predominantly a nuclear protein and provide evidence that its N terminus is necessary to direct the protein into the nucleus. In contrast to I kappa B alpha (MAD3), BCL3 does not cause NF-kappa B p50 to be retained in the cytoplasm; instead, in cotransfection assays, it alters the subnuclear localization of p50. The two proteins colocalize, suggesting that they interact in vivo. Further immunofluorescence experiments showed that a mutant p50, lacking a nuclear localization signal and restricted to the cytoplasm, is brought into the nucleus in the presence of BCL3. Correspondingly, a wild-type p50 directs into the nucleus a truncated BCL3, which, when transfected alone, is found in the cytoplasm. We tested whether BCL3 could overcome the cytoplasmic retention of p50 by I kappa B alpha. Results from triple cotransfection experiments with BCL3, I kappa B alpha, and p50 implied that BCL3 can successfully compete with I kappa B alpha and bring p50 into the nucleus; thus, localization of NF-kappa B factors may be affected by differential expression of I kappa B proteins. These novel properties of BCL3 protein further establish BCL3 as a distinctive member of the I kappa B family.


Safety and efficacy of GalliPro® Fit (Bacillus subtilis DSM 32324, Bacillus subtilis DSM 32325 and Bacillus amyloliquefaciens DSM 25840) for all poultry species for fattening or reared for laying/breeding.
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of GalliPro® Fit (Bacillus subtilis DSM 32324, B. subtilis DSM 32325 and Bacillus amyloliquefaciens DSM 25840) when used as a zootechnical additive in feed and water for drinking for all poultry species for fattening or reared for laying/breeding. The two bacterial species present in the additive are considered suitable for the qualified presumption of safety (QPS) approach to safety assessment. The identity of the active agents was established and the lack of toxigenic potential confirmed. The strains did not show resistance to relevant antibiotics. Therefore, the additive was presumed safe for the target species, consumers and the environment. In the absence of data, no conclusions could be drawn on the skin/eye irritancy or skin sensitisation of the additive. Due to the proteinaceous nature of the active agents, the additive was considered a respiratory sensitiser. The Panel concluded that GalliPro® Fit is compatible with diclazuril, decoquinate and halofuginone. However, the data provided did not allow to conclude on the compatibility of the additive with other coccidiostats. The Panel concluded that the additive has a potential to be efficacious in chickens for fattening at 1.6 × 109 CFU/kg feed and at 5.4 × 108 CFU/L water for drinking. The conclusion was extrapolated to all other poultry species for fattening or reared for laying/breeding. The results from the study in turkeys support this conclusion.


High-resolution three-dimensional tomographic diffractive microscopy of transparent inorganic and biological samples.
We have developed a tomographic diffractive microscope, equipped with a fluorescence confocal scanner. We measure experimentally the lateral resolution using an edge method and by comparing tomographic images of the same samples with wide-field and laser scanning confocal microscopy images; a scanning electron microscope image serves as a reference. The experimental resolution is shown to be to about 130 nm, or lambda/(3.5 NA). This instrument also permits one to measure 3D, complex index of refraction distributions, a quantity that is not accessible to conventional microscopes, and we show how this feature may be used to observe KCl crystals, absorption of which is very weak.


The Drosophila gene taranis encodes a novel trithorax group member potentially linked to the cell cycle regulatory apparatus.
Genes of the Drosophila Polycomb and trithorax groups (PcG and trxG, respectively) influence gene expression by modulating chromatin structure. Segmental expression of homeotic loci (HOM) initiated in early embryogenesis is maintained by a balance of antagonistic PcG (repressor) and trxG (activator) activities. Here we identify a novel trxG family member, taranis (tara), on the basis of the following criteria: (i) tara loss-of-function mutations act as genetic antagonists of the PcG genes Polycomb and polyhomeotic and (ii) they enhance the phenotypic effects of mutations in the trxG genes trithorax (trx), brahma (brm), and osa. In addition, reduced tara activity can mimic homeotic loss-of-function phenotypes, as is often the case for trxG genes. tara encodes two closely related 96-kD protein isoforms (TARA-alpha/-beta) derived from broadly expressed alternative promoters. Genetic and phenotypic rescue experiments indicate that the TARA-alpha/-beta proteins are functionally redundant. The TARA proteins share evolutionarily conserved motifs with several recently characterized mammalian nuclear proteins, including the cyclin-dependent kinase regulator TRIP-Br1/p34(SEI-1), the related protein TRIP-Br2/Y127, and RBT1, a partner of replication protein A. These data raise the possibility that TARA-alpha/-beta play a role in integrating chromatin structure with cell cycle regulation.


Design of novel disturbing peptides against ACE2 SARS-CoV-2 spike-binding region by computational approaches.
The SARS-CoV-2, the virus which is responsible for COVID-19 disease, employs its spike protein to recognize its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequently enters the host cell. In this process, the receptor-binding domain (RBD) of the spike has an interface with the α1-helix of the peptidase domain (PD) of ACE2. This study focuses on the disruption of the protein-protein interaction (PPI) of RBD-ACE2. Among the residues in the template (which was extracted from the ACE2), those with unfavorable energies were selected for substitution by mutagenesis. As a result, a library of 140 peptide candidates was constructed and the binding affinity of each candidate was evaluated by molecular docking and molecular dynamics simulations against the α1-helix of ACE2. Finally, the most potent peptides P23 (GFNNYFPHQSYGFMPTNGVGY), P28 (GFNQYFPHQSYGFPPTNGVGY), and P31 (GFNRYFPHQSYGFCPTNGVGY) were selected and their dynamic behaviors were studied. The results showed peptide inhibitors increased the radius, surface accessible area, and overall mobility of residues of the protein. However, no significant alteration was seen in the key residues in the active site. Meanwhile, they can be proposed as promising agents against COVID-19 by suppressing the viral attachment and curbing the infection at its early stage. The designed peptides showed potency against beta, gamma, delta, and omicron variants of SARS-CoV-2.


Cyclin D1 overexpression perturbs DNA replication and induces replication-associated DNA double-strand breaks in acquired radioresistant cells.
Fractionated radiotherapy (RT) is widely used in cancer treatment, because it preserves normal tissues. However, repopulation of radioresistant tumors during fractionated RT limits the efficacy of RT. We recently demonstrated that a moderate level of long-term fractionated radiation confers acquired radioresistance to tumor cells, which is caused by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression. The resulting cyclin D1 overexpression leads to forced progression of the cell cycle to S-phase, concomitant with induction of DNA double-strand breaks (DSBs). In this study, we investigated the molecular mechanisms underlying cyclin D1 overexpression-induced DSBs during DNA replication in acquired radioresistant cells. DNA fiber data demonstrated that replication forks progressed slowly in acquired radioresistant cells compared with corresponding parental cells in HepG2 and HeLa cell lines. Slowly progressing replication forks were also observed in HepG2 and HeLa cells that overexpressed a nondegradable cyclin D1 mutant. We also found that knockdown of Mus81 endonuclease, which is responsible for resolving aberrant replication forks, suppressed DSB formation in acquired radioresistant cells. Consequently, Mus81 created DSBs to remove aberrant replication forks in response to replication perturbation triggered by cyclin D1 overexpression. After treating cells with a specific inhibitor for DNA-PK or ATM, apoptosis rates increased in acquired radioresistant cells but not in parental cells by inhibiting the DNA damage response to cyclin D1-mediated DSBs. This suggested that these inhibitors might eradicate acquired radioresistant cells and improve fractionated RT outcomes.


Speciation of human plasma high-density lipoprotein (HDL): HDL stability and apolipoprotein A-I partitioning.
The distribution of apolipoprotein (apo) A-I between human high-density lipoproteins (HDL) and water is an important component of reverse cholesterol transport and the atheroprotective effects of HDL. Chaotropic perturbation (CP) with guanidinium chloride (Gdm-Cl) reveals HDL instability by inducing the unfolding and transfer of apo A-I but not apo A-II into the aqueous phase while forming larger apo A-I deficient HDL-like particles and small amounts of cholesteryl ester-rich microemulsions (CERMs). Our kinetic and hydrodynamic studies of the CP of HDL species separated according to size and density show that (1) CP mediated an increase in HDL size, which involves quasi-fusion of surface and core lipids, and release of lipid-free apo A-I (these processes correlate linearly), (2) >94% of the HDL lipids remain with an apo A-I deficient particle, (3) apo A-II remains associated with a very stable HDL-like particle even at high levels of Gdm-Cl, and (4) apo A-I unfolding and transfer from HDL to water vary among HDL subfractions with the larger and more buoyant species exhibiting greater stability. Our data indicate that apo A-I's on small HDL (HDL-S) are highly dynamic and, relative to apo A-I on the larger more mature HDL, partition more readily into the aqueous phase, where they initiate the formation of new HDL species. Our data suggest that the greater instability of HDL-S generates free apo A-I and an apo A-I deficient HDL-S that readily fuses with the more stable HDL-L. Thus, the presence of HDL-L drives the CP remodeling of HDL to an equilibrium with even larger HDL-L and more lipid-free apo A-I than with either HDL-L or HDL-S alone. Moreover, according to dilution studies of HDL in 3 M Gdm-Cl, CP of HDL fits a model of apo A-I partitioning between HDL phospholipids and water that is controlled by the principal of opposing forces. These findings suggest that the size and relative amount of HDL lipid determine the HDL stability and the fraction of apo A-I that partitions into the aqueous phase where it is destined for interaction with ABCA1 transporters, thereby initiating reverse cholesterol transport or, alternatively, renal clearance.


Determinants of the electric field during transcranial direct current stimulation.
Transcranial direct current stimulation (tDCS) causes a complex spatial distribution of the electric current flow in the head which hampers the accurate localization of the stimulated brain areas. In this study we show how various anatomical features systematically shape the electric field distribution in the brain during tDCS. We constructed anatomically realistic finite element (FEM) models of two individual heads including conductivity anisotropy and different skull layers. We simulated a widely employed electrode montage to induce motor cortex plasticity and moved the stimulating electrode over the motor cortex in small steps to examine the resulting changes of the electric field distribution in the underlying cortex. We examined the effect of skull thickness and composition on the passing currents showing that thinner skull regions lead to higher electric field strengths. This effect is counteracted by a larger proportion of higher conducting spongy bone in thicker regions leading to a more homogenous current over the skull. Using a multiple regression model we could identify key factors that determine the field distribution to a significant extent, namely the thicknesses of the cerebrospinal fluid and the skull, the gyral depth and the distance to the anode and cathode. These factors account for up to 50% of the spatial variation of the electric field strength. Further, we demonstrate that individual anatomical factors can lead to stimulation "hotspots" which are partly resistant to electrode positioning. Our results give valuable novel insights in the biophysical foundation of tDCS and highlight the importance to account for individual anatomical factors when choosing an electrode montage.


In-situ electrochemical measurements of total concentration and speciation of heavy metals in acid mine drainage (AMD): assessment of the use of anodic stripping voltammetry.
We assessed the use of anodic stripping voltammetry (ASV) for in-situ determinations of both total concentration and speciation of dissolved heavy metals (Cd, Cu, Pb and Zn) in acid mine drainage (AMD). In the Kwangyang Au-Ag mine area of South Korea, different sites with varying water chemistry within an AMD were studied with a field portable anodic stripping voltammeter. Anodic stripping voltammetry after wet oxidation (acidification) was very sensitive enough to determine total concentration of dissolved Cd because Cd was dominantly present as 'labile' species, whilst the technique was not so effective for determining total Cu especially in the downstream sites from the retention pond, due to its complexation with organic matter. For dissolved Pb, the concentrations determined by ASV after wet oxidation generally agreed with those by ICP-AES. In the downstream samples (pH>5), however, ASV data after wet oxidation were lower than ICP-AES data because a significant fraction of dissolved Pb was present in those samples as 'inert' species associated with colloidal iron oxide particles. The determination of total dissolved Zn by ASV after wet oxidation appeared to be unsatisfactory for the samples with high Cu content, possibly due to the interference by the formation of Zn-Cu intermetallic compounds on the mercury coated electrode. In AMD samples with high dissolved iron, use of ultraviolet irradiation was not effective for determining total concentrations because humate destruction by UV irradiation possibly resulted in the removal of a part of dissolved heavy metals from waters through the precipitation of iron hydroxides.


Allosteric reversion of Haemophilus influenzae β-carbonic anhydrase via a proline shift.
Haemophilus influenzae β-carbonic anhydrase (HICA) has been reverse-engineered in the allosteric site region to resemble the nonallosteric Pisum sativum enzyme in order to identify critical features of allostery and intersusbunit communication. Three variants (W39V/G41A, P48S/A49P, and W39V/G41A/P48S/A49P) were identified, through a comparison with a crystal structure of nonallosteric P. sativum β-carbonic anhydrase (PSCA, PDB 1EKJ ), to potentially revert HICA to a nonallosteric enzyme. The W39V/G41A and P48S/A49P mutations decreased the apparent kcat/Km proton dependence from 4 to 2 and 1, respectively, increasing the overall maximal kcat/Km to 16 ± 2 μM(-1) s(-1) (380% of wild type) and 17 ± 3 μM(-1) s(-1) (405% of wild type). The pKa values of the metal-bound water molecule based on the pH-rate profile kinetics (8.32 ± 0.04 for W39V/G41A and 8.3 ± 0.1 for P48S/A49P) were also slightly higher than that for the wild-type enzyme (7.74 ± 0.04). The P48S/A49P variant has lost all pH-rate cooperativity. The W39V/G41A/P48S/A49P variant's kinetics were unusual and were fit with a log-linear function with a slope 0.9 ± 0.2. The crystal structure of the W39V/G41A variant revealed an active site very similar to the T-state wild-type oligomer with bicarbonate trapped in the escort site. By contrast, the X-ray crystal structure of a proline shift variant (P48S/A49P) reveals that it has adopted an active site conformation nearly identical to that of nonallosteric β-carbonic anhydrase (R-state) for one chain, including a tight association with the dimer-exchanged N-terminal helices; the second chain in the asymmetric unit is associated in a biologically relevant oligomer, but it adopts a T-state conformation that is not capped by dimer-exchanged N-terminal helices. The hybrid R/T nature of HICA P48S/A49P structurally recapitulates the interruption of pH-rate cooperativity observed for this variant. Comparison of the conformations of the R and T chains of P48S/A49P suggests a new hypothesis to explain HICA allosteric communication that is mediated by the N-terminal helices and anion binding at the dimer interface.


Fetuses of lean and obese swine in late gestation: body composition, plasma hormones and muscle development.
The development of obesity in porcine fetuses was investigated using a lean and obese strain of pigs at 80, 90, 100 and 110 d of gestation. In absolute terms, fetuses of obese gilts (FO) generally had lower carcass weight and contained less total protein, dry matter and ash than fetuses of lean gilts (FL). In relative terms (percentage of wet carcass weight) FO, compared with FL, generally had decreased percentages of water and increased percentages of protein and lipid. Comparisons based on absolute terms revealed body composition of the strains to be different at 90 d, indicating that factors responsible for obese-type growth were active before that time. Both body composition and hormone concentration differences were most pronounced at later gestation ages. Depressed growth hormone, elevated cortisol, and a tendency toward elevated insulin concentrations in fetal plasma were apparent in late gestation for FO compared with FL. These hormonal patterns are consistent with onset of obesity in FO in late gestation. Greater weights of semitendinosus and longissimus muscles were observed in FL vs FO at 90, 100 and 110 d of gestation (P less than .05). These greater muscle weights were generally accompanied by greater contents of RNA, DNA and protein in FL muscles at these same ages. However, at 80 d, FL had greater absolute DNA content in semitendinosus muscle whereas muscle weight was similar between the strains. This suggests that greater muscle weights for FL than FO were caused by more nuclei in muscle of FL. In general, indices of hypertrophy (protein/DNA) and protein synthetic capacity (RNA/DNA) of muscle were usually similar for both strains at all gestation ages. It is concluded that decreased muscle growth in late gestation of FO compared with FL is more related to fewer total nuclei and perhaps fewer myofibers than to an impaired cellular capacity for protein synthesis.


Ultra-Fast Insulin-Pramlintide Co-Formulation for Improved Glucose Management in Diabetic Rats.
Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, amphiphilic acrylamide copolymers are used to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 h under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 h. The faster pharmacokinetics of monomeric insulin in this co-formulation result in increased insulin-pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation results in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats, the co-formulation reduces deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.


Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score.
This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.


Osteopontin associates with brain TRM-cell transcriptome and compartmentalization in donors with and without multiple sclerosis.
The human brain is populated by perivascular T cells with a tissue-resident memory T (TRM)-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8+ and CD4+ CD69+ T cells revealed TRM-cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter T cells in MS brains. Genes up-regulated in brain TRM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T cell activity. In line with their parenchymal localization and the increased presence of OPN in active MS lesions, we noticed a reduced production of inflammatory cytokines IL-2, TNF, and IFNγ by lesion-derived CD8+ and CD4+ T cells ex vivo. Our study reports traits of brain TRM cells and reveals their tight control in MS lesions.


Glucose production and utilization in children with glycogen storage disease type I.
Glucose turnover rates were estimated with [2H2]glucose in five children with glycogen storage disease type I (GSD I) during sequential withdrawal of an infusion of glucose to determine whether their hypoglycemia was the result of decreased glucose production or increased rates of glucose utilization. Plasma glucose concentrations were 78 +/- 5 mg/dl during infusion of glucose at 6 mg X kg-1 X min-1 and decreased to 53 +/- 3 and 45 +/- 7 mg/dl during the 3 and 1.5 mg X kg-1 X min-1 glucose infusions, respectively. Total glucose flux during the 6 mg X kg-1 X min-1 glucose infusion was 7.3 +/- 0.7 mg X kg-1 X min-1 and decreased with reduction in the rate of glucose infused. Endogenous glucose production increased with each decrease in the rate of exogenous glucose infused. Following discontinuation of glucose infusion, endogenous glucose production was 3.9 +/- 0.3 mg X kg-1 X min-1, a value that was lower (P less than 0.05) than that observed in overnight-fasted normal children (6.3 +/- 0.3 mg X kg-1 X min-1) but not statistically different from the Ra of normal children fasted for 30 h (4.1 +/- 0.5 mg X kg-1 X min-1). Thus, children with GSD have glucose production rates that are 40% lower than those of normal children fasted overnight but equal to those of normal children fasted 30 h. Rates of glucose utilization during the 6 mg X kg-1 X min-1 glucose infusion were higher (0.05 less than P less than 0.1) than those of overnight-fasted normal children, despite lower plasma glucose concentrations when expressed on a body weight basis but not when expressed on the basis of estimated brain weight.(ABSTRACT TRUNCATED AT 250 WORDS)


Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein.
Mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis coli and also sporadic colorectal cancer development. By using antibodies raised against the N-terminal region of APC protein, we have detected the variable masses of endogenous APC proteins in individual cell lines established from human colorectal carcinomas caused by nonsense mutations of the gene. Phosphorylation of immunoprecipitates of full-length and truncated APC were observed in in vitro kinase reaction, indicating association of APC with protein kinase activity. The kinase activity complexed with APC was sensitive to heparin and used GTP as phosphoryl donor, suggesting an involvement of casein kinase 2 (CK2). Both CK2alpha- and beta-subunits were found to associate with APC in immunoprecipitates as well as in pull-down assays, with preferential interaction of APC with tetrameric CK2 holoenzyme. In synchronized cell populations, the association of APC with CK2 was cell cycle dependent, with the highest association in G(2)/M. Unexpectedly, APC immunoprecipitates containing full-length APC protein inhibited CK2 in vitro, whereas immunoprecipitates of truncated APC had little effect. This was confirmed by using recombinant APC, and the inhibitory region was localized to the C terminus of APC between residues 2086 and 2394. Overexpression of this fragment in SW480 cells suppressed cell proliferation rates as well as tumorigenesis. These results demonstrate a previously uncharacterized functional interaction between the tumor suppressor protein APC and CK2 and suggest that growth-inhibitory effects of APC may be regulated by inhibition of CK2.


The AmP project: Comparing species on the basis of dynamic energy budget parameters.
We developed new methods for parameter estimation-in-context and, with the help of 125 authors, built the AmP (Add-my-Pet) database of Dynamic Energy Budget (DEB) models, parameters and referenced underlying data for animals, where each species constitutes one database entry. The combination of DEB parameters covers all aspects of energetics throughout the full organism's life cycle, from the start of embryo development to death by aging. The species-specific parameter values capture biodiversity and can now, for the first time, be compared between animals species. An important insight brought by the AmP project is the classification of animal energetics according to a family of related DEB models that is structured on the basis of the mode of metabolic acceleration, which links up with the development of larval stages. We discuss the evolution of metabolism in this context, among animals in general, and ray-finned fish, mollusks and crustaceans in particular. New DEBtool code for estimating DEB parameters from data has been written. AmPtool code for analyzing patterns in parameter values has also been created. A new web-interface supports multiple ways to visualize data, parameters, and implied properties from the entire collection as well as on an entry by entry basis. The DEB models proved to fit data well, the median relative error is only 0.07, for the 1035 animal species at 2018/03/12, including some extinct ones, from all large phyla and all chordate orders, spanning a range of body masses of 16 orders of magnitude. This study is a first step to include evolutionary aspects into parameter estimation, allowing to infer properties of species for which very little is known.


Communicating Microbiology Concepts from Multiple Contexts through Poster Presentations.
Accredited environmental engineering degrees require graduates to be able to apply their scholarship to concepts of professional practice and design. This transferable skill of relating what you learn in one setting to another situation is vital for all professions, not just engineering. A course project involving designing and presenting a professional poster was implemented to enhance student mastery in Environmental Engineering Microbiology while also developing communication and transferable skills vital for all majors. Students were asked to read a contemporary non-fiction book relating to microbiology and expand upon the book's thesis by integrating course content, news articles, and peer-reviewed journal articles. They then were required to present this information in class using a professional poster. Students felt the project allowed them to synthesize and organize information, analyze ideas, and integrate ideas from various sources. These transferable skills are vital for students and professionals alike to be able to communicate advanced information and master a topic.


AIM™ platform: A new immunotherapy approach for viral diseases.
In addition to complications of acute diseases, chronic viral infections are linked to both malignancies and autoimmune disorders. Lack of adequate treatment options for Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), and human papillomavirus (HPV) remains. The NexImmune Artificial Immune Modulation (AIM) nanoparticle platform can be used to direct T cell responses by mimicking the dendritic cell function. In one application, AIM nanoparticles are used ex vivo to enrich and expand (E+E) rare populations of multi-antigen-specific CD8+ T cells for use of these cells as an AIM adoptive cell therapy. This study has demonstrated using E+E CD8+ T cells, the functional relevance of targeting EBV, HTLV-1, and HPV. Expanded T cells consist primarily of effector memory, central memory, and self-renewing stem-like memory T cells directed at selected viral antigen peptides presented by the AIM nanoparticle. T cells expanded against either EBV- or HPV-antigens were highly polyfunctional and displayed substantial in vitro cytotoxic activity against cell lines expressing the respective antigens. Our initial work was in the context of exploring T cells expanded from healthy donors and restricted to human leukocyte antigen (HLA)-A*02:01 serotype. AIM Adoptive Cell Therapies (ACT) are also being developed for other HLA class I serotypes. AIM adoptive cell therapies of autologous or allogeneic T cells specific to antigens associated with acute myeloid leukemia and multiple myeloma are currently in the clinic. The utility and flexibility of the AIM nanoparticle platform will be expanded as we advance the second application, an AIM injectable off-the-shelf nanoparticle, which targets multiple antigen-specific T cell populations to either activate, tolerize, or destroy these targeted CD8+ T cells directly in vivo, leaving non-target cells alone. The AIM injectable platform offers the potential to develop new multi-antigen specific therapies for treating infectious diseases, cancer, and autoimmune diseases.


Complete mitochondrial genome of the endangered Prunus pedunculata (Prunoideae, Rosaceae) in China: characterization and phylogenetic analysis.
Prunus pedunculata (Prunoideae: Rosaceae), a relic shrub with strong resistance and multiple application values, is endangered in China. Extensive research had been devoted to gene expression, molecular markers, plastid genome analysis, and genetic background investigations of P. pedunculata. However, the mitochondrial genome of this species has not been systematically described, owing to the complexity of the plant mitogenome. In the present research, the complete mitochondrial genome of P. pedunculata was assembled, annotated, and characterized. The genomic features, gene content and repetitive sequences were analyzed. The genomic variation and phylogenetic analysis have been extensively enumerated. The P. pedunculata mitogenome is a circular molecule with a total length of 405,855 bp and a GC content of 45.63%, which are the smallest size and highest GC content among the known Prunus mitochondrial genomes. The mitogenome of P. pedunculata encodes 62 genes, including 34 unique protein-coding genes (PCGs, excluding three possible pseudogenes), three ribosomal RNA genes, and 19 transfer RNA genes. The mitogenome is rich in repetitive sequences, counting 112 simple sequence repeats, 15 tandem repeats, and 50 interspersed repetitive sequences, with a total repeat length of 11,793 bp, accounting for 2.91% of the complete genome. Leucine (Leu) was a predominant amino acid in PCGs, with a frequency of 10.67%, whereas cysteine (Cys) and tryptophan (Trp) were the least adopted. The most frequently used codon was UUU (Phe), with a relative synonymous codon usage (RSCU) value of 1.12. Selective pressure was calculated based on 20 shared PCGs in the mitogenomes of the 32 species, most of which were subjected to purifying selection (Ka/Ks < 1), whereas ccmC and ccmFn underwent positive selection. A total of 262 potential RNA editing sites in 26 PCGs were identified. Furthermore, 56 chloroplast-derived fragments were ascertained in the mitogenome, ranging from 30 to 858 bp, and were mainly located across IGS (intergenic spacer) regions or rRNA genes. These findings verify the occurrence of intracellular gene transfer events from the chloroplast to the mitochondria. Furthermore, the phylogenetic relationship of P. pedunculata was supported by the mitogenome data of 30 other taxa of the Rosaceae family. Understanding the mitochondrial genome characteristics of P. pedunculata is of great importance to promote comprehension of its genetic background and this study provides a basis for the genetic breeding of Prunus.


Combinatorial Engineering Enables Photoautotrophic Growth in High Cell Density Phosphite-Buffered Media to Support Engineered Chlamydomonas reinhardtii Bio-Production Concepts.
Chlamydomonas reinhardtii has emerged as a powerful green cell factory for metabolic engineering of sustainable products created from the photosynthetic lifestyle of this microalga. Advances in nuclear genome modification and transgene expression are allowing robust engineering strategies to be demonstrated in this host. However, commonly used lab strains are not equipped with features to enable their broader implementation in non-sterile conditions and high-cell density concepts. Here, we used combinatorial chloroplast and nuclear genome engineering to augment the metabolism of the C. reinhardtii strain UVM4 with publicly available genetic tools to enable the use of inorganic phosphite and nitrate as sole sources of phosphorous and nitrogen, respectively. We present recipes to create phosphite-buffered media solutions that enable high cell density algal cultivation. We then combined previously reported engineering strategies to produce the heterologous sesquiterpenoid patchoulol to high titers from our engineered green cell factories and show these products are possible to produce in non-sterile conditions. Our work presents a straightforward means to generate C. reinhardtii strains for broader application in bio-processes for the sustainable generation of products from green microalgae.


[The Reformed Church in Aduard: the oldest hospital in The Netherlands].
The present Dutch Reformed Church building in Aduard (near Groningen) is the only remnant of a large Cistercian monastery founded on June 5, 1192. Typological and archaeological investigations indicate that the church building represents originally the hospital facility for the lay brothers of the monastery, which according to the chronicle of the monastery was built in the beginning of the 14th century. This date is confirmed by the architectural style of the building and corresponds to the date of the original tiled floor which showes some sacred patterns. These findings mark this building as the earliest known hospital facility in the Netherlands, ranking among the earliest buildings of its kind in Europe.


Obatoclax interacts synergistically with the irreversible proteasome inhibitor carfilzomib in GC- and ABC-DLBCL cells in vitro and in vivo.
Interactions between the irreversible proteasome inhibitor carfilzomib and the pan-BH3 mimetic obatoclax were examined in germinal center (GC)- and activated B-cell-diffuse large B-cell lymphoma (ABC-DLBCL) cells. Cotreatment with minimally toxic concentrations of carfilzomib (i.e., 2-6 nmol/L) and subtoxic concentrations of obatoclax (0.05-2.0 μmol/L) synergistically increased apoptosis in multiple DLBCL cell lines and increased lethality toward primary human DLBCL but not normal CD34(+) cells. Synergistic interactions were associated with sharp increases in caspase-3 activation, PARP cleavage, p-JNK induction, upregulation of Noxa, and AKT dephosphorylation. Combined treatment also diminished carfilzomib-mediated Mcl-1 upregulation whereas immunoprecipitation analysis revealed reduced associations between Bak and Mcl-1/Bcl-xL and Bim and Mcl-1. The carfilzomib/obatoclax regimen triggered translocation, conformational change, and dimerization of Bax and activation of Bak. Genetic interruption of c-jun-NH(2)-kinase (JNK) and Noxa by short hairpin RNA knockdown, ectopic Mcl-1 expression, or enforced activation of AKT significantly attenuated carfilzomib/obatoclax-mediated apoptosis. Notably, coadministration of carfilzomib/obatoclax sharply increased apoptosis in multiple bortezomib-resistant DLBCL models. Finally, in vivo administration of carfilzomib and obatoclax to mice inoculated with SUDHL4 cells substantially suppressed tumor growth, activated JNK, inactivated AKT, and increased survival compared with the effects of single-agent treatment. Together, these findings argue that a strategy combining carfilzomib and obatoclax warrants attention in DLBCL.


Evaluation of false ultrasonographic diagnoses in cows by measuring plasma levels of bovine pregnancy-associated glycoprotein 1.
Between days 27 and 59 after artificial insemination (AI), 189 ultrasonographic pregnancy diagnoses were made in 56 dairy cows using a 7.5 MHz linear-array rectal transducer. Blood samples were withdrawn from a jugular vein on the day of AI, on day 21, and after each ultrasonographic examination between days 27 and 31, days 34 and 38, days 41 and 45 and days 55 and 59 after AI. Plasma concentrations of bovine pregnancy-associated glycoprotein 1 (bPAG-1) were measured by radioimmunoassay. The results showed that before day 31, ultrasonographic scanning was not very sensitive because six of the 30 calving cows were incorrectly diagnosed as non-pregnant. In five of these animals, the uterus was located far cranial to the pelvic inlet. Five of the cows examined between days 27 and 31 were pregnant on the basis of plasma bPAG-1 levels on the same day, using 0.5 ng/ml as the cut-off point. Plasma levels of bPAG-1 and progesterone proved that four of the cows which had early positive ultrasonographic diagnoses but did not produce a calf, were pregnant when they were examined.


Iodine isotopes (129I and 127I) in the Baltic Proper, Kattegat, and Skagerrak basins.
Radioactive anthropogenic pollution has raised concerns about the present and future environmental status of the semienclosed Baltic Sea. We here study the distribution and inventory of the anthropogenic radioactive (129)I in water depth profiles collected from 16 sites in August 2006 and 19 sites in April 2007 in the Baltic Proper and related Kattegat and Skagerrak basins. The results reveal considerable differences of (129)I concentration in terms of spatial and temporal variability and expose relatively high concentrations in the deep waters. Variability in the concentration of (127)I, stable natural isotope of iodine, seems to follow changes in the seawater salinity, but in oxygen-poor bottom waters sediment diagenetic release may contribute to the concentration of both isotopes in the water body. Inventory estimates show that (129)I in August 2006 (24.2 ± 15.4 kg) is higher than that in April 2007 (14.4 ± 8.3 kg) within the southern and central Baltic Proper whereas almost a constant load occurs in the Kattegat Basin. Calculated model inventory shows correspondence to empirical data and provides a guideline for future environmental assessment on the impact of (129)I load in the studied region.


Molecular cloning and functional expression in lactobacillus plantarum 80 of xylT, encoding the D-xylose-H+ symporter of Lactobacillus brevis.
A 3-kb region, located downstream of the Lactobacillus brevis xylA gene (encoding D-xylose isomerase), was cloned in Escherichia coli TG1. The sequence revealed two open reading frames which could code for the D-xylulose kinase gene (xylB) and another gene (xylT) encoding a protein of 457 amino acids with significant similarity to the D-xylose-H+ symporters of E. coli, XylE (57%), and Bacillus megaterium, XylT (58%), to the D-xylose-Na+ symporter of Tetragenococcus halophila, XylE (57%), and to the L-arabinose-H+ symporter of E. coli, AraE (60%). The L. brevis xylABT genes showed an arrangement similar to that of the B. megaterium xylABT operon and the T. halophila xylABE operon. Southern hybridization performed with the Lactobacillus pentosus xylR gene (encoding the D-xylose repressor protein) as a probe revealed the existence of a xylR homologue in L. brevis which is not located with the xyABT locus. The existence of a functional XylR was further suggested by the presence of xylO sequences upstream of xylA and xylT and by the requirement of D-xylose for the induction of D-xylose isomerase, D-xylulose kinase, and D-xylose transport activities in L. brevis. When L. brevis was cultivated in a mixture of D-glucose and D-xylose, the D-xylose isomerase and D-xylulose kinase activities were reduced fourfold and the D-xylose transport activity was reduced by sixfold, suggesting catabolite repression by D-glucose of D-xylose assimilation. The xylT gene was functionally expressed in Lactobacillus plantarum 80, a strain which lacks proton motive force-linked D-xylose transport activity. The role of the XylT protein was confirmed by the accumulation of D-xylose in L. plantarum 80 cells, and this accumulation was dependent on the proton motive force generated by either malolactic fermentation or by the metabolism of D-glucose. The apparent affinity constant of XylT for D-xylose was approximately 215 microM, and the maximal initial velocity of transport was 35 nmol/min per mg (dry weight). Furthermore, of a number of sugars tested, only 6-deoxy-D-glucose inhibited the transport of D-xylose by XylT competitively, with a Ki of 220 microM.


"We don't carry that"--failure of pharmacies in predominantly nonwhite neighborhoods to stock opioid analgesics.
We have observed that many black and Hispanic patients receiving palliative care at a major urban teaching hospital are unable to obtain prescribed opioids from their neighborhood pharmacies. In this study, we investigated the availability of commonly prescribed opioids in New York City pharmacies. We surveyed a randomly selected sample of 30 percent of New York City pharmacies to obtain information about their stock of opioids. For each pharmacy, U.S. Census estimates for 1997 were used to determine the racial and ethnic composition of the neighborhood (defined as the area within a 0.4-km [0.25-mile] radius of the pharmacy) and the proportion of residents who were more than 65 years old. Data on robberies, burglaries, and arrests involving illicit drugs in 1997 were obtained for the precinct in which each pharmacy was located. We used a generalized linear model to examine the relation between the racial or ethnic composition of neighborhoods and the opioid supplies of pharmacies, while controlling for the proportion of elderly persons at the census-block level and for crime rates at the precinct level. Pharmacists representing 347 of 431 eligible pharmacies (81 percent) responded to the survey. A total of 176 pharmacies (51 percent) did not have sufficient supplies of opioids to treat patients with severe pain. Only 25 percent of pharmacies in predominantly nonwhite neighborhoods (those in which less than 40 percent of residents were white) had opioid supplies that were sufficient to treat patients in severe pain, as compared with 72 percent of pharmacies in predominantly white neighborhoods (those in which at least 80 percent of residents were white) (P<0.001). Pharmacies in predominantly nonwhite neighborhoods of New York City do not stock sufficient medications to treat patients with severe pain adequately.


Upfront Next Generation Sequencing in Non-Small Cell Lung Cancer.
In advanced non-small cell lung cancer (NSCLC), patients with actionable genomic alterations may derive additional clinical benefit from targeted treatment compared to cytotoxic chemotherapy. Current guidelines recommend extensive testing with next generation sequencing (NGS) panels. We investigated the impact of using a targeted NGS panel (TruSight Tumor 15, Illumina) as reflex testing for NSCLC samples at a single institution. Molecular analysis examined 15 genes for hotspot mutation variants, including AKT1, BRAF, EGFR, ERBB2, FOXL2, GNA11, GNAQ, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET and TP53 genes. Between February 2017 and October 2020, 1460 samples from 1395 patients were analyzed. 1201 patients (86.1%) had at least one variant identified, most frequently TP53 (47.5%), KRAS (32.2%) or EGFR (24.2%). Among these, 994 patients (71.3%) had clinically relevant variants eligible for treatment with approved therapies or clinical trial enrollment. The incremental cost of NGS beyond single gene testing (EGFR, ALK) was CAD $233 per case. Reflex upfront NGS identified at least one actionable variant in more than 70% of patients with NSCLC, with minimal increase in testing cost. Implementation of NGS panels remains essential as treatment paradigms continue to evolve.


What Is the Impact of Engaging With Natural Environments Delivered Via Virtual Reality on the Psycho-emotional Health of People With Spinal Cord Injury Receiving Rehabilitation in Hospital? Findings From a Pilot Randomized Controlled Trial.
This study investigated (1) the effect of engaging with 20-minute simulated natural environments delivered via virtual reality (VR) on current mood state and (2) the effect of engaging with multiple VR sessions over a period of a week on the depressive symptoms of people with a spinal cord injury (SCI). Randomized controlled trial design. Spinal Cord Injury Rehabilitation Unit in Australia. Participants (N=24) were assigned to a group engaging in VR sessions during week 1 (group 1, n=10) or week 2 (group 2, n=14). The intervention week involved participation in up to three 20-minute VR sessions over 3 consecutive days. The control condition involved regular rehabilitation practice over a week. The Patient Health Questionnaire-8 (PHQ-8) was completed prior to the first week (T1), after the first week and prior to the second week (T2), and after the second week (T3). Current feeling states, including depressed/happy, anxious/relaxed, and not feeling good/feeling good, were rated immediately prior and after each VR session. Levels of happiness, relaxation, and feeling good were significantly higher subsequent to engaging with each VR session. Between-group differences in PHQ-8 scores were significantly greater for participants who experienced the intervention during the first week compared to participants within the control group: intervention participants had significant improvements in psycho-emotional health. Within-group PHQ-8 scores were reduced for each group subsequent to experiencing the intervention; however, differences were not significant. Engaging with simulated natural environments delivered via VR can favorably affect the psycho-emotional health of people with SCI receiving rehabilitation in hospital. Future research including larger samples and investigating the effect over a longer time period is required to confirm the findings presented.


Acute myocardial infarction in young adults with antiphospholipid syndrome: report of two cases and literature review.
Acute myocardial infarction (AMI) is rarely associated with antiphospholipid syndrome. The treatment of these patients is a clinical challenge. We report the observations of 2 young adults (1 woman and 1 man), admitted in our acute care unit for acute myocardial infarction (AMI). A coagulopathy work-up concludes the existence of antiphospholipid syndrome (APS) in the 2 cases. APS syndrome was considered primary in 2 cases. All patients presented an intense inflammatory syndrome (high level of CRP). Anticardiolipine was present in the 2 cases. However, anti B2 glycoprotein I antibodies were detected in only one case. Emergency percutaneous transluminal coronary angioplasty (PTCA) with direct stenting had been performed successfully only in the first case, and the follow-up was uncomplicated. Thereafter, long-term oral anticoagulant appeared to be effective. The last patient was admitted because of peripheral acute ischemia of legs. Standard electrocardiogram showed signs of previous silent anteroseptal wall myocardial infarction confirmed by echocardiography. The latter revealed an apical thrombus and a very low left ventricular ejection fraction. Amputation of the right leg was necessary because of consultation occurred too late. However, he died four weeks later. Primary antiphospholipid syndrome should be considered as a cause of acute myocardial infarction in young adults, and PTCA with anticoagulant treatment is effective for initial treatment of this complication.


Relationships between comprehensive characteristics of nurse work schedules and adverse patient outcomes: A systematic literature review.
To review the comprehensive characteristics of adverse nurse work schedules and to synthesise the evidence of their relationships with adverse patient outcomes. To manage nurse shortages and fluctuations in patient censuses, nurses often work overtime. This increases nurses' work hours and causes them to have fewer breaks. Such extended work schedules, long shift length, long weekly work hours and insufficient beaks can be considered as adverse nurse work schedules. Understanding how these adverse nurse work schedules affect patient outcomes is important to ensure patient safety. A systematic review of nursing and healthcare literature was conducted in this study. Eight electronic bibliographic databases (CINAHL, Cochrane Library, DBpia, EBSCO, PubMed, PsycINFO, RISS and Web of Science) were used to search research articles published from 2000 to 2019. The study selection process followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). From the search, 2,366 articles were identified, 22 of which were included in this review. Working more than 12 hours in a day had an adverse effect on patient outcomes, as was working more than 40 hours per week. There were mixed findings in the relationship between nurse overtime and adverse patient outcomes. This study found a conclusive relationship between excessive nurse work hours and adverse patient outcomes. This review highlights the importance of managing adverse nurse schedules such as long daily and weekly work hours to improve patient safety and prevent adverse patient outcomes. Study findings support the importance of monitoring and regulating nurse work schedules and adverse scheduling practices to improve nurse well-being and health and to prevent adverse patient outcomes.


Effects of inhibition of fatty acid oxidation on myocardial kinetics of 11C-labeled palmitate.
The effects of glucose and lactate infusion on palmitate oxidation were compared with the effect of 2-tetradecylglycidic acid (TDGA), an irreversible inhibitor of the carnitine acyltransferase I, in normoxic canine myocardium. The initial capillary transit retention fraction of [1-11C]palmitate and its fractional distribution between oxidation and esterification in myocardium were measured by the residue detection method after intracoronary tracer injection, as well as by effluent measurements of 11CO2, the end product of palmitate oxidation. TDGA reduced the initial capillary transit retention fraction (from 56 +/- 13% to 37 +/- 6%; p less than 0.001) and oxidation of palmitate (n = 19), as also evidenced by the decrease in the fraction of tracer released as 11CO2 from 28 +/- 5% to 6 +/- 3% (p less than 0.001). Infusion of carbohydrate (glucose or lactate; n = 6) reduced 11CO2 production from 30 +/- 7% to 7 +/- 4% (p less than 0.05) but did not alter the initial capillary transit retention fraction of tracer (59 +/- 5% vs. 56 +/- 10%; NS). The latter was due to increased esterification into neutral lipids (41 +/- 11% of injected palmitate after carbohydrate infusion versus 21 +/- 12% in control conditions), as measured from multiexponential curve fittings. When carbohydrates were given after inhibition of palmitate oxidation by TDGA (n = 7), the 11C tissue clearance kinetics were strikingly similar to those observed after carbohydrate infusion alone. Thus, enhanced metabolic trapping of [1-11C]palmitate in myocardium resulted in initial capillary transit retention fractions that were not different from control conditions (41 +/- 5% vs. 48 +/- 12%; NS) despite inhibition of oxidation. The results show that the intracellular metabolism of palmitate contributes to the control of its uptake by myocardium. The findings are consistent with inhibition of palmitate oxidation by carbohydrates occurring at the same site as TDGA.


NILCO biomarkers in breast cancer from Chinese patients.
Notch, IL-1 and leptin are known pro-angiogenic factors linked to breast cancer development, tumor aggressiveness and poor prognosis. A complex crosstalk between these molecules (NILCO) has been reported in breast cancer cell lines. However, whether NILCO biomarkers are differentially expressed in estrogen responsive (ER+), unresponsive (ER-) and triple negative (TNBC) breast cancer tissues is unknown. Expression levels of nine NILCO and targets [Notch1, Notch4, JAG1, DLL4, VEGF, VEGFR2 (FLK-1), leptin, leptin receptor (OB-R) and interleukin-1 receptor type I (IL-1R tI)] were examined via immunohistochemistry in breast cancer tissue microarrays from Chinese patients (ER+, n=33; ER-, n=21; TNBC, n=13) and non-malignant breast tissue (n=5; Pantomics, Inc.) using a semi-quantitative analysis of intensity staining, HSCORE. Categorical expression of NILCO and targets (+ or -) was similar among all cancer tissues. However, TNBC showed differential localization pattern of NILCO. TNBC showed fewer nuclei and cytoplasms positive for Notch4 and JAG1, but more cytoplasms positive for leptin. In addition, fewer TNBC stromas were positive for Notch1 and Notch4, but 100% of TNBC stromas were positive for VEGFR2. Moreover, TNBC had lower DLL4 and IL-1R tI expression. TNBC and ER- showed higher expression of EGFR, but lower expression of AR. Leptin and OB-R were detected in more than 61% of samples. Leptin positively correlated to OB-R, JAG1, VEGF, and marginally to IL-1R tI. Notch1 positively correlated to IL-1R tI. EGFR and Ki67 were positively associated to Notch1, but no associations of NILCO and targets with p53 were found. Present data suggest that NILCO components are differentially expressed in breast cancer. TNBC showed distinctive patterns for NILCO expression and localization. The complex crosstalk between leptin, IL-1 and Notch could differentially drive breast cancer growth and angiogenesis. Furthermore, the analysis of NILCO and targets using Pathway Studio9 software (Ariadine Genomics) showed multiple molecular relationships that suggest NILCO has potential prognostic biomarker value in breast cancer.


The impact of discharging minimally injured trauma patient: does age play a role in trauma admission?
Age is suggested as a triage criteria for transfer to a trauma center, despite poor outcomes after similar injury regardless of trauma center level. The effect of differential triage based on age to a trauma center has not been evaluated. We hypothesized that there would be a difference in the admission rates of geriatric patients compared with the rest of the adult trauma population independent of injury severity. Records of 1,970 adult patients evaluated by the trauma team at a Level I trauma center and discharged directly from the emergency department were reviewed. Data abstracted included demographics, injuries, and physiologic information. These data were compared with 3,232 trauma patients admitted over the same time period who had similar information abstracted via record review. χ analysis of the admission rates of geriatric patients was performed, followed by a binomial logistic regression to determine factors that affected the odds of admission. A total of 451 (8.68%) patients were 65 years or older; 62.2% of the total population was admitted. Significantly more geriatric patients (82%) were admitted (χ = 126.24; p < 0.001). Multivariate analysis showed that age, head injury, Injury Severity Score, Glasgow Coma Scale, and initial blood pressure were significant independent factors in predicting hospital admission (p < 0.001). Age alone is associated with increased odds of being admitted to the hospital, independent of injury severity and other physiologic parameters. This has implications for trauma centers that see a significant proportion of geriatric trauma patients and for trauma systems that must prepare for the "aging of America."


Gypsy, Traveller and Roma experiences, views and needs in palliative and end of life care: a systematic literature review and narrative synthesis.
Gypsy, Traveller and Roma communities are known to experience health inequalities. There has been little focus on palliative care in these communities despite the well-recognised inequalities of access to palliative care in other minority ethnic groups. Systematic review and thematic analysis of the current evidence concerning palliative care experiences, views and needs of Gypsy, Traveller and Roma communities. Medline, Embase, Emcare, CINAHL, PsycINFO, Web of Science, Scopus, AMED, Global Health, Psychological and Behavioural Sciences Collection and BNI were searched up to November 2020, alongside author and citation searching. NHS England, Hospice UK, National Audit Office and OpenGrey were searched as grey literature sources. Gough's 'Weight of Evidence' framework was used for quality appraisal. Thirteen papers from eight studies were included in the synthesis. Although there was variation between communities, three overarching and inter-related themes were identified. (1) Strong family and community values include a preference for healthcare to be provided from within the community, duty to demonstrate respect by attending the bedside and illness as a community problem with decision-making extending beyond the patient. (2) Distinct health beliefs regarding superstitions around illness, personal care, death rituals and bereavement. (3) Practical barriers to non-community healthcare provision include communication difficulties, limited awareness of and access to services, tensions between patients and healthcare professionals and lack of training in delivering culturally appropriate care. A wide range of factors influence Gypsy, Traveller and Roma community access to palliative care. Community diversity requires sensitive and highly individualised approaches to patient care. 42019147905.


Trigeminal stimulation elicits a peripheral vestibular imbalance in migraine patients.
The study explored the hypothesis that spontaneous nystagmus (Ny) in migraine patients can be triggered or modulated by painful trigeminal stimulation, providing evidence of a functional connection between vestibular and trigeminal systems. Vertigo attacks are reported by subjects with migraine or a familiar history of migraine, also independently of headache episodes. Idiopathic vertigo is three times more frequent in migraine patients than in controls. Vestibular investigations in migraine patients have consistently demonstrated spontaneous Ny both of central and peripheral origin. In the first phase of the study 10 outpatients experiencing migraine without aura (MO) and 10 healthy volunteers were submitted to the registration of spontaneous primary-position Ny in the dark by Ulmer's video-ocular-nystagmographic equipment. Two electrodes for electrical stimulation were applied on the supraorbital point of one side of the head and the intensity of stimulation corresponding to pain threshold was calculated. Spontaneous ocular movements were recorded for 5 minutes at baseline and after a sequence of five electric pulses (square waves of .5 Hz frequency and 50 micros duration, at pain threshold intensity). Nystagmographic responses were expressed as latency after stimulation, direction of the quick phase, and duration. The second phase of the study explored, with the same procedure, the effects on Ny of supraorbital versus median nerve stimulation in other 10 MO patients. Responses to stimulation were considered the appearance of de novo Ny after stimulation in subjects without baseline Ny, or the change of the frequency (at last a 50% variation) or of the direction of Ny after stimulation in subjects with baseline Ny. The latency and the duration of responses to stimulation were also calculated. In the first series supraorbital painful electric stimulation was able to modify or to evoke Ny in 8 of 10 migraineurs and in none of 10 volunteers (Fisher's exact test, P<.01). Both the baseline and the induced Ny were second degree, stationary persistent, with a linear slow phase and were suppressed by visual fixation. In the second series, supraorbital nerve stimulation was able to induce or modify Ny in all of 10 patients but only in 1 patient Ny was induced by median nerve stimulation. Characters of Ny were the same as previously described. Statistical comparison of the responses at the two sites of stimulation was significant (Fisher's exact test, P<.01). In those 7 patients who presented de novo Ny after stimulation it was possible to calculate Ny latency and duration. The mean latency was 25 s (SD: 16, range: 14 to 60). The mean duration was 120 s (SD: 94, range: 20 to 290). The main result of our study is that in migraine patients painful trigeminal stimulation elicits de novo, or modifies pre-existing spontaneous Ny, generally increasing it. The finding was obtained after trigeminal stimulation, but not after median nerve stimulation. We suggest that painful trigeminal stimulation can induce an imbalance of the vestibular system in migraine patients and possibly explain their predisposition to vertigo. Our data require confirmation by other studies.


Human neural stem cells genetically modified to express human nerve growth factor (NGF) gene restore cognition in the mouse with ibotenic acid-induced cognitive dysfunction.
Alzheimer's disease (AD) is characterized by degeneration and loss of neurons and synapses throughout the brain, causing the progressive decline in cognitive function leading to dementia. No effective treatment is currently available. Nerve growth factor (NGF) therapy has been proposed as a potential treatment of preventing degeneration of basal forebrain cholinergic neurons in AD. In a previous study, AD patient's own fibroblasts genetically modified to produce NGF were transplanted directly into the brain and protected cholinergic neurons from degeneration and improved cognitive function in AD patients. In the present study, human neural stem cells (NSCs) are used in place of fibroblasts to deliver NGF in ibotenic acid-induced learning-deficit rats. Intrahippocampal injection of ibotenic acid caused severe neuronal loss, resulting in learning and memory deficit. NGF protein released by F3.NGF human NSCs in culture medium is 10-fold over the control F3 naive NSCs at 1.2 µg/10(6) cells/day. Overexpression of NGF in F3.NGF cells induced improved survival of NSCs from cytotoxic agents H2O2, Aβ, or ibotenic acid in vitro. Intrahippocampal transplantation of F3.NGF cells was found to express NGF and fully improved the learning and memory function of ibotenic acid-challenged animals. Transplanted F3.NGF cells were found all over the brain and differentiated into neurons and astrocytes. The present study demonstrates that human NSCs overexpressing NGF improve cognitive function of learning-deficit model mice.


Long-term medical imaging use in children with central nervous system tumors.
Children with central nervous system (CNS) tumors undergo frequent imaging for diagnosis and follow-up, but few studies have characterized longitudinal imaging patterns. We described medical imaging in children before and after malignant CNS tumor diagnosis. We conducted a retrospective cohort study of children aged 0-20 years diagnosed with CNS tumors between 1996-2016 at six U.S. integrated healthcare systems and Ontario, Canada. We collected computed topography (CT), magnetic resonance imaging (MRI), radiography, ultrasound, nuclear medicine examinations from 12 months before through 10 years after CNS diagnosis censoring six months before death or a subsequent cancer diagnosis, disenrollment from the health system, age 21 years, or December 31, 2016. We calculated imaging rates per child per month stratified by modality, country, diagnosis age, calendar year, time since diagnosis, and tumor grade. We observed 1,879 children with median four years follow-up post-diagnosis in the U.S. and seven years in Ontario, Canada. During the diagnosis period (±15 days of diagnosis), children averaged 1.10 CTs (95% confidence interval [CI] 1.09-1.13) and 2.14 MRIs (95%CI 2.12-2.16) in the U.S., and 1.67 CTs (95%CI 1.65-1.68) and 1.86 MRIs (95%CI 1.85-1.88) in Ontario. Within one year after diagnosis, 19% of children had ≥5 CTs and 45% had ≥5 MRIs. By nine years after diagnosis, children averaged one MRI and one radiograph per year with little use of other imaging modalities. MRI and CT are commonly used for CNS tumor diagnosis, whereas MRI is the primary modality used during surveillance of children with CNS tumors.


Visual perception of the physical stability of asymmetric three-dimensional objects.
Visual estimation of object stability is an ecologically important judgment that allows observers to predict the physical behavior of objects. A natural method that has been used in previous work to measure perceived object stability is the estimation of perceived "critical angle"--the angle at which an object appears equally likely to fall over versus return to its upright stable position. For an asymmetric object, however, the critical angle is not a single value, but varies with the direction in which the object is tilted. The current study addressed two questions: (a) Can observers reliably track the change in critical angle as a function of tilt direction? (b) How do they visually estimate the overall stability of an object, given the different critical angles in various directions? To address these questions, we employed two experimental tasks using simple asymmetric 3D objects (skewed conical frustums): settings of critical angle in different directions relative to the intrinsic skew of the 3D object (Experiment 1), and stability matching across 3D objects with different shapes (Experiments 2 and 3). Our results showed that (a) observers can perceptually track the varying critical angle in different directions quite well; and (b) their estimates of overall object stability are strongly biased toward the minimum critical angle (i.e., the critical angle in the least stable direction). Moreover, the fact that observers can reliably match perceived object stability across 3D objects with different shapes suggests that perceived stability is likely to be represented along a single dimension.


Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response.
Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD). To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts. The non-Li group had smaller hippocampal volumes than the controls or the Li group (F 2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t(51) = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t(43) = 2.62, corrected p = 0.02). Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.


Does a 20 minute cognitive task increase concussion symptoms in concussed athletes?
The purpose of the present study was to examine if concussion symptoms worsened immediately (i.e. 20 minutes) following performance on a computerized neurocognitive test. Cross-sectional study; Level of evidence, 2. A total of 165 athletes with a concussion participated in the study. Participants completed the Immediate Post-concussion Assessment and Cognitive Test (ImPACT) and Post-concussion Symptom Scale (PCSS) at baseline, 3 and 10 days post-concussion. Participants completed a second PCSS following the ImPACT test at 3 and 10 days post-injury. Athletes with a concussion exhibited greater symptoms post-neurocognitive test 3 days post-concussion on headache (p = 0.01), nausea (p = 0.03), dizziness (p = 0.03), sadness (p = 0.005), mentally foggy (p= 0.002) and visual problems (p = 0.007). Athletes with a concussion demonstrated increased symptoms on sadness (p = 0.00) and difficulty remembering (p = 0.03) at 10 days post-injury. Athletes also demonstrated neurocognitive impairments in verbal memory (p = 0.009) and slower reaction time (p = 0.01) 10 days post-concussion and visual memory (p = 0.000) and motor processing speed (p = 0.000) impairments at 3 days post-injury. The current study suggests that there may be an increase in concussion symptoms following a 20-minute cognitive task. Thus, it illustrates the need for clinicians to make sure they are symptom free with both physical and cognitive testing.


Isoprenylation of plant proteins in vivo. Isoprenylated proteins are abundant in the mitochondria and nuclei of spinach.
Protein isoprenylation in vivo is demonstrated using spinach seedlings labeled with [3H]mevalonate. This report provides evidence for the occurrence of a large number of isoprenylated proteins in plants. Seedlings, without roots, were labeled quantitatively through the cut stem. Mevinolin treatment of the seedlings resulted in increased incorporation of radiolabel into proteins. Approximately 30 labeled bands could be detected after autoradiography of SDS-polyacrylamide gel electrophoresis-separated polypeptides, ranging in molecular mass from 6 to 200 kDa. Methyl iodide hydrolysis resulted in the release of covalently bound farnesol, geranylgeraniol, phytol, and some unidentified isoprenoid compounds from mevalonate-labeled proteins. It was found that all cellular fractions contained some isoprenylated proteins, although most were located in the mitochondria and nuclei. Subfractionation of the nucleus revealed that the majority of isoprenylated proteins in this compartment were components of the nuclear matrix. The results demonstrate that in vivo labeling of a complex organism can be performed using a plant system in order to study protein isoprenylation and distribution of modified proteins in different cellular compartments.


Molecular cloning and tissue distribution of PHAS-I, an intracellular target for insulin and growth factors.
Although the actions of insulin and a number of growth factors that signal via protein-tyrosine kinase receptors are believed to involve increased phosphorylation of key intracellular proteins, relatively few of the downstream phosphoproteins have been identified. In this report we describe a cDNA encoding one of the most prominent insulin-stimulated phosphoproteins in rat adipocytes. The cDNA encodes a protein, designated PHAS-I, which has 117 amino acids and a M(r) of 12,400. When translated in vitro and subjected to SDS/PAGE, PHAS-I migrates anomalously, having an apparent M(r) of 21,000. The predicted amino acid composition is interesting in that approximately 45% of the PHAS-I protein is accounted for by only four amino acids--serine, threonine, proline, and glycine. The PHAS-I gene is expressed in a variety of tissues, although the highest levels of mRNA are present in fat and skeletal muscle, two of the most insulin-responsive tissues. The nucleotide and deduced amino acid sequences of PHAS-I differ from any that have been reported, and homology screening provided no clues concerning the function of the protein. However, in view of its tissue distribution and the fact that the protein is phosphorylated in response to insulin, we speculate that PHAS-I is important in insulin action.


Noninvasive Monitoring After Azathioprine Withdrawal in Patients With Inflammatory Bowel Disease in Deep Remission.
There is uncertainty regarding the optimal duration of treatment with azathioprine (AZA) in ulcerative colitis (UC) and Crohn's disease (CD). We analyzed the clinical course and predictors of relapse after AZA withdrawal in patients in sustained deep remission. A prospective study was performed on patients who stopped their treatment with AZA while being in steroid-free, extended deep remission (normal clinical, endoscopic, and histologic indexes, C-reactive protein, and fecal calprotectin [FC]). Standard biochemical tests and FC were measured at 3 and 6 months, then every 6 months. Bowel ultrasounds and ileocolonoscopy were performed every 6 and 12 months, respectively. Multivariate analysis for predictors of relapse was performed using a Cox proportional hazards model and hazard ratios were calculated. Spearman nonparametric correlation test was also used. The accuracy of significant predictors was calculated. Fifty-seven patients with inflammatory bowel disease stopped AZA after median 7 years (range, 5-19) and were followed up for median 50 months (range, 25-85). Twenty-six patients (18/31 UC, 8/26 CD; P = .003) relapsed, within a median 15 months (range, 2-37). FC was the only variable significantly correlated with later relapse of both diseases (UC: hazard ratio, 3.3; 95% confidence interval, 1.2-10; CD: hazard ratio, 4.5; 95% confidence interval, 1.4-12.5). The sensitivity, specificity, and positive and negative predictive values of FC were 50%, 100%, 100%, and 59% in UC and 50%, 94%, 80%, and 81% in CD. More than half patients with UC and one-third of patients with CD relapse after AZA withdrawal despite previous deep remission. FC positivity is associated with high risk of relapse, allowing early correction of the therapeutic strategy.


BioImg.org: A Catalog of Virtual Machine Images for the Life Sciences.
Virtualization is becoming increasingly important in bioscience, enabling assembly and provisioning of complete computer setups, including operating system, data, software, and services packaged as virtual machine images (VMIs). We present an open catalog of VMIs for the life sciences, where scientists can share information about images and optionally upload them to a server equipped with a large file system and fast Internet connection. Other scientists can then search for and download images that can be run on the local computer or in a cloud computing environment, providing easy access to bioinformatics environments. We also describe applications where VMIs aid life science research, including distributing tools and data, supporting reproducible analysis, and facilitating education. BioImg.org is freely available at: https://bioimg.org.


DNA Repair Deficiency in Breast Cancer: Opportunities for Immunotherapy.
Historically the development of anticancer treatments has been focused on their effect on tumor cells alone. However, newer treatments have shifted attention to targets on immune cells, resulting in dramatic responses. The effect of DNA repair deficiency on the microenvironment remains an area of key interest. Moreover, established therapies such as DNA damaging treatments such as chemotherapy and PARP inhibitors further modify the tumor microenvironment. Here we describe DNA repair pathways in breast cancer and activation of innate immune pathways in DNA repair deficiency, in particular, the STING (STimulator of INterferon Genes) pathway. Breast tumors with DNA repair deficiency are associated with upregulation of immune checkpoints including PD-L1 (Programmed Death Ligand-1) and may represent a target population for single agent or combination immunotherapy treatment.


Langerhans Cells-Programmed by the Epidermis.
Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels. These cells determine the appropriate adaptive immune response (inflammation or tolerance) by interpreting the microenvironmental context in which they encounter foreign substances. In a normal physiological, "non-dangerous" situation, LCs coordinate a continuous state of immune tolerance, preventing unnecessary and harmful immune activation. Conversely, when they sense a danger signal, for example during infection or when the physical integrity of skin has been compromised as a result of a trauma, they instruct T lymphocytes of the adaptive immune system to mount efficient effector responses. Recent advances investigating the molecular mechanisms underpinning the cross talk between LCs and the epidermal microenvironment reveal its importance for programming LC biology. This review summarizes the novel findings describing LC origin and function through the analysis of the transcriptomic programs and gene regulatory networks (GRNs). Review and meta-analysis of publicly available datasets clearly delineates LCs as distinct from both conventional dendritic cells (DCs) and macrophages, suggesting a primary role for the epidermal microenvironment in programming LC biology. This concept is further supported by the analysis of the effect of epidermal pro-inflammatory signals, regulating key GRNs in human and murine LCs. Applying whole transcriptome analyses and in silico analysis has advanced our understanding of how LCs receive, integrate, and process signals from the steady-state and diseased epidermis. Interestingly, in homeostasis and under immunological stress, the molecular network in LCs remains relatively stable, reflecting a key evolutionary need related to tissue localization. Importantly, to fulfill their key role in orchestrating antiviral adaptive immune responses, LC share specific transcriptomic modules with other DC types able to cross-present antigens to cytotoxic CD8+ T cells, pointing to a possible evolutionary convergence mechanism. With the development of more advanced technologies allowing delineation of the molecular networks at the level of chromatin organization, histone modifications, protein translation, and phosphorylation, future "omics" investigations will bring in-depth understanding of the complex molecular mechanisms underpinning human LC biology.


College women's experience of stalking: mental health symptoms and changes in routines.
Stalking is a serious public health and societal concern affecting many college women. The purpose of this study was to explore college women's experiences of stalking. The specific aims were to compare victims and nonvictims on physical and mental health indicators and to identify lifestyle changes made in response to being stalked. In this cross-sectional design, 601 women from two universities completed a stalking questionnaire, a mental health screening tool, and an injury checklist. Data analysis included frequencies, multivariate analysis of variance, analysis of variance, and chi(2) analysis. A quarter of the sample reported experiencing stalking, most often by an intimate or dating partner. Individuals who reported experiencing stalking reported significantly more mental health symptoms and lower perceived physical health status than individuals who did not. Victims reported changing routines, behaviors, and activities. Psychiatric nurses must be knowledgeable about stalking and its impact on health. Nurses can provide support, services, and community referrals.


Female urethral diverticula.
Most urethral diverticula should be diagnosed on clinical grounds alone, but investigations may be used to confirm the diagnosis in difficult cases, delineate the extent of the disease and investigate other entities such as stress incontinence. A high index of suspicion is required when assessing women with lower urinary tract symptoms to ensure that cases of urethral diverticulum are not missed. The cases presented demonstrate that greater awareness of the signs and symptoms of this not uncommon disease may facilitate early diagnosis. Our cases also show that surgical treatment is effective and worthwhile.


[Surgical therapy of complicated inflammatory bowel disease].
The etiology of chronic inflammatoric bowel disease is unknown, conservative treatment will be reduced to the management of immunologic and inflammatoric reaction. The large majority of patients affected with Crohn's disease and also nearly 50% of patients with ulcerous colitis require surgery during their clinical history. The indication for surgery is a balance between the severity and the complications of the disease and the potential disadvantages of surgery. For surgical therapy the differentiation of Crohn's disease and ulcerous colitis is essential because of the differentiated character of both diseases. In Crohn's disease surgical therapy will be performed by the management of Crohn's specific complications like stenosis, fistula, and abscess by bowel preserveration. Limited resection and/or strictureplasty do not influence morbidity and rate and also time of recurrence. Ulcerous colitis can be cured when the colorectal mucosa will be removed totally by radical surgery, i.e. restorative proctocolectomy. The satisfactory outcome in 70 to 90% of patients with a cumulative failure rate of 10 to 15% over a 10-year-period improves the quality of life.


Primary photon fluence extraction from portal images acquired with an amorphous silicon flat panel detector: experimental determination of a scatter filter.
When dose delivery to the patient is evaluated by extracting the primary photon fluence impinging on a portal imaging device, scattered radiation from the patient acts as noise. Our aim in the present study is to establish and test a procedure to filter out scatter radiations from portal images by experimental determination of a scatter filtering function. We performed a dose calibration of the Varian (Varian Medical Systems, Palo Alto, CA) aS500 electronic portal imaging device in routine use in our institution. We then analyzed the collected data and extracted the scatter filtering function by applying a simple scatter model with the aid of home-made software. To check the reliability of our calculations we compared central axis dose values in a PMMA phantom computed using the extracted primary fluence with those obtained from experimental TMR(0) tabulated values obtaining a agreement within about 3%. We finally performed a check of dose delivery repeatability by calculating the dose delivered to the EPID during portal image acquisition for patient positioning. Delivered dose per MU fluctuations were within 5% over a set of images acquired during routine use with no prior application of any procedure aimed at optimizing dosimetric repeatability.


Transforming UTE-mDixon MR Abdomen-Pelvis Images Into CT by Jointly Leveraging Prior Knowledge and Partial Supervision.
Computed tomography (CT) provides information for diagnosis, PET attenuation correction (AC), and radiation treatment planning (RTP). Disadvantages of CT include poor soft tissue contrast and exposure to ionizing radiation. While MRI can overcome these disadvantages, it lacks the photon absorption information needed for PET AC and RTP. Thus, an intelligent transformation from MR to CT, i.e., the MR-based synthetic CT generation, is of great interest as it would support PET/MR AC and MR-only RTP. Using an MR pulse sequence that combines ultra-short echo time (UTE) and modified Dixon (mDixon), we propose a novel method for synthetic CT generation jointly leveraging prior knowledge as well as partial supervision (SCT-PK-PS for short) on large-field-of-view images that span abdomen and pelvis. Two key machine learning techniques, i.e., the knowledge-leveraged transfer fuzzy c-means (KL-TFCM) and the Laplacian support vector machine (LapSVM), are used in SCT-PK-PS. The significance of our effort is threefold: 1) Using the prior knowledge-referenced KL-TFCM clustering, SCT-PK-PS is able to group the feature data of MR images into five initial clusters of fat, soft tissue, air, bone, and bone marrow. Via these initial partitions, clusters needing to be refined are observed and for each of them a few additionally labeled examples are given as the partial supervision for the subsequent semi-supervised classification using LapSVM; 2) Partial supervision is usually insufficient for conventional algorithms to learn the insightful classifier. Instead, exploiting not only the given supervision but also the manifold structure embedded primarily in numerous unlabeled data, LapSVM is capable of training multiple desired tissue-recognizers; 3) Benefiting from the joint use of KL-TFCM and LapSVM, and assisted by the edge detector filter based feature extraction, the proposed SCT-PK-PS method features good recognition accuracy of tissue types, which ultimately facilitates the good transformation from MR images to CT images of the abdomen-pelvis. Applying the method on twenty subjects' feature data of UTE-mDixon MR images, the average score of the mean absolute prediction deviation (MAPD) of all subjects is 140.72 ± 30.60 HU which is statistically significantly better than the 241.36 ± 21.79 HU obtained using the all-water method, the 262.77 ± 42.22 HU obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method, and the 197.05 ± 76.53 HU obtained via the conventional SVM method. These results demonstrate the effectiveness of our method for the intelligent transformation from MR to CT on the body section of abdomen-pelvis.


Efficacy of antimicrobial photodynamic therapy compared to nystatin therapy in reducing Candida colony count in patients with Candida-associated denture stomatitis: a systematic review and meta-analysis.
Purpose This meta-analysis assessed the efficacy of antimicrobial photodynamic therapy (aPDT) compared to conventional nystatin therapy (NYT) in reducing Candida colony count in patients with Candida-associated denture stomatitis (CADS) and critically appraised the available literature.Methods This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) updated guidelines. A literature search was performed in four electronic databases to identify relevant articles up to 15 August 2021. Randomised controlled trials (RCTs) that assessed the efficacy of aPDT compared to NYT in reducing Candida colony count in patients with CADS were investigated. The weighted mean difference (MD) and 95% confidence interval were calculated. The I2 statistic was used to determine heterogeneity at the level of α = 0.10. The Cochrane risk of bias (RoB 2) tool was used to assess the risk of bias. Certainty of the evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) ranking system.Results Only three eligible RCTs with 141 participants were included in this systematic review and meta-analysis. Based on the pooled results, NYT compared to aPDT generally performed better in reducing Candida colony count (Log10 CFU/mL) in patients' palate and patients' denture. The included studies had a moderate risk of bias and the certainty of the evidence was low.Conclusion Although still inconclusive, based on the current evidence, aPDT may be effective in reducing Candida colony count and treating CADS. Nonetheless, it does not appear to be more effective than conventional NYT in this regard. According to the limited number of included studies, more well-designed RCTs with larger sample sizes and standardised methodology should be conducted to validate this conclusion.


[Evaluation of C reactive protein and others immunologic markers in the diagnosis of neonatal sepsis].
Neonatal sepsis occurs from 1 to 21 newborns out of 1 000 live births with mortality rates as high as 30% up to 69%. The most important risk factors are prematurity, low birth weight, invasive medical procedure and prolonged hospitalization in neonatal intensive care units. An aimed and restrictive antibiotic therapy has an outstanding importance to reduce both morbidity-mortality rates and multiple drug-resistance. Generally, preterm newborns present nonspecific clinical signs of infection. The use of high sensitivity infection markers and a negative predictive value (near 100%) are important to distinguish infected and noninfected patients before the culture results and to verify adequacy and duration of antibiotic therapy. This article reviews the immunologic function and practical use of C reactive protein (CRP) and other markers in the diagnosis of neonatal sepsis. While CRP is a specific late infection marker, cytokines, cell surface markers and procalcitonin (PCT) are early infection markers. The use of multiple markers as CRP, PCT, IL-6, IL-8, CD64, CD11b is useful both to early (24-48 h) diagnose of neonatal sepsis, and to monitorate the antibiotic treatment while waiting for the results of cultural examinations.


Demographic, laboratory and clinical characterisation of adult portuguese asthmatic patients.
Asthma is a heterogeneous chronic inflammatory condition characterised by reversible airway obstruction and hyperresponsiveness associated with underlying bronchial inflammation and structural changes. It represents an increasing health problem and is a huge burden on the patients, their families and society. The aim of the study was to characterise the adult asthmatic population attending a Hospital Allergy Clinic between the years of 2003 and 2006. Clinical files from the Allergy Outpatient Clinic of Cova da Beira Hospital were sequentially studied. The total population analysed included 335 female and 130 male asthmatic patients. Bronchial asthma was characterised by clinical history, skin prick testing to aeroallergens, determination of total and specific IgE and lung function testing, and classified according to international guidelines. Of the patients studied, 70 % had allergic asthma, and 30 % had non-allergic asthma. When compared to allergic asthma, non-allergic asthma was more frequently associated with older age, perennial symptoms and female gender. More allergic than non-allergic asthma patients also had rhinitis and the reverse was true regarding drug allergy and oesophageal reflux. Grass pollen and mites were the major sensitisers for allergic asthmatics. The sensitisation profile was significantly different between urban- and rural-based asthmatic patients regarding tree pollen, fungi and moulds. In this population, rhinitis was more frequently associated with allergic than with non-allergic asthma. The two types of asthma did not differ in clinical severity or changes in lung function. Sensitisation profiles were different between the urban and rural patients.


Circulating C-peptide and diabetic retinopathy.
Basal serum C-peptide concentrations were determined in a series of adult males referred to a diabetic retinopathy clinic. Degree of retinopathy of the most affected eye of each subject was classified using stereoscopic fundus photographs and fluorescein angiograms. A positive correlation was found between low C-peptide concentration (3.0 +/- 2.1 ng/ml) and proliferative or pre-proliferative diabetic retinopathy. A significantly higher (p less than 0.01) C-peptide level was found in subjects with non-proliferative diabetic retinopathy (6.0 +/- 3.7 ng/ml). Determination of fasting C-peptide levels after the first five-year period of insulin-dependent diabetes appears to be useful as a predictor of risk for proliferative disease.


Influences of textured substrates on the heart rate of developing zebrafish embryos.
Identification of the effects of different textured substrates on zebrafish (Danio rerio) embryos provides insights into the influence of external stimuli on normal cardiovascular functions in the developmental stages of the embryos. This knowledge can be used in numerous genetic studies using zebrafish as an animal model as well as in bioanalytical assays using digital microfluidics. In this study, zebrafish embryos were systematically positioned and in vivo imaged on four types of silicon substrates. These substrates exhibited surface textures and surface wettability that were well modulated by wet chemical etching. The heart rate of the developing embryos significantly increased by 9.1% upon exposure to textured Si substrates with nanostructured surfaces compared with bare Si substrates. Modulation of surface wettability in the tested substrates also responded to the increase in the heart rate of the embryo; however, the effect of surface wettability on heart rate was slight compared with the effect of texture. In-depth experimental and statistical investigations of heart rate under the effects of substrate textures imply a pathway through which the inner mass of the embryo reacts to external stimuli. These findings contribute to zebrafish-related studies and suggest other factors to consider in the design of nanostructure-based microfluidics and other biomedical devices.


Reserpine: effect on structure of heart muscle.
We examined the ultrastructure of hearts from dogs given reserpine intramuscularly for 4 days, and from untreated dogs. Sections of the myocardium from treated dogs invariably revealed mitochondrial abnormalities at the 5th and 14th days. These included fragmentation and loss of structure of the cristae, and cyst formation. The appearance at 25 days in the treated as well as in all the untreated dogs was normal. We concluded that reserpine in the dose used produces marked structural changes in the mitochondria of heart muscle, and that these changes are reversible. These changes may account for the myocardial depression sometimes seen after administration of reserpine.


Stimuli responsive dynamic transformations in supramolecular gels.
Supramolecular gels are formed by the self-assembly of small molecules under the influence of various non-covalent interactions. As the interactions are individually weak and reversible, it is possible to perturb the gels easily, which in turn enables fine tuning of their properties. Synthetic supramolecular gels are kinetically trapped and usually do not show time variable changes in material properties after formation. However, such materials potentially become switchable when exposed to external stimuli like temperature, pH, light, enzyme, redox, and chemical analytes resulting in reconfiguration of gel matrix into a different type of network. Such transformations allow gel-to-gel transitions while the changes in the molecular aggregation result in alteration of physical and chemical properties of the gel with time. Here, we discuss various methods that have been used to achieve gel-to-gel transitions by modifying a pre-formed gel material through external perturbation. We also describe methods that allow time-dependent autonomous switching of gels into different networks enabling synthesis of next generation functional materials. Dynamic modification of gels allows construction of an array of supramolecular gels with various properties from a single material which eventually extend the limit of applications of the gels. In some cases, gel-to-gel transitions lead to materials that cannot be accessed directly. Finally, we point out the necessity and possibility of further exploration of the field.


[The effect of weightlessness on amphibians. The ultimobranchial body].
C-cells of Pleurodeles waltilii ultimobranchial bodies (ULT) were studied after a series of two-week spaceflight on the biosatellites. It was shown that under conditions of weightlessness the hypertrophy of ULT and calcitonin secretion activation occurred. Calcitonin accumulated into the ULT which resulted in metaplasia of the surrounding tissues, organ calcification and C-cells death. After landing, the regenerative processes which were not manifest in weightlessness occurred. They were similar to those of embryonic development of the organ.