Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality.
The circadian clock is important for cellular and organ function. However, its function in sickle cell disease (SCD), a life-threatening hemolytic disorder, remains unknown. Here, we performed an unbiased microarray screen, which revealed significantly altered expression of circadian rhythmic genes, inflammatory response genes, and iron metabolic genes in SCD Berkeley transgenic mouse lungs compared with controls. Given the vital role of period 2 (Per2) in the core clock and the unrecognized role of Per2 in SCD, we transplanted the bone marrow (BM) of SCD mice to Per2Luciferase mice, which revealed that Per2 expression was up-regulated in SCD mouse lung. Next, we transplanted the BM of SCD mice to period 1 (Per1)/Per2 double deficient [Per1/Per2 double knockout (dKO)] and wild-type mice, respectively. We discovered that Per1/Per2 dKO mice transplanted with SCD BM (SCD → Per1/Per2 dKO) displayed severe irradiation sensitivity and were more susceptible to an early death. Although we observed an increase of peripheral inflammatory cells, we did not detect differences in erythrocyte sickling. However, there was further lung damage due to elevated pulmonary congestion, inflammatory cell infiltration, iron overload, and secretion of IL-6 in lavage fluid. Overall, we demonstrate that Per1/Per2 is beneficial to counteract elevated systemic inflammation, lung tissue inflammation, and iron overload in SCD.-Adebiyi, M. G., Zhao, Z., Ye, Y., Manalo, J., Hong, Y., Lee, C. C., Xian, W., McKeon, F., Culp-Hill, R., D' Alessandro, A., Kellems, R. E., Yoo, S.-H., Han, L., Xia, Y. Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality.


Depth resolution: a mechanism by which high kilovoltage improves visibility in chest films.
Depth resolution, a measure of the thinnest layer of tissue which will cast a detectable radiographic shadow, significantly limits visibility in conventional chest technique. Depth resolution, averaged over the chest area, improves with increasing kilovoltage, and thin, soft tissues can be seen more readily. The visibility of calcifications increases with kilovoltage in some areas of the chest and decreases in others, which is again explained by depth resolution. Densitometric data verify the mechanism involved: the latitude of the radiographic image matches that of the conventional film at high kilovoltages, so that more chest images are recorded at high contrast where visibility is best.


Acid-sensing ion channel 3 is required for agmatine-induced histamine-independent itch in mice.
Itch is a common symptom of many skin and systemic diseases. Identifying novel endogenous itch mediators and the downstream signaling pathways involved will contribute to the development of new strategies for the treatment of chronic itch. In the present study, we adopted behavioral testing, patch clamp recording and metabonomics analysis to investigate the role of agmatine in itch and the underlying mechanism. Behavioral analysis was used to evaluate the establishing of acute and chronic itch mice model, and to test the effects of different drugs or agents on mice itch behavior. Western blotting analysis was used to test the effect of agmatine on phosphorylation of ERK (p-ERK) expression in the spinal cord. Patch clamp recording was used to determine the effect agmatine on the excitability of DRG neurons and the role of ASIC3. Finally, the metabonomics analysis was performed to detect the concentration of agmatine in the affected skin under atopic dermatitis or psoriasis conditions. We fused a mouse model and found that an intradermal injection of agmatine (an endogenous polyamine) into the nape of the neck or cheek induced histamine-independent scratching behavior in a dose-dependent manner. In addition, the ablation of nociceptive C-fibers by resiniferatoxin (RTX) abolished agmatine-induced scratching behavior. However, agmatine-induced itch was not affected by the pharmacological inhibition of either transient receptor potential vanilloid 1 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1); similar results were obtained from TRPV1-/- or TRPA1-/- mice. Furthermore, agmatine-induced itch was significantly suppressed by the administration of acid-sensing ion channel 3 (ASIC3) inhibitors, APETx2 or amiloride. Agmatine also induced the upregulation of p-ERK in the spinal cord; this effect was inhibited by amiloride. Current clamp recording showed that the acute perfusion of agmatine reduced the rheobase and increased the number of evoked action potentials in acute dissociated dorsal root ganglion (DRG) neurons while amiloride reversed agmatine-induced neuronal hyperexcitability. Finally, we identified significantly higher levels of agmatine in the affected skin of a mouse model of atopic dermatitis (AD) when compared to controls, and the scratching behavior of AD mice was significantly attenuated by blocking ASIC3. Collectively, these results provide evidence that agmatine is a novel mediator of itch and induces itch via the activation of ASIC3. Targeting neuronal ASIC3 signaling may represent a novel strategy for the treatment of itch.


Elevated growth temperature can enhance photosystem I trimer formation and affects xanthophyll biosynthesis in Cyanobacterium Synechocystis sp. PCC6803 cells.
In the thylakoid membranes of the mesophilic cyanobacterium Synechocystis PCC6803, PSI reaction centers (RCs) are organized as monomers and trimers. PsaL, a 16 kDa hydrophobic protein, a subunit of the PSI RC, was previously identified as crucial for the formation of PSI trimers. In this work, the physiological effects accompanied by PSI oligomerization were studied using a PsaL-deficient mutant (ΔpsaL), not able to form PSI trimers, grown at various temperatures. We demonstrate that in wild-type Synechocystis, the monomer to trimer ratio depends on the growth temperature. The inactivation of the psaL gene in Synechocystis grown phototropically at 30°C induces profound morphological changes, including the accumulation of glycogen granules localized in the cytoplasm, resulting in the separation of particular thylakoid layers. The carotenoid composition in ΔpsaL shows that PSI monomerization leads to an increased accumulation of myxoxantophyll, zeaxanthin and echinenone irrespective of the temperature conditions. These xanthophylls are formed at the expense of β-carotene. The measured H2O→CO2 oxygen evolution rates in the ΔpsaL mutant are higher than those observed in the wild type, irrespective of the growth temperature. Moreover, circular dichroism spectroscopy in the visible range reveals that a peak attributable to long-wavelength-absorbing carotenoids is apparently enhanced in the trimer-accumulating wild-type cells. These results suggest that specific carotenoids are accompanied by the accumulation of PSI oligomers and play a role in the formation of PSI oligomer structure.


Development of a membrane-bound random DNA sequence combinatorial array recognition surface (CARS).
A partially overlapping population of random sequence 60mer DNA molecules consisting of many concatamers of varied lengths was spatially separated in one and two dimensions by electrophoresis in polyacrylamide and transferred to nitrocellulose membranes. The spatially separated library serves as a potential sensor interface on which many different molecular recognition events or target analyte-binding patterns may emerge, thereby theoretically representing a "universal sensor" surface. The separated DNA library has been referred to as a DNA combinatorial array recognition surface or "CARS." After UV baking and various fluorescence staining or fluorescent probe interactions, the one-dimensional (1-D) and 2-D membrane-bound CARS were digitally photographed and subjected to image analysis with National Institutes of Health Image-Java software. Image analysis demonstrated relatively consistent and more similar spatial fluorescence patterns within CARS analyte treatment groups but noteworthy pattern differences before and after analyte addition and between different analyte treatments. Taken together, these data suggest a potential role for CARS as a novel, inexpensive, self-assembling universal molecular recognition surface that could be coupled to sophisticated Bayesian or other pattern recognition algorithms to classify analytes or make specific identifications, much like the senses of smell or taste.


Theory of a curved planar waveguide with Robin boundary conditions.
A model of a thin straight strip with a uniformly curved section and with boundary requirements zeroing at the edges a linear superposition of the wave function and its normal derivative (Robin boundary condition) is analyzed theoretically within the framework of the linear Schrödinger equation and is applied to the study of the processes in the bent magnetic multilayers, superconducting films and metallic ferrite-filled waveguides. In particular, subband thresholds of the straight and curved parts of the film are calculated and analyzed as a function of the Robin parameter 1/Lambda , with Lambda being an extrapolation length entering Robin boundary condition. For the arbitrary Robin coefficients which are equal on the opposite interfaces of the strip and for all bend parameters the lowest-mode energy of the continuously curved duct is always smaller than its straight counterpart. Accordingly, the bound state below the fundamental propagation threshold of the straight arms always exists as a result of the bend. In terms of the superconductivity language it means an increased critical temperature of the curved film compared to its straight counterpart. Localized-level dependence on the parameters of the curve is investigated with its energy decreasing with increasing bend angle and decreasing bend radius. Conditions of the bound-state existence for the different Robin parameters on the opposite edges are analyzed too; in particular, it is shown that the bound state below the first transverse threshold of the straight arm always exists if the inner extrapolation length is not larger than the outer one. In the opposite case there is a range of the bend parameters where the curved film cannot trap the wave and form the localized mode; for example, for the fixed bend radius the bound state emerges from the continuum at some nonzero bend angle that depends on the difference of the two lengths Lambda at the opposite interfaces. Various transport properties of the film such as interference blockade of the current flow at some special energies is also discussed with the special attention being paid to the transformation from the Dirichlet to the Neumann case as the extrapolation length Lambda sweeps the positive axis.


Programmable Bidirectional Folding of Metallic Thin Films for 3D Chiral Optical Antennas.
3D structures with characteristic lengths ranging from nanometer to micrometer scale often exhibit extraordinary optical properties, and have been becoming an extensively explored field for building new generation nanophotonic devices. Albeit a few methods have been developed for fabricating 3D optical structures, constructing 3D structures with nanometer accuracy, diversified materials, and perfect morphology is an extremely challenging task. This study presents a general 3D nanofabrication technique, the focused ion beam stress induced deformation process, which allows a programmable and accurate bidirectional folding (-70°-+90°) of various metal and dielectric thin films. Using this method, 3D helical optical antennas with different handedness, improved surface smoothness, and tunable geometries are fabricated, and the strong optical rotation effects of single helical antennas are demonstrated.


RNA synthesis and processing reactions in a subcellular system from mouse L cells.
A subcellular system from mouse L-cells has been used to study RNA synthesis and processing in vitro. The nuclei in this system incorporate nucleoside triphosphates into RNA with high yield for more than 120 min. The capacity for RNA synthesis is stable for extended periods at 4 degrees C. All three RNA polymerases contribute to the overall synthetic activity as shown by differential inhibition with alpha-amanitin. The in vitro labeled RNA contains about 15% of polyadenylated RNA. The non-polyadenylated RNA shows molecules in the range of larger than 20 S down to 4-5 S. The polyadenylated RNA exhibits mainly transcripts around 18 S and below 8 S. Methylation of nucleoside bases and the ribose 2'-OH group including 5'-caps is performed in vitro as well. Base methylation and 5'-cap methylation are partially sensitive to alpha-amanitin. 28% of the methyl groups are found in polyadenylated RNA being distributed throughout molecules of all sizes. The methylated non-polyadenylated RNA shows peaks at 45 S, around 28 S and 18 S, and a very prominent low-molecular weight RNA peak. Addition of the poly(A) tract to RNA molecules in vitro is revealed by the presence of [3H]-uridine-labeled polyadenylated RNA. The poly(A) tract was isolated and analyzed on polyacrylamide gels. Its maximum length coincides with an in vivo poly(A) marker indicating the addition of about 150-200 nucleotides. Poly(A) addition is possible on pre-existing RNA chains, preferably on 3'-oligo(A) tracts. This process is insensitive to alpha-amanitin. In addition, the specificity of polyadenylation may be relaxed since incorporation of [3H]UTP into polyadenylated RNA is only reduced to about 50% under conditions (1 microgram alpha-amanitin/ml) where RNA polymerase II is inhibited. A small fraction of the in vitro labeled RNA binds to polysomes which can be recovered from the cytoplasm adhering to the nuclei. This RNA contains poly(A) and is enriched in base methylations and 5' end caps. It can be dissociated from the polysomes by EDTA. It is likely to be in vitro labeled and maturated mRNA.


Mass spectrometric evidence that proteolytic processing of rainbow trout egg vitelline envelope proteins takes place on the egg.
The rainbow trout egg vitelline envelope (VE) is constructed of three proteins, called VEalpha,VEbeta, and VEgamma, that are synthesized and secreted by the liver and transported in the bloodstream to the ovary, the site of VE assembly around eggs. All three proteins possess an N-terminal signal peptide, a zona pellucida domain, a consensus furin-like cleavage site (CFLCS) close to the C terminus, and a short propeptide downstream of the CFLCS. Proteolytic processing at the CFLCS results in loss of the short C-terminal propeptide from precursor proteins and enables incorporation of mature proteins into the VE. Here mass spectrometry (matrix-assisted laser desorption ionization time-of-flight-mass spectrometry and liquid chromatography-mass spectrometry with a micromass-quadrupole TOF hybrid mass and a QSTAR Pulsar i mass spectrometer) was employed with VE proteins isolated from rainbow trout eggs in a peptidomics-based approach to determine the following: 1) the C-terminal amino acid of mature, proteolytically processed VE proteins; 2) the cellular site of proteolytic processing at the CFLCS of VE precursor proteins; and 3) the relationship between proteolytic processing and limited covalent cross-linking of VE proteins. Peptides derived from the C-terminal region were found for all three VE proteins isolated from eggs, indicating that processing at the CFLCS occurs after the arrival of VE precursor proteins at the egg. Consistent with this conclusion, peptides containing an intact CFLCS were also found for all three VE proteins isolated from eggs. Furthermore, peptides derived from the C-terminal propeptides of VE protein heterodimers VEalpha-VEgamma and VEbeta-VEgamma were found, suggesting that a small amount of VE protein can be covalently cross-linked on eggs prior to proteolytic processing at the CFLCS. Collectively, these results provide important evidence about the process of VE formation in rainbow trout and other non-cyprinoid fish and allow comparisons to be made with the process of zona pellucida formation in mammals.


Simple coupled-cluster singles and doubles method with perturbative inclusion of triples and explicitly correlated geminals: The CCSD(T)R12 model.
To approach the complete basis set limit of the "gold-standard" coupled-cluster singles and doubles plus perturbative triples [CCSD(T)] method, we extend the recently proposed perturbative explicitly correlated coupled-cluster singles and doubles method, CCSD(2)(R12) [E. F. Valeev, Phys. Chem. Chem. Phys. 8, 106 (2008)], to account for the effect of connected three-electron correlations. The natural choice of the zeroth-order Hamiltonian produces a perturbation expansion with rigorously separable second-order energy corrections due to the explicitly correlated geminals and conventional triple and higher excitations. The resulting CCSD(T)(R12) energy is defined as a sum of the standard CCSD(T) energy and an amplitude-dependent geminal correction. The method is technically very simple: Its implementation requires no modification of the standard CCSD(T) program and the formal cost of the geminal correction is small. We investigate the performance of the open-shell version of the CCSD(T)(R12) method as a possible replacement of the standard complete-basis-set CCSD(T) energies in the high accuracy extrapolated ab initio thermochemistry model of Stanton et al. [J. Chem. Phys. 121, 11599 (2004)]. Correlation contributions to the heat of formation computed with the new method in an aug-cc-pCVXZ basis set have mean absolute basis set errors of 2.8 and 1.0 kJmol when X is T and Q, respectively. The corresponding errors of the standard CCSD(T) method are 9.1, 4.0, and 2.1 kJmol when X=T, Q, and 5. Simple two-point basis set extrapolations of standard CCSD(T) energies perform better than the explicitly correlated method for absolute correlation energies and atomization energies, but no such advantage found when computing heats of formation. A simple Schwenke-type two-point extrapolation of the CCSD(T)(R12)aug-cc-pCVXZ energies with X=T,Q yields the most accurate heats of formation found in this work, in error on average by 0.5 kJmol and at most by 1.7 kJmol.


Identification and analysis of hub genes and networks related to hypoxia preconditioning in mice (No 035215).
Hypoxia preconditioning is an effective strategy of intrinsic cell protection. An acute repetitive hypoxic mice model was developed. High-throughput microarray analysis was performed to explore the integrative alterations of gene expression in repetitive hypoxic mice. Data obtained was analyzed via multiple bioinformatics approaches to identify the hub genes, pathways and biological processes related to hypoxia preconditioning. The current study, for the first time, provides insights into the gene expression profiles in repetitive hypoxic mice. It was found that a total of 1175 genes expressed differentially between the hypoxic mice and normal mice. Overall, 113 significantly up-regulated and 138 significantly down-regulated functions were identified from the differentially expressed genes in repetitive hypoxic brains. Among them, at least fourteen of these genes were very associated with hypoxia preconditioning. The change trends of these genes were validated by reverse-transcription polymerase chain reaction and were found to be consistent with the microarray data. Combined the results of pathway and gene co-expression networks, we defined Plcb1, Cacna2d1, Atp2b4, Grin2a, Grin2b and Glra1 as the main hub genes tightly related with hypoxia preconditioning. The differential functions mainly included the mitogen-activated protein kinase pathway and ion or neurotransmitter transport. The multiple reactions in cell could be initiated by activating MAPK pathway to prevent hypoxia damage. Plcb1 was an important and hub gene and node in the hypoxia preconditioning signal networks. The findings in the hub genes and integrated gene networks provide very useful information for further exploring the molecular mechanisms of hypoxia preconditioning.


Playground usability: what do playground users say?
Play, specifically outdoor play, is crucial for a child's development. However, not all playgrounds are designed to provide usable space for children with disabilities. The aim of the study was to gain an understanding of the experiences of playground use for children with disabilities and their caregivers. Using a qualitative descriptive design, interviews were conducted with children with disabilities and their caregivers. Interview transcripts were reviewed and coded. The analysis process resulted in three overarching themes. Playground Experiences addressed the sensory experiences that children seek at playgrounds, the importance of creating environments that promote imaginative play and the need to provide an appropriate level of challenge. In the second theme, Playground Usability, participants described barriers that prevent access and features that promote use. The third theme, Inclusivity, focused on equal access and the importance of providing options in design. The Person-Environment-Occupation model was used to frame the findings and to identify practice and research recommendations. Outdoor play is a key occupation of children, and occupational therapists have a role in promoting usable environments for all children.


Pseudalataspora vanderlingeni n. sp. (Myxosporea: Bivalvulida) from gall bladders of the Cape hakes Merluccius capensis Castelnau, and M. paradoxus Franca (Teleostei: Merlucciidae).
A new species of myxosporean parasite is described from the gall bladders of the hakes Merluccius capensis Castelnau and M. paradoxus Franca (Pisces: Teleostei) caught off the west and south coasts of South Africa. The new species, Pseudalataspora vanderlingeni, is described morphologically and molecularly and compared with the 15 other species of Pseudalataspora previously described from marine fish. Although a molecular description is available on GenBank for only one of these 15 species, the morphological description supports the status of P. vanderlingeni as a new species. Earlier reports, without detailed descriptions, of Leptotheca sp. and Ceratomyxa sp. from the same hosts caught off Namibia were very likely to have been of P. vanderlingeni. These earlier studies reported high prevalences of infection, similar to those of >60% described in the present study. The effects of fixation and freezing on the dimensions of spores of Pseudalataspora spp. are described, and the status of the genus Pseudalataspora within the family Ceratomyxidae is discussed.


The development of biofilm architecture.
We extend the one-dimensional polymer solution theory of bacterial biofilm growth described by Winstanley et al. (2011 Proc. R. Soc. A467, 1449-1467 (doi:10.1098/rspa.2010.0327)) to deal with the problem of the growth of a patch of biofilm in more than one lateral dimension. The extension is non-trivial, as it requires consideration of the rheology of the polymer phase. We use a novel asymptotic technique to reduce the model to a free-boundary problem governed by the equations of Stokes flow with non-standard boundary conditions. We then consider the stability of laterally uniform biofilm growth, and show that the model predicts spatial instability; this is confirmed by a direct numerical solution of the governing equations. The instability results in cusp formation at the biofilm surface and provides an explanation for the common observation of patterned biofilm architectures.


[MRI findings in the diagnosis of pseudotumoral humeral hydatid].
Hydatidosis of bone is rare. Vertebral localizations predominate. Standard imaging may be misleading, suggestive of a malignant tumor or infection. We present the case of a patient with a humeral hydatid. This localization is very rare and presents an unusual radiographic aspect. Computed tomography produces an image suggestive of a tumor. The correct diagnosis can be established with MRI, particularly with the STIR sequence. In our patient, MRI enabled us to establish the diagnosis preoperatively and evaluate extension. MRI has been found to be highly contributive to the diagnosis of hydatidosis of bone and for assessment of intra- and peri-osseous extension.


Polysaccharides from Enteromorpha Prolifera Ameliorate Acute Myocardial Infarction in Vitro and in Vivo via Up-Regulating HIF-1α.
Acute myocardial infarction (AMI) is a serious heart disease and the main reason for heart failure and sudden death worldwide. This study investigated the effects of polysaccharides from Enteromorpha prolifera (PEP) on AMI in vitro and in vivo, as well as the underlying mechanisms.Human cardiac microvascular endothelial cells (HCMVEC) were cultured in vitro in an oxygen-glucose deprivation (OGD) environment to induce injury. The viability and apoptosis of HCMVEC were then detected using CCK-8 assay and Annexin V-FITC/PI staining, respectively. ELISA was performed to measure the concentrations of inflammatory cytokines. Cell transfection was conducted to reduce the expression of HIF-1α. Expression of key factors involving in cell proliferation, apoptosis, autophagy, MEK/ERK, and the NF-κB and mTOR pathways were evaluated using Western blotting. In vivo, Wistar rats were pre-treated by PEP and AMI was induced. The infarct size and cardiac functions (LVEDD, LVEF and LVFS) were measured.In vitro, PEP treatment significantly protected HCMVEC from OGD-induced viability loss, proliferation inhibition, apoptosis, inflammatory cytokine expression, and autophagy. Moreover, PEP enhanced the expression of HIF-1α in HCMVEC via the MEK/ERK pathway. HIF-1α participated in the protective effects of PEP on OGD-treated HCMVEC. Furthermore, PEP attenuated OGD-induced NF-κB pathway activation and promoted the mTOR pathway in HCMVEC. In vivo, PEP pre-treatment reduced the infarct size and enhanced the LVEDD, LVEF and LVFS of rats via up-regulation of HIF-1α.PEP ameliorated AMI in vitro and in vivo through up-regulation of HIF-1α. In vitro, PEP could activate the MEK/ERK and mTOR pathways, but inactivate the NF-κB pathway in OGD-treated HCMVEC.


Processing techniques for the demonstration of myelin basic protein in paraffin-embedded optic nerve: an immunoperoxidase study of the developing albino rat.
A comparison was made of the effects of various fixation and processing conditions upon the antigenicity of myelin basic protein (MBP) in sections of paraffin-embedded optic nerve from the developing albino rat as judged by the unlabeled peroxidase-antiperoxidase technique. The fixatives used were: Perfix, 4% and 2% buffered paraformaldehyde (pH 7.4), 10% buffered formalin (pH 7.4); Bouin's, Clark's, and Carnoy's fixatives, and 20% formalin in a solution of HgCl2 that had been saturated at 1 degrees C. Perfix appeared to be the best fixative for the preservation of morphology and MBP antigenicity during the early stages of myelinogenesis but was not satisfactory during the later stages. The buffered aldehydes were slightly more destructive of MBP antigenicity than was Perfix, but they produced satisfactory results following the first postnatal week. Bouin's fixative was similar in effect to the buffered aldehydes, but nonspecific background staining was higher. HgCl2/formalin, Clark's and Carnoy's fixatives were unsuitable. No differences were noted in staining between material processed for embedding using 5, 30, or 60 min schedules.


Valproic Acid in the Management of Delirium.
Antipsychotics and benzodiazepines do not improve delirium. Valproic acid (VPA) has been used recently to treat agitation in delirium. To review the evidence for VPA in the management of Delirium. Systematic review. English language, age 19 and above, from 1946 to January 12, 2021. "Valproic acid", "valproate", "sodium valproate", "delirium", "acute mania with delirium" in PubMed and Ovid. Studies of VPA used for diagnoses other than delirium. 21 abstracts were identified and 10 studies were included in the review (252 patients): One prospective open label study (n: 7), 2 case series (n: 22), 4 retrospective studies (n: 219) and 3 case reports (n: 4). No randomized controlled trial (RCT) evaluates the effect of VPA in delirium. 237/250 (94.8%) patients were in the ICU. Mean age was 59.7 (27-87). 153/204 (74%) were male. The mean starting dose was 733 mg/day in 148 patients and the mean dose at follow up was 1061 mg/day in 205 patients. CAM ICU was used to diagnose delirium in 6 reviews. Delirium improved in case series in 19/22 patients. Delirium improved in retrospective studies at day 3 compared to day 1. VPA levels were not consistently reported. Hyperammonemia (12-19%) and thrombocytopenia (9-13%) were the most common side effects. No deaths were attributed to VPA. VPA is being used more frequently for delirium. The evidence is limited to retrospective studies and case series. There is a need for RCT to evaluate the effect of VPA in delirium compared to other alternatives and placebo.


Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways.
Mantle-cell lymphoma (MCL) is a well-defined subtype of B-cell non-Hodgkin's lymphomas (B-NHL), accounts for approximately 6% of all lymphoid neoplasms, and has a median survival of 3 to 4 years. The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. This genetic event is present in virtually all cases of MCL, whereas additional genetic alterations that occur in subsets of MCL have been described. Most of these alterations appear to disturb the cell cycle machinery/interfere with the cellular response to DNA damage, thus making MCL a paradigm for cell cycle and DNA damage response dysregulation in cancer in general. In particular, Cyclin D1 upregulation, genomic amplification of the cyclin-dependent kinase (CDK) -4, deletions of the CDK inhibitor p16(INK4a) and overexpression of BMI-1, a transcriptional repressor of the p16(INK4a) locus, are associated with dysregulation of the cell cycle machinery in MCL. The DNA damage response pathway is affected by frequent alterations of the ataxia-telangiectasia mutated (ATM) kinase as well as occasional inactivation of checkpoint kinase (CHK)-1 and CHK2 that are kinases that act downstream of ATM in response to detection of DNA damage. Moreover, p53 is frequently targeted by alterations in MCL. A recent gene expression profiling study defined the proliferation signature, a quantitative measure of gene expression of proliferation-associated genes as the strongest survival predictor available to date allowing the definition of prognostic MCL subgroups that differ in median survival by more than 5 years.


The influence of family ties on men's prostate cancer screening, biopsy, and treatment decisions.
Extensive research has focused on understanding family dynamics of men with prostate cancer. However, little qualitative work has examined the role of family ties on men's prostate cancer decisions across the spectrum of screening, diagnosis, and treatment. Using data from a larger study, we qualitatively explored the influence of family ties on men's prostate cancer decisions. Semistructured interviews were conducted with men ages ≥50 (N = 64), and data were analyzed using a grounded theory approach and a series of immersion/crystallization cycles. Three major themes of spousal/family member influence were identified: (a) spousal/family member alliance marked by open communication and shared decision making, (b) men who actively opposed spouse/family member pressure and made final decisions themselves, and (c) men who yielded to spouse/family member pressure. Our findings provide insights into men's relational dynamics that are important to consider for the shared decision-making process across the prostate cancer spectrum.


Engineering of phenylalanine dehydrogenase from Thermoactinomyces intermedius for the production of a novel homoglutamate.
The dramatic increase in healthcare costs has become a significant burden to this era. Many patients are unable to access medication because of the high price of drugs. Genetic engineering has made advances to increase the yield, titer, and productivity in the bio-based production of chemicals, materials of interest, and identification of innovative targets for drug discovery. Currently, the production of homoglutamate (α-Aminoadipic acid) involves petrochemical routes that are costly with low yield and often not suitable for industrial production. Here, we established the development of NADH-dependent homoglutamate by engineering NADH-dependent phenylalanine dehydrogenase (PDH) from Thermoactinomyces intermedius, which provides a novel tool for in-vivo metabolic engineering and in-vitro catalysis. Based on computational insight into the structure, we proposed the site-specific directed mutagenesis of the two important residues of PDH through docking simulations by AutoDock Vina which elucidated the binding mode of PDH with α-Ketoadipic acid and ligands. Our results demonstrated that the catalytic efficiency Km/Kcat of the final mutant Ala135Arg showed a 3-fold increase amination activity towards the ketoadipic acid as compared to the other mutant Gly114Arg, a double mutant Gly114Arg/Ala135Arg, and wild type TiPDH. Furthermore, we have introduced formate dehydrogenase as a cofactor regenerative system in this study which further made this study economically viable. Our study unfolds the possibility of biosynthesis of other non-proteinogenic amino acids that might be valuable pharmaceutical intermediaries.


Impaired function of the Tie-2 receptor contributes to vascular leakage and lethality in anthrax.
The anthrax lethal toxin (LT) enters host cells and enzymatically cleaves MAPKKs or MEKs. How these molecular events lead to death from anthrax remains poorly understood, but published reports suggest a direct effect of LT on vascular permeability. We have found that LT challenge in mice disrupts signaling through Tie-2, a tonically activated receptor tyrosine kinase in the endothelium. Genetic manipulations favoring Tie-2 activation enhanced interendothelial junctional contacts, prevented vascular leakage, and promoted survival following a lethal dose of LT. Cleavage of MEK1/2 was necessary for LT to induce endothelial barrier dysfunction, and activated Tie-2 signaled through the uncleaved fraction of MEKs to prevent LT's effects on the endothelium. Finally, primates infected with toxin-secreting Bacillus anthracis bacilli developed a rapid and marked imbalance in the endogenous ligands that signal Tie-2, similar to that seen in LT-challenged mice. Our results show that B. anthracis LT blunts signaling through Tie-2, thereby weakening the vascular barrier and contributing to lethality of the disease. Measurement of circulating Tie-2 ligands and manipulation of Tie-2 activity may represent future prognostic and therapeutic avenues for humans exposed to B. anthracis.


A nuclear lamin of the nematode Caenorhabditis elegans with unusual structural features; cDNA cloning and gene organization.
This report describes the characterization of the nuclear lamin CeLam-1 of the nematode Caenorhabditis elegans by molecular analysis of the corresponding complete cDNA and gene sequences. The primary structure of CeLam-1, representing only the third non-vertebrate lamin sequence currently known, follows essentially the features displayed by the B-type lamins of vertebrates and Drosophila. The nematode lamin shows, however, some exceptional properties. First, it lacks the SPTR sequence in front of the coil 1a domain which constitutes the major mitotic cdc2 kinase phosphorylation site. Second, two prominent deletions occur in the CeLam-1 sequence. One eliminates 14 amino acid residues from the coil 2 domain. A larger deletion of approximately 25 residues results in the shortest lamin tail domain documented so far. The latter corresponds to a region which varies considerably in sequence from highly acidic in vertebrate B-type lamins to rather basic in Drosophila lamin Dmo. CeLam-1 is encoded by a single 2.3 kb mRNA which is abundantly expressed in mixed-stage worm populations. The 5'-end of the mRNA is generated by trans-splicing to the SL1 leader sequence. The CeLam-1 gene extending over 2.7 kb is located on chromosome I. The gene is composed of 6 exons and 5 short introns, which all interrupt the coding sequence. Surprisingly, none of the intron positions has a counterpart in either the Drosophila lamin Dmo or the vertebrate lamin genes.


Comparison of expectations and beliefs about good teaching in an academic day release medical education program: a qualitative study.
In a professional learner-centered(ness) educational environment, communication and alignment of expectations about teaching are indispensable. Professional education of residents could benefit from an analysis and comparison of teachers' and residents' educational expectations and beliefs. Our purpose is to identify success factors and barriers related to aligning expectations and beliefs and building a supportive professional learner-centered educational environment. We conducted semi-structured individual interviews with teachers and semi-structured focus groups with residents. A single interview format was used to make it possible to compare the results. Data were analysed using a qualitative software package (AtlasTi). Data analysis steps were followed by the author team, which identified four domains of good teaching: personal traits, knowledge, relationships and teaching qualities. Teachers and residents agreed about the importance of personal professional characteristics like being a role model and having an open and enthusiastic attitude. They all thought that having a specific knowledge base was essential for teaching. Approaching residents as adult learners was found to be an important element of the learner-centred environment and it was agreed that teachers should take practical experiences to a higher level. However, teachers and residents had different expectations about the practical consequences of being a role model, adult learning, coaching and openness, and the type of knowledge that was needed in the professional development program. Communication about different expectations appeared to be difficult. Teachers and residents agreed on a conceptual level about expectations and beliefs regarding good teaching, but disagreed on an executive level. According to the residents, the disagreement about good teaching was not the biggest barrier to creating alignment and a supportive professional relationship; instead, it was the absence of a proper dialogue regarding issues about expectations and beliefs.


Current status of lung cancer in Spain: a retrospective analysis of patient characteristics, use of healthcare resources and in-hospital mortality.
Objective: This study aimed to describe the current status of lung cancer in Spain, including patient characteristics and in-hospital mortality, and to revise disease management and the direct medical costs of secondary care.Methods: A retrospective observational study was set to analyse anonymized primary and secondary care records of patients admitted with lung cancer in Spain between 2011 and 2016. Data were obtained from the Primary Care Dataset and the Centralised Hospital Discharge Database.Results: Admissions files from 12,119 primary care and 113,574 secondary care patients were analyzed. Only 21% of all patients were females, yet the number of female patients presented an increasing trend over the study period. Non-small-cell lung carcinoma represented 85.29% of all lung malignant neoplasms; metastatic or secondary malignant neoplasms were diagnosed in 76.66% of admissions. Other relevant comorbid conditions registered at the hospital level were hypertension, disorders of lipoid metabolism, diabetes mellitus and a history of tobacco use. In-hospital mortality was 22% over the study period and was associated with respiratory failure. Mean hospitalization time was 9.57 days and most admissions were due to emergencies. The mean cost of secondary care per patient was €8475, increasing significantly over the study period. Cost per patient was higher in those diagnosed with a squamous cell carcinoma.Conclusions: Preventive and early detection measures are recommended, continuing to focus on females. In parallel, a multidisciplinary approach could optimize patient journey considering the presence of disease comorbidities, although its role in lung cancer mortality should be further explored.


Maintenance of estrous cycle in female rats with anterior or posterior deafferentation of the suprachiasmatic nucleus.
The aim of the present study was to determine which of the anterior or posterior efferents of the suprachiasmatic nucleus (SCN) predominantly act for the maintenance of estrous cycle in female rats. A small knife (0.8 mm in radius) was used for anterior (ASD), posterior (PSD) and complete suprachiasmatic deafferentations (CSD). The rats subjected to CSD were divided into two groups, the first group bearing lesions on the medial preoptic nucleus (MPN; group CSD-MPN-L) and the other group bearing no lesions on the MPN (group CSD). For reference, anterior hypothalamic deafferentation (AHD) was carried out using a large knife (2.0 mm in radius). All rats with AHD or CSD-MPN-L and some of CSD rats showed persistent estrus, but all animals with ASD or PSD resumed regular estrous cycles after transient irregular periods. Ovaries of AHD, CSD and CSD-MPN-L rats contained very few, if any, corpora lutea, while the number of corpora lutea in ASD or PSD rats was not significantly different from that of sham-operated controls. Immunohistochemical examination revealed that in AHD rats LHRH immunoreactivity in the median eminence was markedly reduced as compared with that of sham-operated controls. In contrast, in ASD, PSD, CSD and CSD-MPN-L rats, the LHRH immunoreactivity in the median eminence was similar to that of sham-operated controls.(ABSTRACT TRUNCATED AT 250 WORDS)


Reversed-phase high-performance liquid chromatographic separation of LY309887 (thienyl-5,10-dideazatetrahydrofolate) stereoisomers using beta-cyclodextrin as a mobile phase additive.
The separation of the four stereoisomers of LY309887 (thienyl-5,10-dideazatetrahydrofolate) is studied here using commercially available high-performance liquid chromatography column technology. The selectivity needed to resolve the four stereoisomers is provided by an achiral reversed-phase column used with beta-cyclodextrin as a mobile phase additive. The separation is dependent on triethylamine and beta-cyclodextrin concentration in the buffer portion of the eluent, eluent strength, and buffer pH.


Axonal growth inhibitors and their receptors in spinal cord injury: from biology to clinical translation.
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelin-associated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19 (that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the RhoA/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.


Nutritive value and qualitative assessment of secondary compounds in seeds of eight tropical browse, shrub and pulse legumes.
Seeds of four tropical multipurpose trees (Albizia saman, Albizia lebbeck, Albizia rhizonse, Leucaena leucocephala), two shrubs (Tephrosia candida, Tephrosia bracteolata) and two pulse legume (Lablab purpureus, Canavalia ensiformis) were chemically analysed for dry matter (DM), ash, crude protein (CP), neutral detergent fibre (NDF) and ether extract (EE). Qualitative evaluation of secondary metabolites (saponins, phenols, steroids, and alkaloids) was elucidated. The DM, ash, CP, NDF and EE ranged between 88.9-93.6 %, 3.0-5.4 %, 24.8-38.2 %, 22.1-46.9 % and 2.0-17.0 % respectively. All seed species contained at least one group of secondary plant metabolites and steroids were common to all except C. ensiformis that was not implicated for any. A. lebbeck and A. rhizonse showed low saponin content. Indications for water soluble tannins were reported for L. leucocephala while the two species of Tephrosia contained flavonoids or condensed tannins. The study suggested the potentials of the legumes seed species as a feed source for ruminants.


Health Benefits In 2023: Premiums Increase With Inflation And Employer Coverage In The Wake Of Dobbs.
In 2023 the average annual premium for employer-sponsored family health insurance coverage was $23,968-an increase of $1,505 (7 percent) from 2022. Both single and family premiums increased faster in 2023 than in 2022, in a period of generally high inflation throughout the US economy. On average, covered workers contributed 17 percent ($1,401) of the cost of single coverage and 29 percent ($6,575) of the cost of family coverage. When compared to employers' perceptions of the number of primary care providers in their networks, a smaller share of employers believed that their provider networks had a sufficient number of mental health and substance abuse providers to provide timely access to services. One-quarter of employers indicated that their employees had a "high" level of concern with the level of cost sharing required by their plans. When asked about abortion coverage in the wake of the Supreme Court Dobbs decision, almost a third of large employers reported that their largest plan covered abortion in most or all circumstances.


Characteristics of inhalable particulate matter concentration and size distribution from power plants in China.
In this investigation, the collection efficiency of particulate emission control devices (PECDs), particulate matter (PM) emissions, and PM size distribution were determined experimentally at the inlet and outlet of PECDs at five coal-fired power plants. Different boilers, coals, and PECDs are used in these power plants. Measurement in situ was performed by an electrical low-pressure impactor with a sampling system, which consisted of an isokinetic sampler probe, precut cyclone, and two-stage dilution system with a sample line to the instruments. The size distribution was measured over a range from 0.03 to 10 microm. Before and after all of the PECDs, the particle number size distributions display a bimodal distribution. The PM2.5 fraction emitted to atmosphere includes a significant amount of the mass from the coarse particle mode. The controlled and uncontrolled emission factors of total PM, inhalable PM (PM10), and fine PM P(M2.5) were obtained. Electrostatic precipitator (ESP) and baghouse total collection efficiencies are 96.38-99.89% and 99.94%, respectively. The minimum collection efficiency of the ESP and the baghouse both appear in the particle size range of 0.1-1 microm. In this size range, ESP and baghouse collection efficiencies are 85.79-98.6% and 99.54%. Real-time measurement shows that the mass and number concentration of PM10 will be greatly affected by the operating conditions of the PECDs. The number of emitted particles increases with increasing boiler load level because of higher combustion temperature. During test run periods, the data reproducibility is satisfactory.


Self-assembled polypeptide nanoparticles for intracellular irinotecan delivery.
In this research poly(l-lysine)-b-poly(l-leucine) (PLys-b-PLeu) polymersomes were developed. It was shown that the size of nanoparticles depended on pH of self-assembly process and varied from 180 to 650nm. The biodegradation of PLys-b-PLeu nanoparticles was evaluated using in vitro polypeptide hydrolysis in two model enzymatic systems, as well as in human blood plasma. The experiments on the visualization of cellular uptake of rhodamine 6g-loaded and fluorescein-labeled nanoparticles were carried out and the possibility of their penetration into the cells was approved. The cytotoxicity of polymersomes obtained was tested using three cell lines, namely, HEK, NIH-3T3 and A549. It was shown that tested nanoparticles did not demonstrate any cytotoxicity in the concentrations up to 2mg/mL. The encapsulation of specific to colorectal cancer anti-tumor drug irinotecan into developed nanocontainers was performed by means of pH gradient method. The dispersion of drug-loaded polymersomes in PBS was stable at 4°C for a long time (at least 1month) without considerable drug leakage. The kinetics of drug release was thoroughly studied using two model enzymatic systems, human blood serum and PBS solution. The approximation of irinotecan release profiles with different mathematical drug release models was carried out and allowed identification of the release mechanism, as well as the morphological peculiarities of developed particles. The dependence of encapsulation efficiency, as well as maximal loading capacity, on initial drug concentration was studied. The maximal drug loading was found as 320±55μg/mg of polymersomes. In vitro anti-tumoral activity of irinotecan-loaded polymersomes on a colon cancer cell line (Caco-2) was measured and compared to that for free drug.


Mekong Delta at the crossroads: more control or adaptation?
Development in the Mekong Delta of Vietnam has been very dynamic in the recent past, and currently it stands at an interesting crossroads. On one hand, agricultural production has developed successfully, and economic growth has been very rapid, but on the other hand, intensifying agriculture and large-scale water-control structures have challenged the environmental sustainability and social equity. The development plans have included a strong belief in the human mastery over the nature and waters of the Mekong Delta. In many cases, water resources planners have underestimated the complexity and integrated nature of the ecology and livelihoods of the Mekong Delta. This article examines cases where development efforts, while successful in some dimensions, have also contributed to create new risks for, especially, the poorest groups. The current situation calls for a more sustainable future route that would require examination of more adaptive measures in relation to the changing water flows of the Mekong River.


Psychedelic Research and Therapeutic Practices: Embracing Communities, Groups, and Traditional Knowledge.
The global prevalence of substance abuse and mental disorders continues to challenge healthcare systems, with one in eight individuals affected. The therapeutic potential of psychedelics is recognized not only for treating mental disorders but also for enhancing well-being and promoting pro-social behaviors. Conventional biomedical research models fall short in addressing the broader health needs of populations and poorly suited for overcoming barriers to service delivery. This special issue includes six articles that explore alternative approaches to psychedelic research and practice, emphasizing collaboration with diverse actors, including indigenous communities, and incorporating traditional knowledge systems into contemporary psychedelic research. They underscore the need for innovative research methods that engage multidisciplinary approaches while promoting culturally relevant outcome measures. They emphasize the importance of shifting from punitive drug policies to those grounded in public health and human rights, allowing for multi-country studies and the development of evidence-based care models for community mental health. Incorporating traditional knowledge and community-based methodologies into psychedelic science is vital for its evolution beyond biomedical research for widespread dissemination, offering new avenues for improved health outcomes and promotion of human flourishing.


Ultrafine Particles from Residential Biomass Combustion: A Review on Experimental Data and Toxicological Response.
Biomass burning is considered an important source of indoor and outdoor air pollutants worldwide. Due to competitive costs and climate change sustainability compared to fossil fuels, biomass combustion for residential heating is increasing and expected to become the major source of primary particulate matter emission over the next 5-15 years. The understanding of health effects and measures necessary to reduce biomass emissions of harmful compounds is mandatory to protect public health. The intent of this review is to report available data on ultrafine particles (UFPs, i.e., particles with diameter smaller than 100 nm) emitted by residential biomass combustion and their effects on human health (in vitro and in vivo studies). Indeed, as far as we know, papers focusing specifically on UFPs originating from residential biomass combustion and their impact on human health are still lacking.


Structure and function of the Fgd family of divergent FYVE domain proteins 1.
FYVE domains are highly conserved protein modules that typically bind phosphatidylinositol 3-phosphate (PI3P) on the surface of early endosomes. Along with pleckstrin homology (PH) and phox homology (PX) domains, FYVE domains are the principal readers of the phosphoinositide (PI) code that mediate specific recognition of eukaryotic organelles. Of all the human FYVE domain containing proteins, those within the faciogenital dysplasia (Fgd) subfamily are particularly divergent and couple with GTPases to exert unique cellular functions. The subcellular distributions and functions of these evolutionarily conserved signal transducers, which also include Dbl homology (DH) and two PH domains, are discussed here to better understand the biological range of processes that such multidomain proteins engage in. Determinants of their various functions include specific multidomain architectures, posttranslational modifications including PIP stops that have been discovered in sorting nexins, PI recognition motifs, and phospholipid-binding surfaces as defined by the Membrane Optimal Docking Area (MODA) program. How these orchestrate Fgd function remains unclear but has implications for developmental diseases including Aarskog-Scott syndrome, which is also known as faciogenital dysplasia, and forms of cancer that are associated with mutations and amplifications of Fgd genes.


Conceptualizations of fairness and legitimacy in the context of Ethiopian health priority setting: Reflections on the applicability of accountability for reasonableness.
A critical element in building stronger health systems involves strengthening good governance to build capacity for transparent and fair health planning and priority setting. Over the past 20 years, the ethical framework Accountability for Reasonableness (A4R) has been a prominent conceptual guide in strengthening fair and legitimate processes of health decision-making. While many of the principles embedded within the framework are congruent with Western conceptualizations of what constitutes procedural fairness, there is a paucity in the literature that captures the degree of resonance between these principles and the views of decision makers from non-Western settings; particularly in Africa, where many countries have only recently, within the last 20-30 years, become more democratic. This paper contributes to the ethics literature by examining how Ethiopian decision makers conceptualize fair and legitimate health decision-making, and reflects on the degree of conceptual resonance between these views and the principles embedded in A4R. A qualitative case study approach from three districts in Ethiopia was undertaken. Fifty-eight decision makers from district, regional, zonal, and national levels were interviewed to describe their conceptualization of fairness and legitimacy in the district health planning process. Findings revealed that Ethiopians have a broad conception of fairness and legitimacy that while congruent with procedural justice, also aligned with principles of distributive and organizational justice. Researchers and practitioners seeking to strengthen procedural fairness in health priority setting must therefore recognize the significance of other philosophical dimensions influencing how fairness and legitimacy of health decision-making are constructed within the Ethiopian setting.


In silico model of the early effects of radiation therapy on the microcirculation and the surrounding tissues.
Radiation-induced organ dysfunction are frequently described by Normal Tissue Complication Probability models. The approximations of this radiobiological approach do not allow to consider the important role played by the microvasculature not only in the dose-response of the blood vessels but also of the organs where it is located. To this purpose, we presented a computational model that describes the fluid dynamics of microcirculation when the parameters of the network and the surrounding tissues are affected by radio-induced changes. The effects of the ionizing radiation on the capillary bed are mediated by the inflammatory response. We derived from a literature search the possible morphological and functional variations of the network due to the process of the acute inflammation. Specifically, we considered vasodilation, increased membrane permeability with consequent fluid extravasation and increased wall elasticity. These perturbations to the system were included in a computational model, already able to describe the physics of the microcirculation and its exchanges with the surrounding tissues. Two computational descriptions were considered. In the first one, we changed a set of 4 parameters associated with the increased fluid exchange from the health scenario at the baseline to a seriously compromised scenario with the edema formation. The second study investigated the effect of a perturbation to the vessel wall elasticity. These simulations represent a first step towards the challenging objective of understanding and describing in a mechanistic way the effects of radiation on the vascular microenvironment.


Obituaries online: new connections with the living--and the dead.
This study examines online obituary pages at nine major U.S. daily newspapers seeking to understand how these sites use new technologies, and how they publicly portray people's lives and deaths. These mainstream dailies provide a forum, and potentially large audiences, for mourners who send messages to the dead, express emotion, and tell stories. They also facilitate connections between readers and build new kindsof virtual communities. This represents a departure from traditional obituary content. Indeed, the "cyber obit" now allows the bereaved to help frame the death stories and build the memorials, liberated from the linear, non-interactive formats of the past. This study builds on work of bereavement scholars as well as literature in journalism and mass communication.


Co-localisation of advanced glycation end products and D-β-aspartic acid-containing proteins in gelatinous drop-like corneal dystrophy.
Gelatinous drop-like corneal dystrophy (GDLD), also known as familial subepithelial corneal amyloidosis, is an autosomal recessive disorder that causes progressive corneal opacity due to accumulation of amyloid fibrils in the corneal stroma. Genetic analyses have revealed that a mutation in membrane component chromosome 1 surface marker 1 gene is responsible for GDLD. However, the mechanism of amyloid formation in the corneal stroma remains unclear. The present study attempted to reveal the role of advanced glycation end products (AGE) and d-amino acids in amyloid formation in GDLD. Informed consent was obtained from five patients with GDLD, three patients with bullous keratopathy and three patients with interstitial keratitis and all the specimens were analysed. Localisation of amyloid fibrils was analysed using Congo-red and thioflavin T staining. In addition, the localisation of AGE (N(ε)-carboxy(methyl)-L-lysine, pyrraline and pentosidine) and D-β-aspartic acid-containing proteins, a major form of d-amino acid-containing proteins, was analysed immunohistochemically. In all GDLD specimens, strong immunoreactivity to AGE and D-β-aspartic acid-containing proteins was detected in the subepithelial amyloid-rich region. In contrast, amyloid fibrils, AGE, or D-amino acid-containing proteins were slightly detected in the corneal stroma of patients with bullous keratopathy and interstitial keratitis. Abnormally accumulated proteins rich in AGE and D-β-aspartic acid co-localise in the amyloid lesions in GDLD. These results indicate that non-enzymatic post-translational modifications of proteins, including AGE formation and isomerisation of aspartyl residues, will be the cause as well as the result of amyloid fibril formations in GDLD.


Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.
The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.


Primary and secondary structures of Escherichia coli MRE 600 23S ribosomal RNA. Comparison with models of secondary structure for maize chloroplast 23S rRNA and for large portions of mouse and human 16S mitochondrial rRNAs.
We determined 90% of the primary structure of E.coli MRE 600 23S rRNA by applying the sequencing gel technique to products of T1, S1, A and Naja oxiana nuclease digestion. Eight cistron heterogeneities were detected, as well as 16 differences with the published sequence of a 23S rRNA gene of an E.coli K12 strain. The positions of 13 post-transcriptionally modified nucleotides and of single-stranded, double-stranded and subunit surface regions of E.coli 23S rRNA were identified. Using these experimental results and by comparing the sequences of E.coli 23S rRNA, maize chloro. 23S rRNA and mouse and human mit 16S rRNAs, we built models of secondary structure for the two 23S rRNAs and for large portions of the two mit rRNAs. The structures proposed for maize chloroplast and E.coli 23S rRNAs are very similar, consisting of 7 domains closed by long-range base-pairings. In the mitochondrial 16S rRNAs, 3 of these domains are strongly reduced in size and have a very different primary structure compared to those of the 23S rRNAs. These domains were previously found to constitute a compact area in the E.coli 50S subunits. The conserved domains do not belong to this area and contain almost all the modified nucleotides. The most highly conserved domain, 2042-2625, is probably part of the ribosomal A site. Finally, our study strongly suggests that in cytoplasmic ribosomes the 3'-end of 5.8S rRNA is basepaired with the 5'-end of 26S rRNA. This confirms the idea that 5.8S RNA is the counterpart of the 5'-terminal region of prokaryotic 23S rRNA.


How does the persistence of depression influence the continuity and type of health insurance and coverage limits on mental health therapy?
To determine the structural effect of the persistence of depression on continuity and type of health insurance and coverage limits on mental health therapy. Data came from the Partners in Care study (PIC), a randomized controlled trial examining the effect of quality improvement (QI) programs involving medication or psychotherapy on the outcomes of initially depressed patients in seven managed care settings. The sample included approximately 945 adult patients under the age of 63 years who were primarily depressed and insured at baseline. Single-equation multivariate probit regressions were estimated to determine the association of depression burden days aggregated over the 6 to 24-month period post-baseline with the following dichotomous outcomes: continuous health insurance over 6 to 24 months; continuous private health insurance over 6 to 24 months; any public health insurance over 6 to 24 months; and reporting no insurance limits on mental health therapy coverage at 24 months. Other control variables included baseline insurance status, age, sex, race, marital status, education, income, assets, fixed site effects, and (in sensitivity analyses) number of medical comorbidities, alcohol use and drug use. To address the possibility of endogeneity bias in the relationship between depression and insurance, consistent estimates were derived from instrumental variables (IV) probit regressions and the endogeneity of depression burden days was tested. Potential instruments included the random assignment to intervention and control groups in the PIC study, type of depression at baseline, and baseline Mental Component Summary (MCS) score from the Short Form-12 (SF-12). In sensitivity analyses, data pooled (rather than aggregated) across waves were used to estimate probit and IV probit regressions, using Generalized Estimating Equations methods to adjust for within-person correlation of the error terms. Evidence was found that depression burden days were exogenous to all of the health insurance outcomes except for coverage limits on mental health therapy. Based on the appropriate estimates (single-equation if exogenous, IV if endogenous), depression burden days appeared to increase the probability of having any public health insurance coverage and decrease the probability of having no coverage limits on mental health therapy. However, these effects were small in magnitude. Reverse causality may be more of a concern when examining the influence of depression on mental health care coverage than on health insurance in general. Consistent with the government's historical role in financing mental health services, patients whose depression persisted to a greater extent were slightly more likely to have some public health insurance during an 18-month follow-up period. Furthermore, they were slightly more likely to have limits on mental health therapy coverage, suggesting that insurers may be more likely to control access at the level of the benefits structure than at the level of insurance coverage per se. Future analyses should examine the mediating factors in the relationship between depression and limits on mental health therapy coverage, e.g., diminished employment opportunities with large companies that offer more generous benefits.


Predictors of Posttraumatic Stress Symptoms Among Adolescent and Young Adult Survivors of Childhood Cancer: Importance of Monitoring Survivors' Experiences of Family Functioning.
The purpose of this study was to identify factors associated with posttraumatic stress symptoms (PTSS) among Japanese long-term childhood cancer survivors (CCSs). Subjects comprised 185 adolescent and young adult (AYA) CCSs who completed anonymous self-report questionnaires. Attending physicians also completed an anonymous disease/treatment data sheet. Mean age of survivors was approximately 8 years at diagnosis and 23 years at participation. Multiple regression analysis showed that family functioning, satisfaction with social support, being female, and interactions between family functioning and gender and age at the time of diagnosis were associated with PTSS among survivors. This study revealed family functioning as the most predictive factor of PTSS among AYA CCSs in Japan. Even when the survivor may have unchangeable risk factors, family functioning can potentially moderate the effects on PTSS. Thus, it is crucial for health professionals to carefully monitor and attend to survivors' experiences of family functioning to mitigate PTSS.


Porous Coordination Polymers Based on {Mn6} Single-Molecule Magnets.
In this paper, three isostructural porous coordination polymers, namely, [Mn6(μ3-O)2(sao)6(DMF)4(L(1))2/3]·4DMF·2H2O·2CH3OH (1), [Mn6(μ3-O)2(sao)6(DMF)4(L(2))2/3]·4DMF·2H2O·2CH3OH (2), and [Mn6(μ3-O)2(sao)6(DMF)4(L(3))2/3]·4DMF·4H2O·2CH3OH (3) (DMF = dimethylformamide, H2sao = salicylaldoxime, H3L(1) = benzene-1,3,5-trisbenzoic acid, H3L(2) = 4,4',4″-s-triazine-2,4,6-triyltribenzoic acid, and H3L(3) = 2,4,6-tris(4-carboxyphenoxy)-1,3,5-s-triazine), based on the oximato-bridged {Mn6} single-molecule magnet (SMM) and tricarboxylic acid ligands, were designed and synthesized. X-ray structural analysis shows that they possess a two-dimensional layered structure, where the {Mn6} moieties are linked by the corresponding (L(x))(3-) carboxylate ligands (x = 1, 2, 3) forming a huge honeycomb layer. These compounds not only show the SMM behavior as confirmed by alternative current susceptibility measurements but also show selectivity for CO2 over N2 at 273 K. On the basis of the magnetic fitting to the magnetic susceptibilities and the field dependence of magnetization for complexes 1-3, the spin ground states are S = 4. Compared with isolated {Mn6} SMMs with S = 4, the out-of-phase susceptibilities of 1-3 show obvious peaks only under the external direct-current field of 2 kOe. However, no peaks in χm″ are observed in the partially desolvated sample of compound 1.


Genotyping single-nucleotide polymorphisms by minisequencing using tag arrays.
The need for large-scale and high-throughput methods for SNP genotyping has rapidly increased during the last decade. Our system, presented here, combines the highly specific genotyping principle of minisequencing with the advantages of a microarray format that allows highly multiplexed and parallel analysis. Cyclic minisequencing reactions with fluorescently labeled dideoxynucleotides (ddNTPs) are performed in solution using multiplex PCR product as template and detection primers, designed to anneal immediately adjacent and upstream of the SNP site. The detection primers carry unique 5' tag sequences and oligonucleotides complementary to the tag sequence, cTags, are immobilized on a microarray. After extension, the tagged detection primers are allowed to hybridize to the cTags; then the fluorescent signals from the array are measured, and the genotypes are deduced according to the label incorporated. The "array of arrays" format of the system, accomplished by a silicon rubber grid giving separate reaction chambers, allows either 80 or 14 samples to be analyzed for up to 200 or 600 SNPs, respectively, on a single microscope slide.


P73 C-terminus is dispensable for multiciliogenesis.
The p53 family transcriptional factor p73 plays a pivotal role in development. Ablation of p73 results in severe neurodevelopmental defects, chronic infections, inflammation and infertility. In addition to this, Trp73-\- mice display severe alteration in the ciliated epithelial lining and the full-length N-terminal isoform TAp73 has been implicated in the control of multiciliogenesis transcriptional program. With our recently generated Trp73Δ13/Δ13 mouse model, we interrogate the physiological role of p73 C-terminal isoforms in vivo. Trp73Δ13/Δ13 mice lack exon 13 in Trp73 gene, producing an ectopic switch from the C-terminal isoforms p73α to p73β. Trp73Δ13/Δ13 mice show a pattern of expression of TAp73 comparable to the wild-type littermates, indicating that the α to β switch does not significantly alter the expression of the gene in this cell type. Moreover, Trp73Δ13/Δ13 do not display any significant alteration in the airway ciliated epithelium, suggesting that in this context p73β can fully substitute the function of the longer isoform p73α. Similarly, Trp73Δ13/Δ13 ciliated epithelium of the brain ependyma also does appear defective. In this district however expression of TAp73 is not detectable, indicating that expression of the gene might be compensated by alternative mechanisms. Overall our work indicates that C-terminus p73 is dispensable for the multiciliogenesis program and suggests a possible tissue-specific effect of p73 alternative splicing.


Fractal Weyl laws for quantum decay in dynamical systems with a mixed phase space.
Weyl's law approximates the number of states in a quantum system by partitioning the energetically accessible phase-space volume into Planck cells. Here, we show that resonances in open quantum systems can follow a modified fractal Weyl law, even when their classical dynamics is not globally chaotic but also contains domains of regular motion. Using an appropriate phase-space representation for open quantum systems, we connect this behavior to emerging quantum-to-classical correspondence.


Tier-based treatment for opioid use disorder in the primary care setting.
Background: Two primary care clinics implemented an opioid use disorder (OUD) treatment program that integrates behavioral health counseling with buprenorphine treatment and uses tiers. This project aimed to understand how patients moved through tiers in this program. Method: We purposively sampled 20 patients with at least 10 OUD-related treatment visits; we documented tier changes at all visits between September 1, 2016 and December 31, 2018 using a standard data collection instrument. These data were used to construct run-charts. Results: About 45% of sampled patients had at least one relapse noted and 60% of patients dropped in tier during the study. Reductions in tier often happened when the patient was navigating difficult psychosocial situations in their life, whereas increases in tier often accompanied positive life events. We also found variation in use of the tiers. Discussion: OUD treatment from two clinics by tier illustrates that recovery is an individualized process based on patient need that can fluctuate due to psychosocial triggers and significant life events. Having tiers can guide treatment and provide both clinicians and patients with information about what to expect during treatment while still allowing the flexibility to meet patients where they are. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Psychological adjustment in adolescents conceived by assisted reproduction techniques: a systematic review.
Adolescence is a transitional time for identity formation and relationships with parents. While people born through assisted reproduction techniques (ART) appear to be well adjusted in childhood, it is unclear whether these findings carry into adolescence, and whether diverse ART have different psychological outcomes. This review summarizes what is known about the psychological adjustment and family relationships of the growing number of children born through ART who are reaching adolescence. The Pubmed, Web of Knowledge, PsycINFO and Scopus databases were searched systematically for peer reviewed papers focusing on adolescent psychological adjustment and parent-adolescent relationships in families created by ART. Key search inclusion criteria included all papers published in English relating to adolescents aged between 11 and 18 years. Seventeen publications with varied methodologies were identified by this review. Only papers relating to in vitro fertilization (IVF), egg donation and donor insemination were identified. Results were categorized according to ART that used the parents' own gametes (IVF) and those that involved reproductive donation (egg donation, and donor insemination). Compared with naturally conceived adolescents and standardized normative samples, adolescents born through all ARTs seemed to be equally well adjusted, and to have positive parent-adolescent relationships. Some differences were however identified based on the type of ART used. In particular, the sex of the parent and child, along with age and process of disclosure of the adolescent's conception were identified as key mediators of parent-adolescent relationships in families created by donor insemination. The studies in this review indicate that children born through ART have positive parent-adolescent relationships and are well adjusted, with some slight differences based on different ART. The generalizability of findings may be limited by the general low level of disclosure to adolescents in some of the publications, the small sample sizes of studies in the field, along with the large age range that encompasses adolescence. Findings should also be interpreted in light of the fact that many publications focus on singleton births. Future studies should also focus on egg donation, surrogacy and embryo donation, as well as the disclosure processes, and adolescents born into non-traditional families (same-sex or single parents) or those born using different types of donor (anonymous, identity-release or known).


Polarizable Embedding Potentials through Molecular Fractionation with Conjugate Caps Including Hydrogen Bonds.
Polarizable embedding (PE) refers to classical embedding approaches, such as those used in quantum mechanics/molecular mechanics (QM/MM), that allow mutual polarization between the quantum and classical regions. The quality of the embedding potential is critical to provide accurate results, e.g., for spectroscopic properties and dynamical processes. High-quality embedding-potential parameters can be obtained by dividing the classical region into smaller fragments and deriving the parameters from ab initio calculations on the fragments. For solvents and other systems composed of small molecules, the fragments can be individual molecules, while a more complicated fragmentation procedure is needed for larger molecules, such as proteins and nucleic acids. One such fragmentation strategy is the molecular fractionation with conjugate caps (MFCC) approach. As is widely known, hydrogen bonds play a key role in many biomolecular systems, e.g., in proteins, where they are responsible for the secondary structure. In this work, we assess the effects of including hydrogen-bond fragmentation in the MFCC procedure [MFCC(HB)] for deriving the embedding-potential parameters. The MFCC(HB) extension is evaluated on several molecular systems, ranging from small model systems to proteins, directly in terms of molecular electrostatic potentials and embedding potentials and indirectly in terms of selected properties of chromophores embedded in water and complex protein environments.


Simvastatin reverses target organ damage and oxidative stress in Angiotensin II hypertension: comparison with apocynin, tempol, and hydralazine.
The ability of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor simvastatin to reverse established cardiovascular and renal alterations and oxidative stress was assessed in angiotensin II (AngII) hypertension. Sprague-Dawley rats infused with AngII (200 ng/kg per minute for 17 days) were concomitantly treated or not for the last 7 days with simvastatin, apocynin, tempol, and hydralazine (60, 60, 30, and 15 mg/kg per day, respectively). Only hydralazine lowered AngII hypertension. Simvastatin and apocynin lowered cardiac hypertrophy by 52% and 54% and reversed the marked rise in albuminuria by 25% and 70%. Neither tempol nor hydralazine affected cardiac mass or albuminuria. None of the treatments modified the AngII-induced increase in carotid media thickness. The rise in cardiac superoxide anion production (lucigenin-enhanced chemiluminescence method) induced by AngII was reversed by all treatments. Enhanced plasma concentration of advanced oxidation protein products (spectrophotometry using chloramine T) was unaffected by simvastatin and tempol, but it was reversed by apocynin and hydralazine. Our results indicate that simvastatin reverse established cardiac and renal alterations in AngII hypertension independently of arterial pressure. It is suggested that oxidative stress participates in the maintenance of target organ damage and that antioxidant properties are involved in the beneficial influence of the statin.


Beyond the guidelines: new and novel agents for the prevention of atrial fibrillation after cardiothoracic surgery.
Postoperative atrial fibrillation (POAF), a common complication of cardiac surgery, can increase the morbidity and mortality, as well as the costs of the surgery being preformed. Guidelines recommend the use of β-blockers, amiodarone, or sotalol to decrease the risk of experiencing POAF. However, none of these agents fully protect the patient from POAF, thus newer agents are needed to be used in combination with them. Many different agents have been studied to fit this role and may be grouped into 2 categories: agents with antiarrhythmic activity such as magnesium and polyunsaturated fatty acids and agents with anti-inflammatory activity such as statins and free radical scavengers. Most of these novel agents have been studied in a wide variety of trials; however, some clearly have more effect than others. Although none of these newer agents have the data required to make blanket recommendations for use at this point, given the safety profile and low costs of some, many continue to be evaluated in randomized-controlled trials.


Pharmacokinetics and immunogenicity of a recombinant human butyrylcholinesterase bioscavenger in macaques following intravenous and pulmonary delivery.
Recombinant (r) and native butyrylcholinesterse (BChE) are potent bioscavengers of organophosphates (OPs) such as nerve agents and pesticides and are undergoing development as antidotal treatments for OP-induced toxicity. Because of the lethal properties of such agents, regulatory approval will require extensive testing under the Animal Rule. However, human (Hu) glycoprotein biologicals, such as BChE, present a challenge for assessing immunogenicity and efficacy in heterologous animal models since any immune responses to the small species differences in amino acids or glycans between the host and biologic may alter pharmacodynamics and preclude accurate efficacy testing; possibly underestimating their potential protective value in humans. To establish accurate pharmacokinetic and efficacy data, an homologous animal model has been developed in which native and PEGylated forms of CHO-derived rMaBChE were multiply injected into homologous macaques with no induction of antibody. These now serve as controls for assessing the pharmacokinetics and immunogenicity in macaques of multiple administrations of PEGylated and unmodified human rBChE (rHuBChE) by both intravenous (IV) and pulmonary routes. The results indicate that, except for maximal concentration (Cmax), the pharmacokinetic parameters following IV injection with heterologous PEG-rHuBChE were greatly reduced even after the first injection compared with homologous PEG-rMaBChE. Anti-HuBChE antibody responses were induced in all monkeys after the second and third administrations regardless of the route of delivery; impacting rates of clearance and usually resulting in reduced endogenous MaBChE activity. These data highlight the difficulties inherent in assessing pharmacokinetics and immunogenicity in animal models, but bode well for the efficacy and safety of rHuBChE pretreatments in homologous humans.


Large molecular third-order optical nonlinearities in polarized carotenoids.
Garito and co-workers have suggested a mechanism to dramatically increase the second hyperpolarizability, gamma, in linear pi-electron-conjugated molecules. Polarization is introduced that leads to a difference between the dipole moments of the molecule's ground state and excited state. Here a series of carotenoids was examined that had increasing intramolecular charge transfer (ICT) from the polyenic chain to the acceptor moiety in the ground state, and gamma was measured for these compounds as a function of wavelength by third-harmonic generation. The compound with the greatest ICT exhibited a 35-fold enhancement of gammamax (the gamma measured at the peak of the three-photon resonance) relative to the symmetric molecule beta-carotene, which itself has one of the largest third-order nonlinearities known. Stark spectroscopic measurements revealed the existence of a large difference dipole moment, Delta mu, between the ground and excited state. Quantum-chemical calculations underline the importance of interactions involving states with large Delta mu.


Analysis of methods for growth detection in the search for extraterrestrial life.
In the search for life on other planets, experiments designed to detect the growth of microorganisms may prove to be definitive when coupled with chemical characterization and metabolic experiments. If organisms are not abundant, growth provides the only means for obtaining a large mass of biological material suitable for chemical compositional analyses and metabolic assays. Several methods of monitoring growth are described. Of these, optical monitoring in a unique system free of soil particles is advanced as the most appropriate. Theoretical problems related to the formulation of culture media are discussed, and several possible solutions are proposed. The sampling system, the type of monitoring, the size and placement of inoculum, and the medium volume and composition are contingent upon one another and must be integrated without sacrifice to the biological demands.


[Epidemiological survey of prevalence of HIV infection, syphilis and hepatitis C in female sex workers and other 6 risk populations in Tibet Autonomous Region].
Objective: To understand the prevalence of HIV infection, syphilis and hepatitis C and related behavioral factors in female sex workers (FSWs) and other 6 risk populations in Tibet Autonomous Region. Methods: A cross-sectional survey was conducted among 2 000 FSWs, 200 men who have sex with men (MSM), 200 drug users, 1 200 male migrants, 5 600 young students, as well as hospital patients and pregnant women in Lhasa, Qamdo, Nyingchi, Xigaze Shannan, Ali and Nagqum from June to December 2015. Face to face interviews were conducted to collect their demographic and behavioral information, and blood samples were collected for the tests of HIV, syphilis and hepatitis C virus (HCV) antibodies. The enumeration data were described by using rate and constituent. Results: A total of 20 597 participants were involved in cross-sectional survey. The positive rates of HIV and syphilis antibodies were 5.81%(124/2 133) and 0.05% (1/2 133) respectively among FSWs. The positive rates of HIV and syphilis antibodies were the same (9.80%,10/102) among MSM. There were no HIV infection detected in among drug users, male migrants and young students, but the positive rates of syphilis antibody were 4.00%(4/100), 0.33%(4/1 297) and 0.08%(4/5 095) respectively. The positive rates of HIV and syphilis antibodies were 0.04%(2/5 565) and 1.64%(91/5 565) among hospital patients. The positive rates of HIV and syphilis antibodies were 0.11%(7/6 305) and 1.19%(75/6 305)among pregnant women. The positive rates of HCV antibody were 1.00% (1/100) among drug users and less than 0.50% in other risk populations. The overall consistent condom use rate was low. Conclusions: In Tibet, HIV infection mainly occurred in the MSM, syphilis mainly occurred in FSWs and MSM, HCV infection mainly occurred in drug users. The AIDS related knowledge awareness rate was low in these risk populations, and less of them received intervention service.


[Methodology for the elaboration of prognosis studies].
Prognostic studies are investigations to estimate the risk or probability of future outcomes in people with established disease. Ideally based on cohort studies where it is established: the time of onset or analysis of the evolution of a disease, the follow-up period for the outcome of interest, the type of outcome and the prognostic factors or markers to investigate. Ultimately, the decision on how to run and analyze forecast studies will depend on their purpose: exploratory, explanatory, or predictive.


Outcomes of stereotactic radiosurgery in young adults with vestibular schwannomas.
Vestibular schwannomas (VSs) are comparatively rare in younger patients, and stereotactic radiosurgery (SRS) outcome data are limited. We aimed to evaluate long-term SRS outcomes concerning sporadic VSs in patients aged ≤ 40 years. Of 383 patients with VS who had undergone SRS at our institution between 1990 and 2017, we retrospectively compared younger and older patients' tumor control and radiation-induced complication rates using case-control propensity score (PS) matching. The mean follow-up was 83 and 92 months in older and younger patients, respectively. Compared with older patients, younger patients were more likely to have a history of resection (20% vs. 39%, p = 0.006) and be treated with higher marginal doses (median, 12 Gy vs. 14 Gy; p = 0.014). Cumulative 5- and 10-year tumor control rates were higher in older patients (97.7% and 93.9%, respectively) than in younger patients (90.2% and 85.4%, respectively, p = 0.024). After PS matching, younger patients' cumulative tumor control rates (93.6%, 85.4%, and 85.4% at 5, 10, and 15 years, respectively) were similar to those of older patients (p = 0.411). No significant between-cohort differences in hearing preservation rates or other cranial nerve complications were observed. Two younger patients had malignant tumors several years post-SRS, with one patient having confirmed histological transformation. SRS is equally effective for younger and older patients. Complications other than hearing deterioration are uncommon. However, malignant transformation is possible, and long-term post-SRS surveillance MRI is important. These data are useful for decision-making involving young adults with VSs.


Large Cell Carcinoma with Adenocarcinoma in Lung.
Large cell neuroendocrine carcinoma (LCNC) is a rare and aggressive cancer accounting for 3% of all lung cancers. A small percentage of LCNC called combined LCNC, can be seen in combinations with other lung tumor types. Multimodal therapy is proposed for this type of tumor but there is no any significant therapy since it is very rare tumor. This patient was a 66-year male and a heavy smoker with no symptoms of lung disease. Computed tomography core biopsy showed suspected adenocarcinoma. Right lower lobectomy was performed with mediastinal lymph node dissection via mini thoracotomy. The tumor was diagnosed as combined LCNC with adenocarcinoma. The patient was discharged on the seventh postoperative day and sent to the oncology clinic for chemotherapy. There has been no recurrence for eight months after surgery.


Controlled self-assembly of amphiphilic oligopeptides into shape-specific nanoarchitectures.
Here, we report a novel, programmable, molecular self-assembling system to fabricate shape-specific, three-dimensional nanoarchitectures. Three types of simple 16-mer peptides consisting of hydrophobic Leu and hydrophilic Lys, LKL16, KLK16, and LK16, were prepared as building blocks for nanofabrications. A detailed analysis of the conformation and self-assembling mechanism was performed by using circular dichroism (CD), FTIR spectroscopy, and atomic force microscopy (AFM). A wide variety of self-assembled nanoarchitectures, such as beta-sheet-plates, beta-sheet-fibers, alpha-helix-particles, and alpha-helix-plates, could be fabricated by tuning the peptide sequence, reaction time, and solution pH. The ability to control the self-assembled nanostructures should provide a simple and/or essential insight into the mechanism of peptide aggregation, including amyloid formation, and it should be useful for the design of novel bio-related nanomaterials.


Thyroid hormone deficiency during zebrafish development impairs central nervous system myelination.
Thyroid hormones are messengers that bind to specific nuclear receptors and regulate a wide range of physiological processes in the early stages of vertebrate embryonic development, including neurodevelopment and myelogenesis. We here tested the effects of reduced T3 availability upon the myelination process by treating zebrafish embryos with low concentrations of iopanoic acid (IOP) to block T4 to T3 conversion. Black Gold II staining showed that T3 deficiency reduced the myelin density in the forebrain, midbrain, hindbrain and the spinal cord at 3 and 7 dpf. These observations were confirmed in 3 dpf mbp:egfp transgenic zebrafish, showing that the administration of IOP reduced the fluorescent signal in the brain. T3 rescue treatment restored brain myelination and reversed the changes in myelin-related gene expression induced by IOP exposure. NG2 immunostaining revealed that T3 deficiency reduced the amount of oligodendrocyte precursor cells in 3 dpf IOP-treated larvae. Altogether, the present results show that inhibition of T4 to T3 conversion results in hypomyelination, suggesting that THs are part of the key signaling molecules that control the timing of oligodendrocyte differentiation and myelin synthesis from very early stages of brain development.


Caffeinated Alcoholic Beverages - An Emerging Trend in Alcohol Abuse.
Alcohol use disorders are pervasive in society and their impact affects quality of life, morbidity and mortality, as well as individual productivity. Alcohol has detrimental effects on an individual's physiology and nervous system, and is associated with disorders of many organ and endocrine systems impacting an individual's health, behavior, and ability to interact with others. Youth are particularly affected. Unfortunately, adolescent usage also increases the probability for a progression to dependence. Several areas of research indicate that the deleterious effects of alcohol abuse may be exacerbated by mixing caffeine with alcohol. Some behavioral evidence suggests that caffeine increases alcohol drinking and binge drinking episodes, which in turn can foster the development of alcohol dependence. As a relatively new public health concern, the epidemiological focus has been to establish a need for investigating the effects of caffeinated alcohol. While the trend of co-consuming these substances is growing, knowledge of the central mechanisms associated with caffeinated ethanol has been lacking. Research suggests that caffeine and ethanol can have additive or synergistic pharmacological actions and neuroadaptations, with the adenosine and dopamine systems in particular implicated. However, the limited literature on the central effects of caffeinated ethanol provides an impetus to increase our knowledge of the neuroadaptive effects of this combination and their impact on cognition and behavior. Research from our laboratories indicates that an established rodent animal model of alcoholism can be extended to investigate the acute and chronic effects of caffeinated ethanol.