Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation.
Point mutations in the 5' UTR of ankyrin repeat domain 26 (ANKRD26) are associated with familial thrombocytopenia 2 (THC2) and a predisposition to leukemia. Here, we identified underlying mechanisms of ANKRD26-associated thrombocytopenia. Using megakaryocytes (MK) isolated from THC2 patients and healthy subjects, we demonstrated that THC2-associated mutations in the 5' UTR of ANKRD26 resulted in loss of runt-related transcription factor 1 (RUNX1) and friend leukemia integration 1 transcription factor (FLI1) binding. RUNX1 and FLI1 binding at the 5' UTR from healthy subjects led to ANKRD26 silencing during the late stages of megakaryopoiesis and blood platelet development. We showed that persistent ANKRD26 expression in isolated MKs increased signaling via the thrombopoietin/myeloproliferative leukemia virus oncogene (MPL) pathway and impaired proplatelet formation by MKs. Importantly, we demonstrated that ERK inhibition completely rescued the in vitro proplatelet formation defect. Our data identify a mechanism for development of the familial thrombocytopenia THC2 that is related to abnormal MAPK signaling.


Graphdiyne and Nitrogen-Doped Graphdiyne Nanotubes as Highly Efficient Electrocatalysts for Oxygen Reduction Reaction.
Electrocatalysts with high efficiency and low cost are always urgently needed for oxygen reduction reaction (ORR). As a new carbon allotrope, graphdiyne (GDY) has received much attention due to its unique chemical structure containing sp- and sp2-hybridized carbons, and intrinsic electrochemical activity ascribed to its inherent conductivity. Herein, we prepared two graphdiyne materials named GDY nanotube and nitrogen-doped GDY (NGDY) nanotube via cross-coupling reactions on the surface of Cu nanowires. As metal-free catalysts, their electrocatalytic activities for ORR were demonstrated. The results showed that the NGDY nanotube presents more excellent electrochemical performance than that of the GDY nanotube, including more positive potential and faster kinetics and charge transfer process. The improvement can be ascribed to the greater number of structural electrocatalytic active sites from nitrogen atoms as well as the hollow nanotube morphology, which is beneficial to the adsorption of oxygen and acceleration of the catalytic reaction. This work helps develop high-quality graphdiyne-based electrocatalysts with well-defined chemical structures and morphologies for various electrochemical reactions.


Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice.
Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia. A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined. Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre-clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia. At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind-like 1 protein from myonuclear foci and improved mRNA alternative splicing. Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild-type (SED-WT) mice, as well as sedentary human skeletal actin-long repeat animals, a murine model of DM1 myopathy (SED-DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX-DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70-85% decrease in the duration of myotonic discharges in muscles from EX-DM1 compared to SED-DM1 animals. The exercise-induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle-specific chloride channel (CLC-1) transcripts. CLC-1 protein content and sarcolemmal expression were lower in SED-DM1 versus SED-WT animals, but they were similar between SED-WT and EX-DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG)n foci-positive myonuclei and sequestered Muscleblind-like 1 (MBNL1). Our data indicate that chronic exercise-induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss-of-function, and alternative mRNA splicing.


Effects of proteins and polynucleotides on the activity of various hydrolases.
The effect of various macromolecules on the activity of several hydrolases was studied. Dilution of partially purified acid beta-galactosidase from ileal mucosa of suckling rats resulted in a decrease of specific activity. The relationship between specific activity and dilution of the enzyme suggests a dissociation of the enzyme. This could be prevented by addition of several proteins tested. However, addition of DNA to the assay mixture for acid beta-galactosidase caused an inhibition. This inhibition could be prevented by addition of proteins. Other polynucleotides and tRNA also exert an inhibitory effect that is prevented by albumin, but nucleotides have no effect. This inhibition occurs maximally at a low pH (3.0-4.0); no inhibition is observed at pH5.5. A similar pH-dependent inhibition by DNA was also found with various other acid hydrolases.


Subpapillary continuous sling suturing method for soft tissue grafting with the tunneling technique.
This paper describes a new suturing method, the subpapillary continuous sling suture, for use with soft tissue grafts in tunnel procedures to treat gingival recession. This method combines the graft suture and the sutures used to advance the pouch margins over the graft into a single continuous sling suture. It is indicated particularly for sites with shallow recessions and those treated for augmentation rather than root coverage because of a lack of graft access for standard suture placement. The single-suture method may also be used for sites with moderate to severe recession. The advantages of this method include elimination of the need to place additional sutures for coronal advancement of the pouch, resulting in reduced suturing time and reduced opportunity to inadvertently cut the continuous suture with the needle when suturing the pouch.


H-ras-1 point mutation in malignant peripheral nerve sheath tumors: polymerase chain reaction restriction fragment length polymorphism analysis and direct sequencing from paraffin-embedded tissues.
It has been shown that the NF1 (neurofibromatosis type 1) gene encodes a tumor suppressor which inactivates ras proteins. Among malignant mesenchymal tumors, H-ras-1 mutations have been found in malignant fibrous histiocytoma, leiomyosarcoma and embryonal rhabdomyosarcoma. However, studies on H-ras-1 mutation of many cases of malignant peripheral nerve sheath tumors (MPNST) have not been documented. Therefore, we investigated H-ras-1 mutations of MPNST. In 45 cases of MPNSTs of our files, DNA was extracted from the formalin-fixed paraffin-embedded tissue, and the mutations of the H-ras-1 gene were detected by using PCR-RFLP (polymerase chain reaction- restriction fragment length polymorphisms) method and direct sequencing. We found two cases with H-ras-1 point mutation in MPNST for the first time. Both cases showed the same mutation in codon 13.1 [GGT(Gly) to AGT(Ser) transition]. Interestingly, both cases were associated with NF1. It is possibile that the mutation of the H-ras-1 gene occurred after the mutation of the NF1 gene in the MPNST.


Health-related quality of life and mortality in a general and elderly population of patients with type 2 diabetes (ZODIAC-18).
Diabetes negatively impacts the health-related quality of life (HRQOL) of patients with type 2 diabetes. An earlier analysis showed HRQOL to be associated with mortality, which suggests that measuring HRQOL could have clinical implications. We studied the association between HRQOL and total and cardiovascular mortality in patients with type 2 diabetes during long-term follow-up and specifically focused on old age and sex differences. HRQOL was measured in a prospectively followed cohort of 1,353 patients with type 2 diabetes using the RAND-36. Cox proportional hazard models were used to measure the independent effect of baseline HRQOL on mortality. During a mean follow-up of 9.6 years, 570 (42%) patients died, 280 of whom died of cardiovascular disease (49%). The Physical Component Score (PCS) and the Mental Component Score (MCS) were inversely associated with total mortality, with hazard ratios of 0.988 (95% CI 0.983-0.993) and 0.990 (95% CI 0.985-0.995), respectively. A 10-point-higher score on the PCS and MCS decreased the risk for total mortality by 11 and 10%, respectively. An inverse relationship with mortality was also seen for men, women, and for patients aged>75 years. Mental health was significantly related to mortality in men but not in women. Lower physical and mental HRQOL was associated with a higher total mortality and cardiovascular mortality in patients with type 2 diabetes; this is also the case when studying men and women and the elderly separately. The dimension mental health, related to depression and anxiety, was only associated with mortality in men, not in women.


Enhanced dissolution rate of felodipine using spherical agglomeration with Inutec SP1 by quasi emulsion solvent diffusion method.
Felodipine is a second generation calcium channel blocker widely used as antihypertensive and antianginal drug which belongs to BCS class II category. Hence, its low water solubility limits the pharmacological effect. The aim of this study was to improve the dissolution rate of felodipine using spherical agglomeration technique with acetone, water and dichloromethane as good solvent, poor solvent and bridging liquid, respectively. The quasi emulsion solvent diffusion technique was used as a method for spherical agglomeration. Inutec SP1 was used as an emulsion stabilizer and as hydrophilic polymer in agglomeration process. The FTIR and DSC results showed no change in the drug after crystallization process. PXRD studies showed sharp peaks in the diffractograms of spherical agglomerates with minor reduction in height of the peaks. The particle size of spherical agglomerates (FI-2) was about 134.33 ± 13.57 µm, n=3 and the dissolution efficiency of felodipine up to 120 min increased to about 4-fold in phosphate buffer containing 1.8% Tween 80 (pH 6.8). Spherical agglomerates showed enhanced solubility compared to untreated powder possibly due to the partial conversion to amorphous form.


Direct gene expression analysis.
The direct analysis of single biological molecules is getting increasingly important in basic as well as pharmaceutical research (e.g. for gene expression analysis). In particular single-molecule fluorescence detection provides exciting new opportunities to probe biochemical processes in unprecedented detail. Currently several academic and industrial research groups work on the development of single molecule detection based technologies in order to directly detect and analyze RNA and DNA molecules. As these developed methods are characterized as homogenous assays and obviate any amplification of the target or the signal, they provide clear advantages compared to methods like real-time PCR or DNA- arrays. In the following we describe a recently developed approach based on fluorescence correlation spectroscopy (FCS). This expression assay is based on gene-specific hybridization of two dye-labeled DNA probes to a selected target molecule (either DNA or RNA) in solution. The subsequent dual color cross-correlation analysis allows the quantification of the bio-molecule of interest in absolute numbers. Target concentrations of less than 10(-12) M can be easily monitored, covering the direct analysis of the expression levels of high, medium and low abundant genes.


Rapid automated three-dimensional tracing of neurons from confocal image stacks.
Algorithms are presented for fully automatic three-dimensional (3-D) tracing of neurons that are imaged by fluorescence confocal microscopy. Unlike previous voxel-based skeletonization methods, the present approach works by recursively following the neuronal topology, using a set of 4 x N2 directional kernels (e.g., N = 32), guided by a generalized 3-D cylinder model. This method extends our prior work on exploratory tracing of retinal vasculature to 3-D space. Since the centerlines are of primary interest, the 3-D extension can be accomplished by four rather than six sets of kernels. Additional modifications, such as dynamic adaptation of the correlation kernels, and adaptive step size estimation, were introduced for achieving robustness to photon noise, varying contrast, and apparent discontinuity and/or hollowness of structures. The end product is a labeling of all somas present, graph-theoretic representations of all dendritic/axonal structures, and image statistics such as soma volume and centroid, soma interconnectivity, the longest branch, and lengths of all graph branches originating from a soma. This method is able to work directly with unprocessed confocal images, without expensive deconvolution or other preprocessing. It is much faster that skeletonization, typically consuming less than a minute to trace a 70-MB image on a 500-MHz computer. These properties make it attractive for large-scale automated tissue studies that require rapid on-line image analysis, such as high-throughput neurobiology/angiogenesis assays, and initiatives such as the Human Brain Project.


Using dynamic biomaterials to study the temporal role of osteogenic growth peptide during osteogenesis.
The extracellular matrix is a highly dynamic environment, and the precise temporal presentation of biochemical signals is critical for regulating cell behavior during development, healing, and disease progression. To mimic this behavior, we developed a modular DNA-based hydrogel platform to enable independent and reversible control over the immobilization of multiple biomolecules during in vitro cell culture. We combined reversible DNA handles with a norbornene-modified hyaluronic acid hydrogel to orthogonally add and remove multiple biomolecule-DNA conjugates at user-defined timepoints. We demonstrated that the persistent presentation of the cell adhesion peptide RGD was required to maintain cell spreading on hyaluronic acid hydrogels. Further, we discovered the delayed presentation of osteogenic growth peptide (OGP) increased alkaline phosphatase activity compared to other temporal variations. This finding is critically important when considering the design of OGP delivery approaches for bone repair. More broadly, this platform provides a unique approach to tease apart the temporal role of multiple biomolecules during development, regeneration, and disease progression.


Delayed presentation of posterior urethral valves: a not so benign condition.
Posterior urethral valves are usually detected during infancy by prenatal sonography. Rarely they may be diagnosed during later childhood, adolescence or even adulthood. Less is known about presentation and outcome in these older patients. We reviewed our experience at 4 institutions with the late presentation of posterior urethral valves. A 13-year retrospective review revealed the late presentation of posterior urethral valves in 47 patients 5 to 35 years old (mean age 8). Data collected included presenting symptomatology, radiographic findings and renal function. Statistical analysis determined the relationships among presenting symptoms, patient age at diagnosis and renal function. The most common presenting symptoms were diurnal enuresis in 60% of the cases, urinary tract infection in 40% and voiding pain in 13%. Other presenting symptoms in less than 10% of the cases included poor stream, gross hematuria and proteinuria. At diagnosis hydronephrosis and vesicoureteral reflux were present in 40 and 33% of the patients, respectively, while serum creatinine was elevated in 35% and end stage renal disease had developed in 10%. The severity of presenting signs and symptoms was significantly associated with renal impairment, while patient age at diagnosis was not. Posterior urethral valves is not merely a disease of infancy. Voiding cystourethrography should be considered in boys older than 5 years who have voiding complaints, especially in association with diurnal enuresis or urinary tract infection. Patients who present late with posterior urethral valves are at risk for progression to end stage renal disease.


[Mathematical modeling of transmembrane calcium transport kinetics in smooth muscle cells].
A mathematical model, which describes kinetics of transmembrane calcium transport in a smooth muscular cell, has been elaborated and investigated taking into account that the change of calcium cations concentration within a cell is determined by two mutually opposite processes: an increase of a carrying capacity of calcium channels of plasma membrane under signal substance action and calcium removal from the intracellular space by Mg2+, ATP-dependent calcium pump localized on the plasma membrane. The fundamental difference of the proposed model against the models analyzed in literature before is that the cellular system returns to the initial stationary state after enzyme-catalysed transformation of the signal substance. The results of calculations showed that this model really described the experimental kinetics of the transmembrane calcium transport. In this paper the influence of different parameters (Michaelis constant and ultimate rate of calcium pump, initial concentrations of signal substance and enzyme decomposing it, rate constants) on kinetics of calcium transport through the plasma membrane has been investigated in detail.


Global health in medical education: a call for more training and opportunities.
Worldwide increases in global migration and trade have been making communicable diseases a concern throughout the world and have highlighted the connections in health and medicine among and between continents. Physicians in developed countries are now expected to have a broader knowledge of tropical disease and newly emerging infections, while being culturally sensitive to the increasing number of international travelers and ethnic minority populations. Exposing medical students to these global health issues encourages students to enter primary care medicine, obtain public health degrees, and practice medicine among the poor and ethnic minorities. In addition, medical students who have completed an international clinical rotation often report a greater ability to recognize disease presentations, more comprehensive physical exam skills with less reliance on expensive imaging, and greater cultural sensitivity. American medical students have become increasingly more interested and active in global health, but medical schools have been slow to respond. The authors review the evidence supporting the benefits of promoting more global health teaching and opportunities among medical students. Finally, the authors suggest several steps that medical schools can take to meet the growing global health interest of medical students, which will make them better physicians and strengthen our medical system.


Roseivivax pacificus sp. nov., isolated from deep-sea sediment.
A Gram-stain-negative, short-rod-shaped bacterium, designated 22DY03(T), was isolated from a sediment sample collected from the East Pacific Rise. The isolate required NaCl and grew best with 3-7 % (w/v) sea salts at temperature of between 30 and 35 °C at pH 7.0. It formed non-pigmented colonies and produced exopolysaccharide, but did not produce bacteriochlorophyll a. Strain 22DY03(T) was positive for hydrolysis of aesculin and Tween 20 and negative for hydrolysis of casein, DNA, gelatin, starch and Tween 40, 60 and 80. The major respiratory quinone was ubiquinone-10. The polar lipid profile consisted of a mixture of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, diphosphatidylglycerol, two unidentified phospholipids and four unidentified polar lipids. The major fatty acids were C19 : 0 cyclo ω8c, C18 : 1ω7c and 11-methyl C18 : 1ω7c. The genomic DNA G+C content was 64.6 mol%. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strain 22DY03(T) should be assigned to the genus Roseivivax. The 16S rRNA gene sequence similarities between the isolate and the type strains of species of the genus Roseivivax were in the range of 94.1-95.8 %. On the basis of phenotypic and genotypic data, it is concluded that strain 22DY03(T) represents a novel species of the genus Roseivivax, for which the name Roseivivax pacificus sp. nov. (type strain 22DY03(T) = CGMCC 1.12410(T) = JCM 18866(T)) is proposed.


Why do participants initiate free recall of short lists of words with the first list item? Toward a general episodic memory explanation.
Participants who are presented with a short list of words for immediate free recall (IFR) show a strong tendency to initiate their recall with the 1st list item and then proceed in forward serial order. We report 2 experiments that examined whether this tendency was underpinned by a short-term memory store, of the type that is argued by some to underpin recency effects in IFR. In Experiment 1, we presented 3 groups of participants with lists of between 2 and 12 words for IFR, delayed free recall, and continuous-distractor free recall. The to-be-remembered words were simultaneously spoken and presented visually, and the distractor task involved silently solving a series of self-paced, visually presented mathematical equations (e.g., 3 + 2 + 4 = ?). The tendency to initiate recall at the start of short lists was greatest in IFR but was also present in the 2 other recall conditions. This finding was replicated in Experiment 2, where the to-be-remembered items were presented visually in silence and the participants spoke aloud their answers to computer-paced mathematical equations. Our results necessitate that a short-term buffer cannot be fully responsible for the tendency to initiate recall from the beginning of a short list; rather, they suggest that the tendency represents a general property of episodic memory that occurs across a range of time scales.


Baseline monitoring of codling moth (Lepidoptera: Tortricidae) larval response to benzoylhydrazine insecticides.
A diet-incorporation larval bioassay was developed to measure the response of codling moth, Cydia pomonella (L.), to the benzoylhydrazine insecticides tebufenozide and methoxyfenozide. The bioassay tested neonates and third, fourth, and fifth instars from a laboratory colony and neonates and fourth instars from a pooled population collected from five certified-organic apple orchards. Bioassays were scored after 6 and 14 d. No differences between the laboratory and field population were found for either insecticide. Significant differences were found in the response of third and fifth instars between the 6 and 14 d bioassays, primarily due to a high proportion of moribund larvae in the shorter assay. Larval age had a significant effect in bioassays and was more pronounced in 6- versus 14-d tests. Fifth instars were significantly less susceptible to both insecticides than other stages, while responses of third and fourth instars were similar. The response of neonates was significantly different from third and fourth instars to tebufenozide but not with methoxyfenozide in the 14-d test. Field bioassays excluded the use of fifth instars and were scored after 14 d. LC50s estimated for 18 field-collected populations varied five- and ninefold for tebufenozide and methoxyfenozide, respectively. The responses of all but six field-collected populations were significantly different from the laboratory strain. Five of these six populations were collected from orchards with no history of organophosphate insecticide use. The LC50 for methoxyfenozide of one field-collected population reared in the laboratory for three generations declined fourfold, but was still significantly different from the laboratory population. These data suggest that transforming current codling moth management programs in Washington from a reliance on organophosphate insecticides to benzoylhydrazines may be difficult.


Oncogenic roles of SMARCB1/INI1 and its deficient tumors.
SMARCB1/INI1 is one of the core subunit proteins of the ATP-dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16-RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway. Initially, no detectable SMARCB1/INI1 protein expression was found in malignant rhabdoid tumor cells, whereas all other kinds of tumor cells and non-tumorous tissue showed SMARCB1/INI1 protein expression. Therefore, immunohistochemical testing for the SMARCB1/INI1 antibody has been considered useful in confirming the histologic diagnosis of malignant rhabdoid tumors. However, recently, aberrant expression of SMARCB1/INI1 has been found in various tumors such as epithelioid sarcomas, schwannomatosis, synovial sarcomas, and so on. In addition, it has been reported that aberrant expression can be classified into three patterns: complete loss, mosaic expression and reduced expression. Although the various pathways related to mechanisms of tumorigenesis and tumor proliferation are complexly intertwined, the clarification of these mechanisms may contribute to therapeutic strategies in SMARCB1/INI1-deficient tumors. In terms of pathological classifications, SMARCB1/INI1-deficient tumors may be re-classified by genetic backgrounds.


Effect of hesperetin on chaperone activity in selenite-induced cataract.
Chaperone activity of α-crystallin in the lens works to prevent protein aggregation and is important to maintain the lens transparency. This study evaluated the effect of hesperetin on lens chaperone activity in selenite-induced cataracts. Thirteen-day-old rats were divided into four groups. Animals were given hesperetin (groups G2 and G4) or vehicle (G1 and G3) on Days 0, 1, and 2. Rats in G3 and G4 were administered selenite subcutaneously 4 hours after the first hesperetin injection. On Days 2, 4, and 6, cataract grades were evaluated using slit-lamp biomicroscopy. The amount of a-crystallin and chaperone activity in water-soluble fraction were measured after animals sacrificed. G3 on day 4 had developed significant cataract, as an average cataract grading of 4.6 ± 0.2. In contrast, G4 had less severe central opacities and lower stage cataracts than G3, as an average cataract grading of 2.4 ± 0.4. The a-crystallin levels in G3 lenses were lower than in G1, but the same as G4. Additionally, chaperone activity was weaker in G3 lenses than G1, but the same as in G4. Our results suggest that hesperetin can prevent the decreasing lens chaperone activity and a-crystallin water solubility by administered of selenite.


High concentrations of persistent organic pollutants including PCBs, DDT, PBDEs and PFOS in little brown bats with white-nose syndrome in New York, USA.
White-nose syndrome (WNS) is a condition associated with white fungal growth on ears, wings, and nose of hibernating bats; this condition has recently resulted in high bat mortality in the northeastern United States. Nevertheless, the pathogenesis of morbidity and mortality are still unknown. Elevated exposure to toxic contaminants could be a contributing factor via the consequent immunosuppression and endocrine disruption. In this study, diseased little brown bats (Myotis lucifugus) were collected from several hibernacula in eastern New York State in 2008. Fat tissues of bats were analyzed for polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polybrominated biphenyls (PBBs), and organochlorine pesticides (OCPs; DDT, chlordanes, HCB, and HCH), and liver was analyzed for perfluorinated compounds (PFCs). A reference population of little brown bats, not affected by WNS, was also collected from a cave in Kentucky for the analysis of trace organic contaminants. Concentration of PCBs in fat tissues of bats from New York ranged from 1900 ng g(-1) to 35000 ng g(-1), lipid wt, with the highest concentrations found in bats collected from caves in Albany County. High concentrations of PCBs were also found in bats from Kentucky (17100-18400 ng g(-1), lipid wt). Total PBDE concentrations in fat tissues ranged from 520 ng g(-1) to 10900 ng g(-1), lipid wt, in bats from New York and from 4300 ng g(-1) to 13000 ng g(-1), lipid wt, in bats from Kentucky. High concentrations of DDT (26900 ng g(-1), lipid wt), chlordanes (6350 ng g(-1), lipid wt), and HCB (260 ng g(-1), lipid wt) were found in bats from New York. Concentrations of hexabromobiphenyl congener 153 (PBB 153) in bats from New York ranged from 8.6ngg(-1) to 124000 ng g(-1), lipid wt. Concentrations of PFCs were on the order of a few tens to a few hundreds of nanograms per gram liver, on a wet weight basis. Overall, high concentrations of PCBs, PBDEs, DDT, and chlordanes were found in fat tissues of diseased bats from New York, although the concentrations in bats from non-diseased, reference population, from Kentucky were also high.


Maintaining a catalog of manually-indexed, clinically-oriented World Wide Web content.
With no quality controls and a highly distributed means of posting information, finding high-quality, clinically-oriented content on the World Wide Web can be difficult. Maintaining a catalog of such information can be equally challenging. CliniWeb is a catalog of quality-filtered and clinically-oriented content on the Web designed to enhance access to such information. This paper describes a group of semi-automated tools have been developed to maintain the CliniWeb database. One allows easier identification of content by utilizing Web crawling techniques from high-level pages. Another allows easier selection of content for inclusion and its indexing. A final one checks links to help keep the database current. These are augmented by general plans to adopt more detailed metadata and linkages into the medical literature.


Intracellular storage and regulated secretion of von Willebrand factor in quantitative von Willebrand disease.
Several missense mutations in the von Willebrand Factor (VWF) gene of von Willebrand disease (VWD) patients have been shown to cause impaired constitutive secretion and intracellular retention of VWF. However, the effects of those mutations on the intracellular storage in Weibel-Palade bodies (WPBs) of endothelial cells and regulated secretion of VWF remain unknown. We demonstrate, by expression of quantitative VWF mutants in HEK293 cells, that four missense mutations in the D3 and CK-domain of VWF diminished the storage in pseudo-WPBs, and led to retention of VWF within the endoplasmic reticulum (ER). Immunofluorescence and electron microscopy data showed that the pseudo-WPBs formed by missense mutant C1060Y are indistinguishable from those formed by normal VWF. C1149R, C2739Y, and C2754W formed relatively few pseudo-WPBs, which were often short and sometimes round rather than cigar-shaped. The regulated secretion of VWF was impaired slightly for C1060Y but severely for C1149R, C2739Y, and C2754W. Upon co-transfection with wild-type VWF, both intracellular storage and regulated secretion of all mutants were (partly) corrected. In conclusion, defects in the intracellular storage and regulated secretion of VWF following ER retention may be a common mechanism underlying VWD with a quantitative deficiency of VWF.


The diagnosis of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by the immune mediated destruction of small intrahepatic bile duct epithelial cells leading to cholestasis and cirrhosis. The autoimmune basis of PBC is supported by the highly specific anti-mitochondrial antibodies (AMAs) and autoreactive T cells, the former being the basis for diagnosis in the vast majority of cases. Although a rare disease, the incidence rates of PBC have been increasing, possibly due to increased testing and diagnosis as opposed to a true increase in disease incidence. Presently, most cases are asymptomatic and only suspected based upon routine liver tests. Those with symptoms typically complain of pruritus and fatigue. The diagnosis of PBC is based on the presence of at least 2 of 3 key criteria including a persistently elevated serum alkaline phosphatase, the presence of serum AMAs, and liver histology consistent with PBC. Anti-nuclear antibodies specific to PBC are useful in cases in which AMAs are not detected and may indicate a more aggressive course. Ursodeoxycholic acid is the only proven therapy for PBC and in most cases can delay or prevent disease progression. However, a subgroup of patients does not adequately respond to ursodeoxycholic acid and for whom new therapies are needed.


Quantitative challenges facing patient-centered outcomes research.
Patient-centered outcomes research collects and analyzes data from patients and other stakeholders to improve health care delivery and outcomes and guide health care decisions. However, there are a number of challenges in conducting quantitative analyses of patient-centered data. This article provides an overview of the analytical challenges and describes approaches to consider to overcome the challenges, as well as directions for future development.


Mucosal Thickening Occurs in Contralateral Paranasal Sinuses following Sinonasal Malignancy Treatment.
Objective To investigate the incidence and degree of contralateral sinus disease following treatment of sinonasal malignancy (SNM) using radiological findings as an outcome measure. Study Design Retrospective case series. Setting Tertiary referral academic center. Participants Patients with SNM treated with surgical and adjuvant radiotherapy with or without concurrent chemotherapy. Main Outcome Measures Pre- and posttreatment computed tomography and magnetic resonance imaging scans, Lund-Mackay (LM) score, date of diagnosis, chemotherapy, and dosage of radiation therapy (RT). Results There was a significant difference between pre- and posttreatment LM scores ( p < 0.001) of the contralateral paranasal sinuses. There was no statistical significance between the change in pre- and posttreatment LM scores and patient age, gender, chemotherapy, RT dosage, and time lapse between diagnosis and when we performed this study in the univariate and the multivariable analyses. Conclusions Following treatment of SNM with surgical resection and RT, there was a significant increase in incidence and degree of mucosal thickening of the contralateral sinus by LM grading that persisted after the completion of treatment. This indicates the need for long-term follow-up to monitor for chronic rhinosinusitis as a delayed complication following treatment of SNM.


Medial and lateral pectoral nerves: course and branches.
During modified radical mastectomy or cosmetic surgery, denervation of the lower part of the pectoralis major frequently occurs and may reduce muscle spasm, with consequent better reconstruction of the breast. The aim of this study was to determine the relationship between the pectoral nerves and the pectoral muscles. Eight unembalmed female cadavers were dissected and vascular and radiologic studies performed. The lateral pectoral nerves showed a constant course, parallel to the thoraco-acromial vessels. They coursed for 55 +/- 7 mm inferomedially on the deep surface of pectoralis major, under its fascia. The medial pectoral nerves showed two main patterns of branching, which correlated with the extent of the costal attachments of the pectoralis minor muscles. In pattern A (56%), associated with costal attachments narrower than 6.0 cm, the nerve pierced the deep aspect of the pectoralis minor as a single trunk, ramified in the muscle, and gave some branches that appeared on the superficial aspect to enter the pectoralis major. In pattern B (44%), associated with costal attachments wider than 6.6 cm, the nerve divided before entering pectoralis minor and its branches passed through the muscle or round its lower border to reach pectoralis major. The most medial branch of the medial pectoral nerve directed to the pectoralis major muscle emerged from pectoralis minor at the third intercostal space in the midclavicular line, a mean of 10.3 cm lateral to the margin of the sternum. Knowledge of the relationship between the extent of the costal attachment of pectoralis minor and the two patterns of branching of the medial pectoral nerve may be useful when performing elective denervation of the major pectoralis muscle.


An investigation of intensity-modulated radiation therapy versus conventional two-dimensional and 3D-conformal radiation therapy for early stage larynx cancer.
Intensity modulated radiation therapy (IMRT) has been incorporated at several institutions for early stage laryngeal cancer (T1/T2N0M0), but its utility is controversial. In three representative patients, multiple plans were generated: 1) Conventional 2D planning, with the posterior border placed at either the anterior aspect ("tight" plan) or the mid-vertebral body ("loose" plan), 2) 3D planning, utilizing both 1.0 and 0.5 cm margins for the planning target volume (PTV), and 3) IMRT planning, utilizing the same margins as the 3D plans. A dosimetric comparison was performed for the target volume, spinal cord, arytenoids, and carotid arteries. The prescription dose was 6300 cGy (225 cGy fractions), and the 3D and IMRT plans were normalized to this dose. For PTV margins of 1.0 cm and 0.5 cm, the D95 of the 2D tight/loose plans were 3781/5437 cGy and 5372/5869 cGy, respectively (IMRT/3D plans both 6300 cGy). With a PTV margin of 1.0 cm, the mean carotid artery dose was 2483/5671/5777/4049 cGy in the 2D tight, 2D loose, 3D, and IMRT plans, respectively. When the PTV was reduced to 0.5 cm, the the mean carotid artery dose was 2483/5671/6466/2577 cGy to the above four plans, respectively. The arytenoid doses were similar between the four plans, and spinal cord doses were well below tolerance. IMRT provides a more ideal dose distribution compared to 2D treatment and 3D planning in regards to mean carotid dose. We therefore recommend IMRT in select cases when the treating physician is confident with the GTV.


MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux.
As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of "switch" genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.


[A permanent magnetic field alters the phospholipase activity in the snake venom from Vipera lebetina].
It was found that at the exposure of Vipera lebetina snakes (during 10 days for 30 min daily) to SMF (0.15 T1) the specific activity of venom phospholipase A1, A2 and phosphodiesterase C increased by 20.6 +/- 2.8; 31.7 +/- 3.2 and 32.7 +/- 1.3% correspondingly. The above mentioned changes of venom enzyme activity were accompanied with the decrease of its total protein amount by 31.6 +/- 2.2%. It could be supposed that the described changes are able to cause significant changes in the total metabolic activity of cells and the organism as a whole.


Superhydrophobic composite films produced on various substrates.
Hydrophilic silica (SiO2) nanoparticles were dispersed in solutions of poly(methyl methacrylate) (PMMA) and in solutions of a commercial poly(alkyl siloxane) (Rhodorsil 224), and the suspensions were sprayed on glass surfaces. The effect of the particle concentration on the hydrophobic character of PMMA-SiO2 and Rhodorsil-SiO2 films was investigated and showed the following: (i) Static contact angles (theta s), measured on surfaces that were prepared from dilute dispersions (particle concentration <1% w/v), increase rapidly with particle concentration and reach maximum values (154 and 164 degrees for PMMA-SiO2 and siloxane-SiO2, respectively). Further increases in particle concentration do not have any effect on theta s. (ii) The effect of particle concentration on the contact angle hysteresis (thetaAlpha - thetaR) is more complicated: as the particle concentration increases, we first notice an increase in hysteresis, which then decreases and finally becomes constant at elevated particle concentrations. The lowest thetaAlpha - thetaR values were 5 degrees for PMMA-SiO2 and 3 degrees for siloxane-SiO2, respectively. (iii) SEM and AFM images show that a two-length-scale hierarchical structure is formed on the surface of the superhydrophobic films. It is demonstrated that superhydrophobicity can be achieved using various hydrophilic nanoparticles (alumina and tin oxide nanoparticles were successfully tested) and that the substrate has almost no effect on the hydrophobic character of the applied coatings, which were produced on silicon, concrete, aluminum, silk, wood, marble, and of course glass. The results are discussed in light of Wenzel and Cassie-Baxter models.


Synergistic Effect of Feeding Time and Diet on Hepatic Steatosis and Gene Expression in Male Wistar Rats.
Eating out of phase with the endogenous biological clock alters clock and metabolic gene expression in rodents and can induce obesity and type 2 diabetes mellitus. Diet composition can also affect clock gene expression. This study assessed the combined effect of diet composition and feeding time on (1) body composition, (2) energy balance, and (3) circadian expression of hepatic clock and metabolic genes. Male Wistar rats were fed a chow or a free-choice high-fat, high-sugar (fcHFHS) diet, either ad libitum or with food access restricted to either the light or dark period. Body weight, adiposity, and hepatic fat accumulation as well as hepatic clock and metabolic mRNA expression were measured after 5 weeks of the diet. Energy expenditure was measured using calorimetric cages. Animals with access to the fcHFHS diet only during the light period showed more hepatic fat accumulation than fcHFHS dark-fed animals despite less calories consumed. In contrast, within the chow-fed groups, light-fed animals showed the lowest hepatic fat content, but they also showed the lowest caloric intake. Locomotor activity and heat production followed feeding times, except in the fcHFHS light-fed group. Hepatic clock and metabolic gene expression rhythms also followed timing of food intake. Yet, in the fcHFHS light-fed animals, clock gene expression appeared 3 hours advanced compared with chow light-fed animals, an effect not observed in the fcHFHS dark-fed animals. An fcHFHS diet consumed in the light period promotes hepatic fat accumulation and advances clock gene expression in male Wistar rats, likely because of a mismatch between energy intake and expenditure.


The Effect of Different Vegetable Oils on Cedar Wood Surface Energy: Theoretical and Experimental Fungal Adhesion.
Despite having been used for ages to preserve wood against several effects (biological attack and moisture effects) that cause its degradation, the effect of vegetable oils on the cedar wood physicochemical properties is poorly known. Thus, in this study, the hydrophobicity, electron-acceptor (γ +), and electron-donor (γ -) properties of cedar wood before and after treatment with vegetable oils have been determined using contact angle measurement. The cedar wood has kept its hydrophobic character after treatment with the different vegetable oils. It has become more hydrophobic quantitatively with values of surface energy ranged from -25.84 to -43.45 mJ/m2 and more electron donors compared to the untreated sample. Moreover, the adhesion of four fungal strains (Penicillium commune (PDLd"), Thielavia hyalocarpa, Penicillium commune (PDLd10), and Aspergillus niger) on untreated and treated cedar wood was examined theoretically and experimentally. For untreated wood, the experimental adhesion showed a positive relationship with the results obtained by the extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) approach which found that all fungal strains could adhere strongly to the cedar wood material. In contrast, this relationship was not always positive after treatment. The Environmental Scanning Electron Microscopy (ESEM) has shown that P. commune (PDLd10) and A. niger were found unable to adhere to the wood surface after treatment with sunflower and rapeseed oils. In addition, the results showed that the four fungal strains' adhesion was decreased with olive and linseed oils treatment except that of P. commune (PDLd10) treated with linseed oil.


Neuroimmunology of stress: skin takes center stage.
Like few other organs, the skin is continuously exposed to multiple exogenous and endogenous stressors. Superimposed on this is the impact of psychological stress on skin physiology and pathology. Here, we review the "brain-skin connection," which may underlie inflammatory skin diseases triggered or aggravated by stress, and we summarize relevant general principles of skin neuroimmunology and neuroendocrinology. Specifically, we portray the skin and its appendages as both a prominent target of key stress mediators (such as corticotropin-releasing hormone, ACTH, cortisol, catecholamines, prolactin, substance P, and nerve growth factor) and a potent source of these prototypic, immunomodulatory mediators of the stress responses. We delineate current views on the role of mast cell-dependent neurogenic skin inflammation and discuss the available evidence that the skin has established a fully functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis as an independent, local stress response system. To cope with stress-induced oxidative damage, the skin and hair follicles also express melatonin, probably the most potent neuroendocrine antioxidant. Lastly, we outline major, as-yet unmet challenges in cutaneous stress research, particularly in the study of the cross-talk between peripheral and systemic responses to psychological stress and in the identification of promising molecular targets for therapeutic stress intervention.


Plant Identification Based on Leaf Midrib Cross-Section Images Using Fractal Descriptors.
The correct identification of plants is a common necessity not only to researchers but also to the lay public. Recently, computational methods have been employed to facilitate this task, however, there are few studies front of the wide diversity of plants occurring in the world. This study proposes to analyse images obtained from cross-sections of leaf midrib using fractal descriptors. These descriptors are obtained from the fractal dimension of the object computed at a range of scales. In this way, they provide rich information regarding the spatial distribution of the analysed structure and, as a consequence, they measure the multiscale morphology of the object of interest. In Biology, such morphology is of great importance because it is related to evolutionary aspects and is successfully employed to characterize and discriminate among different biological structures. Here, the fractal descriptors are used to identify the species of plants based on the image of their leaves. A large number of samples are examined, being 606 leaf samples of 50 species from Brazilian flora. The results are compared to other imaging methods in the literature and demonstrate that fractal descriptors are precise and reliable in the taxonomic process of plant species identification.


[Interaction of the polyene antibiotic nystatin with bivalent copper ions].
Characteristic features of interaction of nystatin with bivalent copper salts in water, methanol and dimethylsulfoxide were studied. It was shown that stable compounds of copper and nystatin at ratios of 1 : 2 and 1 : 4 formed in the above solvents. The antibiotic in these compounds was in an inert, native or activated state. Physicochemical and biological properties of the compounds were investigated.


Cognitive functions and the state of nonspecific brain systems in panic disorders.
A total of 93 patients with panic disorders and 36 healthy control subjects were studied. Clinical-neurological, psychometric, neuropsychological, and neurophysiological (auditory cognitive evoked potentials) investigations were performed. Patients with typical panic disorders were characterized by increased levels of anxiety and depression, along with impairments to cognitive functions in the form of decreases in short-term memory and attention, as compared with healthy subjects. Patients with atypical panic disorders differed from patients with typical panic disorders in having lower levels of anxiety, more severe depression, and more marked cognitive disorders. As compared with healthy subjects, patients with atypical panic disorders showed reductions in the amplitude of the P300 evoked potential wave, while patients with typical panic disorders showed increases. It is suggested that changes in the amplitude parameters of the P300 wave are associated with dysfunction of the limbic-reticular structures of the brain in patients with panic disorders.


Place effects for areas defined by administrative boundaries.
This study estimates the effects of place on the distribution of health problems, health-related quality of life, general well-being, and family functioning for youths and adults aged 12 years and older. Data come from the Ontario Health Survey, a cross-sectional study done in 1990 to provide baseline statistical data on population health within 42 public health units throughout the province. Place effects were generally small and were influenced by both the size of the geographic area used to define place and the health indicator selected for study. Variations in health explainable at the public health region level were less than 1%. Variations in health explainable within smaller geographic boundaries (enumeration areas) ranged from 4.7% for health problems to 0.2% for family functioning. Adjustment for area differences in the age, gender, education, marital status, income, and birthplace of inhabitants reduced these place effects at the enumeration area level to 3.7% for health problems and to less than 0.1% for family functioning. The lack of evidence for place effects within large jurisdictional boundaries raises questions about both the usefulness of carrying out health needs assessment surveys within these areas and the informativeness of these geographic boundaries for studying place effects.


Overweight and obesity among non-pregnant women of reproductive age in Nigeria: findings from the 2008-2018 Nigerian Demographic and Health Survey.
Overweight and obesity are known risk factors for diabetes, heart disease, certain cancers and pregnancy-related problems. This study aimed to determine the prevalence and change in prevalence of overweight and obesity among non-pregnant women of reproductive age and relationship with individual- and community-level factors over a decade. This was a cross-sectional survey with two-stage probability sampling design. Data sets were pooled from the 2008, 2013 and 2018 Nigerian Demographic and Health Survey - a cross-sectional, nationally representative sample of the entire Nigerian population aged 15-49 years. Body mass index (BMI) was used to classify overweight and obesity. Multilevel logistic regression was used to assess associations between overweight (25.0-29.9 kg/m2), obesity (≥30.0 kg/m2) and individual and community factors. There were 76,729 non-pregnant women (38.0% in 2008, 44.5% in 2013 vs 17.5% in 2018) with a mean age of 29.0 years and a BMI of 23.0 kg/m2 across the three survey periods. Overweight and obesity prevalence were 16.0% and 6.2% in 2008, 17.2% and 7.5% in 2013 and 18.1% and 9.9% in 2018, respectively. There was 76% (95% confidence interval: 44% to twofold) increased odds of obesity in 2018 compared with 2008 in adjusted analysis. Older women with at least primary education living in urban areas, ever married and from wealthier households are at a greater odd of being overweight and obese. Over a decade, overweight and obesity prevalence increased among non-pregnant women of reproductive age in Nigeria. There is an urgent need for public health strategies and interventions to improve on deficient knowledge and low awareness about healthy foods and physical activity at individual and community levels especially in urban areas.


A role for social media? A community-based response to guns, gangs, and violence online.
Social media represents a relatively novel environment for prevention efforts targeting youth gun and gang violence, and associated trauma. The aim of this study is, therefore, to present findings from a novel intervention designed to complement existing, community-based violence prevention efforts. In doing so, we focus on the role of adult empathy in the relationships between youth and the adult credible messengers (CMs) who deliver the program. Guided by the purpose of complementarity, our mixed methods data analyses combine insights gained from CM's quantitative reports of 145 instances of risky online behavior with qualitative analyses of three focus groups addressing their experiences. Results underscore the complexities of social media as a context with the potential to simultaneously contribute to, and serve to prevent, trauma. Results also indicate that empathic concern and perspective taking were important in informing the type of intervention tactics employed by CMs. Relatedly, CM's perspective taking mattered not only in their responses to risky and/or trauma-related content, but also in their identification of some relevant social media posts.


A quantitative connection of experimental and simulated folding landscapes by vibrational spectroscopy.
For small molecule reaction kinetics, computed reaction coordinates often mimic experimentally measured observables quite accurately. Although nowadays simulated and measured biomolecule kinetics can be compared on the same time scale, a gap between computed and experimental observables remains. Here we directly compared temperature-jump experiments and molecular dynamics simulations of protein folding dynamics using the same observable: the time-dependent infrared spectrum. We first measured the stability and folding kinetics of the fastest-folding β-protein, the GTT35 WW domain, using its structurally specific infrared spectrum. The relaxation dynamics of the peptide backbone, β-sheets, turn, and random coil were measured independently by probing the amide I' region at different frequencies. Next, the amide I' spectra along folding/unfolding molecular dynamics trajectories were simulated by accurate mixed quantum/classical calculations. The simulated time dependence and spectral amplitudes at the exact experimental probe frequencies provided relaxation and folding rates in agreement with experimental observations. The calculations validated by experiment yield direct structural evidence for a rate-limiting reaction step where an intermediate state with either the first or second hairpin is formed. We show how folding switches from a more homogeneous (apparent two-state) process at high temperature to a more heterogeneous process at low temperature, where different parts of the WW domain fold at different rates.


Organometallic Phyllosilicate-Gold Nanocomplex: An Effective Oral Delivery System of Methotrexate for Enhanced in vivo Efficacy Against Colorectal Cancer.
Oral administration, although convenient and preferred for treating colorectal cancer (CRC), faces challenges due to limited CRC-related intestinal positioning and a dense mucus barrier. In the present study, a gold-nanoparticle decorated-organometallic phyllosilicate nanocomposite (AC-Au), with a pH-dependent surface coating, was employed for more effective oral delivery of anticancer drugs to treat CRC. The organometallic AC-Au was synthesized using the in-situ sol-gel method. Subsequently, methotrexate (MTX) was loaded into AC-Au, and the complex (AC-Au/MTX) was surface-coated with poly (methacrylic acid-co-methyl methacrylate) (1:2), a pH-dependent polymer (E/AC-Au /MTX). The in vitro characteristics of nanoparticles were examined using various analytical methods. In vivo efficacy studies were also conducted using an HCT-116 orthotopic colorectal cancer model. AC-Au emerged as a spherical nanoparticle with a mean size of 26.5 ± 0.43 nm, displaying a positive charge over the pH range of 2-10. Both the uncoated and coated drug-loaded nanocomplexes (AC-Au/MTX and E/AC-Au/MTX) were fabricated with high entrapment efficiency (> 80%). Various analyses, including ultraviolet-visible spectroscopy, X-ray powder diffraction, transmission electron microscopy, and energy dispersive X-ray spectroscopy, confirmed the formation of the nanocomplexes. While AC-Au/MTX achieved rapid and extensive drug release at the pH range of 1.2-7.4, E/AC-Au/MTX exhibited pH-dependent drug release, with approximately 23% at pH 1.2 and 74% at pH 7.4. Relative to free MTX, the AC-Au-based nanocomplex significantly enhanced the cytotoxicity of MTX in HCT-116 cells. Furthermore, orally administered E/AC-Au/MTX significantly improved the anti-tumor activity of MTX in an HCT-116 orthotopic colorectal cancer model, resulting in approximately 60% suppression of tumor mass compared with the positive control. The organometallic AC-Au nanocomplex coated with a pH-dependent polymer has the potential to be an effective colonic drug delivery system of MTX, enhancing in vivo efficacy against colorectal cancer.


High expression of VEGFA in MSCs promotes tendon-bone healing of rotator cuff tear via microRNA-205-5p.
To explore the role of vascular endothelial growth factor A (VEGFA) in tendon-bone healing of rotator cuff tear (RCT) and to investigate its possible mechanism. Mesenchymal stem cells (MSCs) were transfected with pcDNA-VEGFA. The viability of MSCs was detected by cell counting kit-8 (CCK-8) assay. Expression levels of type I and type II collagen in MSCs were detected by quantitative Real time-polymerase chain reaction (qRT-PCR). RCT was constructed in rats. Meanwhile, all rats were divided into MSCs group and MSCs-pcDNA-VEGFA group, respectively. Biomechanical test was performed to detect ultimate load of failure and stiffness in RCT rats. Dual-luciferase reporter gene assay was conducted to analyze the binding condition between microRNA-205-5p and VEGFA, which was further verified by Western blot and qRT-PCR. VEGFA overexpression significantly promoted viability and proliferation of MSCs. Expression levels of type I and type II collagen were significantly upregulated after VEGFA overexpression in MSCs. Biomechanical test showed that VEGFA overexpression in RCT rats remarkably elevated ultimate load of failure and stiffness. Dual-luciferase reporter gene assay elucidated that VEGFA was the target gene of microRNA-205-5p. Furthermore, VEGFA negatively regulated microRNA-205-5p expression. VEGFA promotes tendon-bone healing of RCT via inhibiting microRNA-205-5p expression.


A study on the electronic and interfacial structures of monolayer ReS2-metal contacts.
In this paper, we perform a systematic and rigorous study to evaluate the Ohmic nature of the top-contact formed by the monolayer ReS2 (mReS2) and metals (gold, silver, platinum, nickel, titanium, and scandium) by means of first-principles density functional theory calculations. We investigate the potential barrier, charge transfer and atomic orbital overlap at the mReS2-metal interface in consideration of van der Waals forces to understand how efficiently carriers could be injected from the metal contact to the mReS2 channel. ReS2 is physisorbed on Au and Ag, which leads to little perturbation of its electronic structures and forms a larger Schottky contact and a higher tunnel barrier at the interface. ReS2 is chemisorbed on Ti and Sc, where the bonding strongly perturbs the electronic structures and is found to be purely Ohmic. The bonding of ReS2 on Pt and Ni lies between these two extreme cases, demonstrating an intermediate behavior. These findings not only provide an insight into the mReS2-metal interfaces but may also prove to be instrumental in the future design of ReS2-based devices with good performance.


GABAA receptors in damaged cerebral cortex areas in human chronic alcoholics.
Chronic alcoholics without complicating disease showed greater densities of GABA agonist sites (labelled with the selective ligand [3H]muscimol) on the GABAA receptor in the superior frontal gyrus, in comparison with both precentral gyrus in the same cases, and with superior frontal gyrus in matched controls. Whereas cases with concomitant Wernicke encephalopathy may also have had greater numbers of superior frontal [3H]muscimol binding sites than controls, alcoholics with cirrhosis of the liver showed more muted differences. Since the GABAA receptor is a multimeric complex which also possesses binding sites for "central-type" benzodiazepine ligands, it would be expected that data obtained with these compounds should mimic that obtained with [3H]muscimol. This was not so. [3H]Flunitrazepam binding sites showed little variation between case groups, although they showed clear regional differences. [3H]Diazepam sites followed those for [3H]muscimol in uncomplicated alcoholics and alcoholics with cirrhosis of the liver, but were at lower density in superior frontal gyrus in Wernicke cases. Differential expression of GABAA receptor subunit isoform genes may give rise to these disparities.


Conserved metabolic steps for sporopollenin precursor formation in tobacco and rice.
The development of pollen wall with proper sporopollenin deposition is essential for pollen viability and male fertility in flowering plants. Sporopollenin is a complex biopolymer synthesized from fatty acid and phenolic derivatives. Recent investigations in Arabidopsis have identified a number of anther-specific genes involved in the production of fatty-acyl monomers potentially required for exine formation. The existence of ancient biochemical pathways for sporopollenin biosynthesis has been widely proposed but experimental evidence from plant species other than Arabidopsis is not extensively available. Here, we investigated the metabolic steps catalyzed by the anther-specific acyl-CoA synthetase (ACOS), polyketide synthase (PKS) and tetraketide α-pyrone reductase (TKPR). Using fatty acids as starting substrates, sequential activities of heterologously expressed tobacco enzymes NtACOS1, NtPKS1 and NtTKPR1 resulted in the production of reduced tetraketide α-pyrones. Transgenic RNA interference lines were then generated for the different tobacco genes which were demonstrated to be indispensable for normal pollen development and male fertility. Similarly, recombinant rice OsPKS1 and OsTKPR1 were shown to function as downstream enzymes of NtACOS1. In addition, insertion mutant lines for these rice genes displayed different levels of impaired pollen and seed formation. Taken together, reduced tetraketide α-pyrones appear to represent common sporopollenin fatty-acyl precursors essential for male fertility in taxonomically distinct plant species.


Endocrine regulation of sex differences in hepatic histidase activity.
Hepatic histidase activity in adult female rats is twice that in adult male rats. Hypophysectomy and thyroidectomy result in a significant increase in hepatic histidase activities in males, but not in females. This effect on histidase is reversed by the exogenous administration of tri-iodothyronine, but not by ectopic pituitary glands or purified pituitary hormones.


Prostate cancer-derived small extracellular vesicle proteins: the hope in diagnosis, prognosis, and therapeutics.
Current diagnostic tools for prostate cancer (PCa) diagnosis and risk stratification are insufficient. The hidden onset and poor efficacy of traditional therapies against metastatic PCa make this disease a heavy burden in global men's health. Prostate cancer-derived extracellular vesicles (PCDEVs) have garnered attention in recent years due to their important role in communications in tumor microenvironment. Recent advancements have demonstrated PCDEVs proteins play an important role in PCa invasion, progression, metastasis, therapeutic resistance, and immune escape. In this review, we briefly discuss the applications of sEV proteins in PCa diagnosis and prognosis in liquid biopsy, focus on the roles of the PCa-derived small EVs (sEVs) proteins in tumor microenvironment associated with cancer progression, and explore the therapeutic potential of sEV proteins applied for future metastatic PCa therapy.


Clonorchis sinensis antigens alter hepatic macrophage polarization in vitro and in vivo.
Clonorchis sinensis infection elicits hepatic inflammation, which can lead to cholangitis, periductal hepatic fibrosis, liver cirrhosis, and even cholangiocarcinoma. Hepatic macrophages are an intrinsic element of both innate and acquired immunity. This study was conducted to demonstrate the dynamics of hepatic macrophage polarization during C. sinensis infection in mice and to identify factors regulating this polarization. Treatment of hepatic macrophages isolated from normal mice with C. sinensis excretory/secretory products (ESPs) resulted in the preferential generation of classically activated hepatic macrophages (M1 macrophages) and the production of pro-inflammatory cytokines. Additionally, cells stimulated with C. sinensis ESPs exhibited changes in cellular morphology. During the early stages of C. sinensis infection, hepatic macrophages preferentially differentiated into M1 macrophages; however, during the C. sinensis mature worm stage, when eggs are released, there were significant increases in the abundance of both M1 macrophages and alternatively activated hepatic macrophages (M2 macrophages). Moreover, there was a further increase in the M2 macrophage count during the fibrotic and cirrhotic stage of infection. Notably, this fibrotic and cirrhotic stage promoted a strong increase in the proportion of Arg-1-producing macrophages (M2 phenotype), which were associated with fibrosis and tissue repair in the liver. Our results suggest that the dynamic polarization of hepatic macrophages as C. sinensis infection progresses is related to the histological lesions present in liver tissue. Hepatic macrophages thus play an important role in local immunity during C. sinensis infection.


EMR based telegeriatric system.
As medical services improve due to new technologies and breakthroughs, it has lead to an increasingly aging population. There has been much discussion and debate on how to solve various aspects such as psychological, socioeconomic and medical problems related to aging. Our effort is to implement a feasible telegeriatric medical service with the use of the state of the art technology to deliver medical services efficiently to remote sites where elderly homes are based. Telegeriatric system will lead to rapid decision-making in the presence of acute or subacute emergencies. This triage will also lead to a reduction of unnecessary admission. It will enable the doctors who visit these elderly homes on a once-a-week basis to improve their geriatric management skills by communication with geriatric specialist. Nursing skills in geriatric care will also benefit from this system. Integrated EMR service will be indispensable in the face of emergency admissions to hospitals. Evolution of EMR database would lead to future research in telegeriatrics and will help to identify the areas where telegeriatrics can be optimally used. This system is based on current web browsing technology and broadband communication. EMR web based server is developed using Java Technology. EMR database was developed using Microsoft SQL server. Both are based at the Medical Informatics Programme, National University of Singapore. Two elderly homes situated in the periphery of Singapore and a leading government hospital in geriatric care has been chosen for the project. These three institutions and National University of Singapore are connected via ADSL protocol, which support high bandwidth, which is necessary for high quality videoconferencing. Each time a patient needs a teleconsultation, a nurse or doctor in the remote site sends the history to the EMR server. EMR server forwards the request to the Alexandra Hospital for consultation. Geriatrics specialists at Alexandra Hospital carry out teleward rounds twice weekly and on demand basis. Following the implementation of the system, a trial run has been done. This shows a high degree of coordination and cooperation between remote site and the Alexandra Hospital Also the patient compliance is very high and they prefer teleconsultation. Initial results show that telegeriatric system has definite advantages in managing geriatric patients at a remote site. As the system evolves, further research will show the areas where telegeriatrics can be used optimally.


The inherited genetic contribution and polygenic risk score for risk of CLL and MBL: a narrative review.
Chronic lymphocytic leukemia (CLL) is a neoplasm of B-cells in the blood and monoclonal B-cell lymphocytosis (MBL) is a precursor state to CLL. This narrative review provides an overview of the genetic studies that identified 43 common variants associated with risk of CLL among individuals of European ancestry. Emerging studies found that ∼50% of these variants are associated with MBL risk. Moreover, the polygenic risk score (PRS) calculated from these CLL variants has been shown to be a robust predictor for both CLL and MBL risk among European ancestry individuals but a weak predictor among African ancestry individuals. By summarizing these genetic studies, we conclude that additional studies are needed in other race/ethnic populations to identify race-specific susceptibility variants, that functional studies are needed to validate the biological mechanisms of the variants, and that the clinical utility of the PRS is limited until preventive strategies for CLL are developed.


Interfacial Properties and Bottom/Top Hardness Ratio Produced by Bulk Fill Composites in Dentin Cavities.
The aim of this study was to evaluate the bond strength, bottom/top hardness ratio, marginal adaptation, and interfacial nanoleakage of regular viscosity bulk fill composites (RVBFC) and regular viscosity traditional composites (RVTC). Two RVBFC (Filtek Bulk Fill and Aura Bulk Fill) and two RVTC (Filtek Z250XT and Aura) were assessed. Forty conical cavities (4.8×2.8×4.0) were prepared in bovine dentin and restored with composites (n=10). After 24h in water, marginal adaptation was evaluated by staining with a caries detector. The top and bottom surfaces of the conical restorations were stained for five seconds and the gap percentage in the composite/dentin interface was determined using digital images on a measurement program (ImageTool). The Vickers microhardness was measured and the bottom/top microhardness ratio (B/T) was determined. Push-out bond strength test was performed in a universal testing machine (0.5mm/min) and failure modes were evaluated in a stereomicroscope (20×). Other specimens (n=3) were produced for interfacial nanoleakage evaluation. Data were analyzed using one and two-way ANOVA and Tukey's test (α=0.05). The gap percentage was higher in the bottom compared to the top. The B/T ratio of the Aura Bulk Fill was statistically lower than other composites. Push-out bond strength were similar among composites. The RVBFC presented lower nanoleakage than the RVTC in the bottom of the conical restoration and there was no difference among the materials in the top surfaces. In conclusion, Filtek Bulk Fill performed better than Aura Bulk Fill regarding the analyzed properties.


Aflatoxins and kwashiorkor: a study in Sudanese children.
Blood and urine samples from 252 Sudanese children were investigated for their aflatoxin content by high-performance liquid chromatography. The children comprised 44 with kwashiorkor, 32 with marasmic kwashiorkor, 70 with marasmus, and 106 age-matched, normally nourished controls. Aflatoxins were detected more often and at higher concentrations in sera from children with kwashiorkor than in the other malnourished and control groups. Aflatoxicol, a metabolite of aflatoxins B1 and B2, was detected in the sera of children with kwashiorkor and marasmic kwashiorkor but not in the controls and only once in a marasmic child. The difference between children with kwashiorkor or marasmic kwashiorkor and those in the control or marasmus groups was significant. Urinary aflatoxin was most often detected in children with kwashiorkor but their mean concentration was lower than in the other groups. Aflatoxicol was not detected in urine in any group. These findings suggest either that the children with kwashiorkor have a greater exposure to aflatoxins or that their ability to transport and excrete aflatoxins is impaired by the metabolic derangements associated with kwashiorkor. The presence of aflatoxicol in the sera of children with kwashiorkor but not in the others suggests a difference in metabolism between the two groups. Further studies are needed, and measurement of aflatoxins in the food eaten by these children is already underway.


Predictors of Organ Damage Progression and Effect on Health-related Quality of Life in Systemic Lupus Erythematosus.
To describe organ damage accrual, predictors of damage progression, and effect on health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). A longitudinal database of patients who met the American College of Rheumatology (ACR) classification criteria for SLE was used. Annual assessments included the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) and the Medical Outcomes Study Short Form-36 (SF-36). The prognostic significance of demographic, disease-related, and treatment-related factors on damage progression was examined using multivariable Cox regression. The effect of changes in SDI scores on HRQOL, measured using the SF-36 summary and subscale scores, was assessed using linear mixed-effects modeling. There were 273 patients with SLE studied over a mean (SD) duration of followup of 7.3 (4.3) years. During followup, 126 (46.2%) had an increase in SDI scores. Patients with preexisting damage at baseline were more likely to have earlier damage progression (HR 2.09, 95% CI 1.44-3.01). Older age, ≥ 8 ACR classification criteria, immunosuppressive drugs, cigarette smoking, and higher mean serum C-reactive protein levels were associated with an earlier increase in SDI scores in multivariable analysis. In general, changes in SDI scores were associated with initial declines in SF-36 scores at the time that damage occurred, with subsequent change comparable to that seen in patients without damage progression. This study identified multiple risk factors, some modifiable, associated with damage progression in patients with SLE. The negative effect on HRQOL emphasizes the need for treatment strategies to reduce the risk of organ damage over time.


Computerizing management in an optometric practice.
Successful computer automated management of an optometric practice requires software products which are suitably engineered and designed to accomplish all required tasks cost and time effectively without intimidating the user. The design of the software's "human interface" which determines the ease of use and acceptance is discussed. The prioritization of management problem areas and the software requirements for their solution are evaluated.


The consistency of a species' response to press perturbations with high food web uncertainty.
Predicting species responses to perturbations is a fundamental challenge in ecology. Decision makers must often identify management perturbations that are the most likely to deliver a desirable management outcome despite incomplete information on the pattern and strength of food web links. Motivated by a current fishery decline in inland lakes of the Midwestern United States, we evaluate consistency of the responses of a target species (walleye [Sander vitreus]) to press perturbations. We represented food web uncertainty with 193 plausible topological models and applied four perturbations to each one. Frequently the direction of the focal predator response to the same perturbation is not consistent across food web topologies. Simultaneous application of management perturbations led to less consistent outcomes compared to the best single perturbation. However, direct manipulation of the adult focal predator produced a desirable outcome in 77% of 193 plausible topologies. Identifying perturbations that produce consistent outcomes in the face of food web uncertainty can have important implications for natural resource conservation and management efforts.


Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin E1 Study Group.
To determine the epidemiology of multiple organ failure (MOF) in patients with the adult respiratory distress syndrome. We followed up 50 patients with serial determinations of respiratory and nonrespiratory organ function for seven days after diagnosis. Data were stratified between patients who died and those who survived (defined as hospital discharge). Values that did not differ at any time between the two groups of patients included oxygen availability, oxygen consumption, oxygen extraction, PaCO2, respiratory rate, heart rate, systolic blood pressure, cardiac output, stroke index, systemic vascular resistance, and temperature. Patients who died had greater defects in oxygenation (from day 1 through day 7). They also exhibited decreased arterial oxygen content (from day 1 to day 4), decreased mixed venous oxygen content (day 1), increased peak inspiratory pressure (present on day 2, persisted to day 5, reappeared on day 7), decreased diastolic blood pressure (seen on days 1 through 3, reappeared on day 7), and increased mean pulmonary artery pressure (seen on days 2 and 3). Nonsurvivors also exhibited greater degrees of thrombocytopenia (from day 1 to day 4). Decreases in pH (seen on day 1, reappeared from days 4 to 7), abnormalities in liver function (seen only on day 1), and increases in serum creatinine levels (appeared on day 7) were also observed. Multiorgan dysfunction (MOD) was frequently observed in both groups of patients. Alterations in organ function and the pattern of abnormalities were often subtle and would not be characterized as significant organ dysfunction by most available organ scoring systems. Adult respiratory distress syndrome is a manifestation of systemic disease produced by widespread increases in endothelial permeability; lung dysfunction dominates the early clinical course. When respiratory function is supported, it becomes evident that alterations occur in other organs. Multiorgan failure is really a misnomer; the term emphasizes end-stage changes. Multiorgan dysfunction is common and often resolves without progressing to MOF. Alternatively, MOD can progress to MOF.


Circulating Interleukin-6 and CD16 positive monocytes increase following angioplasty of an arteriovenous fistula.
Arteriovenous fistulas are the ideal form of vascular access that allows provision of haemodialysis. Stenotic lesions caused by neointimal hyperplasia commonly occur resulting in patients requiring a fistuloplasty. This is effective but there is a high recurrence rate. We sought to investigate the effects of a fistuloplasty on monocyte populations. Blood samples were taken from patients before and after their fistuloplasty procedure. Samples were analysed using flow cytometry, ELISA and Luminex assays. Univariate cox regression was carried out to investigate associations with post fistuloplasty patency. At 1-2 days post fistuloplasty, the proportion of classical (CD14++CD16-) monocytes decreased (p < 0.001), whilst intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocytes increased (both p < 0.01) in a cohort of 20 patients. A time course study carried out in 5 patients showed that this was due to an increase in absolute numbers of non-classical and intermediate monocytes. Higher levels of non-classical monocytes pre-fistuloplasty were associated with an increased risk for patency loss (p < 0.05). We measured 41 soluble factors in plasma samples taken before a fistuloplasty in 54 patients, with paired post-fistuloplasty samples (1-2 days) available in 30 patients. After correcting for false discovery, the only factor with a significant change in level was IL-6 (P = 0.0003, q = 0.0124). In a further time-course study in 6 patients, peak level of IL-6 occurred 2-3 h post fistuloplasty. This study demonstrates that there is a systemic inflammatory response to the fistuloplasty procedure and that monocyte subsets and IL-6 may be important in the pathophysiology of restenosis.


A₁ adenosine receptor modulation of chemically and electrically evoked lumbar locomotor network activity in isolated newborn rat spinal cords.
It is not well-studied how the ubiquitous neuromodulator adenosine (ADO) affects mammalian locomotor network activities. We analyzed this here with focus on roles of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)-sensitive A(1)-type ADO receptors. For this, we recorded field potentials from ventral lumbar nerve roots and electrically stimulated dorsal roots in isolated newborn rat spinal cords. At ≥ 25μM, bath-applied ADO slowed synchronous bursting upon blockade of anion-channel-mediated synaptic inhibition by bicuculline (20 μM) plus strychnine (1 μM) and this depression was countered by DPCPX (1 μM) as tested at 100 μM ADO. ADO abolished this disinhibited rhythm at ≥ 500 μM. Contrary, the single electrical pulse-evoked dorsal root reflex, which was enhanced in bicuculline/strychnine-containing solution, persisted at all ADO doses (5 μM-2 mM). In control solution, ≥ 500 μM ADO depressed this reflex and pulse train-evoked bouts of alternating fictive locomotion; this inhibition was reversed by 1 μM DPCPX. ADO (5 μM-2 mM) did not depress, but stabilize alternating fictive locomotion evoked by serotonin (10 μM) plus N-methyl-d-aspartate (4-5 μM). Addition of DPCPX (1μM) to control solution did not change either the dorsal root reflex or rhythmic activities indicating lack of endogenous A(1) receptor activity. Our findings show A(1) receptor involvement in ADO depression of the dorsal root reflex, electrically evoked fictive locomotion and spontaneous disinhibited lumbar motor bursting. Contrary, chemically evoked fictive locomotion and the enhanced dorsal root reflex in disinhibited lumbar locomotor networks are resistant to ADO. Because ADO effects in standard solution occurred at doses that are notably higher than those occurring in vivo, we hypothesize that newborn rat locomotor networks are rather insensitive to this neuromodulator.


Investigation Regarding Early Cognitive Function of Women in the Postpartum Period and the Analysis of Influencing Factors.
The present study aims to assess the cognitive function of healthy full-term puerperae and compare it with the cognitive function of healthy non-pregnant women in order to analyze possible influencing factors. The study subjects were divided into two groups: the maternal (case) group (n = 80) and the control group (n = 30). A total of 50 healthy single-birth full-term primiparous women and 30 women undergoing a second pregnancy were assigned to the maternal group, while 30 non-pregnant women matched by general data were assigned to the control group. Subject cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) (Beijing version) and the Birmingham Cognitive Screen (BCoS) (Mandarin version); related influencing factors were analyzed. In the maternal group, the results showed a MoCA score of 26.52 ± 2.13 points and a cognitive impairment incidence of 26% in primiparous women, along with a MoCA score of 25.83 ± 2.49 points and a cognitive impairment incidence of 36.7% in women undergoing a second pregnancy. All scores were lower in the maternal group than in the control group, which had a MoCA score of 27.47 ± 1.28 points and cognitive impairment incidence of 6.7% (p < 0.05). The differences in MoCA score and cognitive impairment incidence between the primiparous sub-group and the second pregnancy sub-group were not statistically significant (p > 0.05). The visual space and executive function MoCA scale scores were lower in the maternal group than in the control group (p < 0.01). Furthermore, the scores were lower in the maternal group than in the control group in the following BCoS items: instant story recall, total apple deletion number, auditory attention, rule conversion, and gesture imitation (p < 0.05). Women in the postpartum period may develop cognitive dysfunction; however, the difference in cognitive impairment incidence between the primiparous sub-group and the second pregnancy sub-group in this study was not statistically significant. The educational level, labor analgesia, and total labor time (min) were found to be influencing factors in the postpartum cognitive function decline (p < 0.05).


Changes in the activity of units of the cat motor cortex with rapid conditioning and extinction of a compound eye blink movement.
Patterns of spike activity were measured in the pericruciate cortex of conscious cats before and after development of a Pavlovian conditioned eye blink response. Unit activity was tested with presentations of a click conditioned stimulus (CS) and a hiss discriminative stimulus (DS) of similar intensity to the click. Unit discharge in response to the CS increased after conditioning, but not after backward conditioning when conditioned reflexes (CRs) were not performed. Rates of spontaneous, baseline discharge were not increased after conditioning with respect to rates of discharge measured in the naive state. It appeared that an increase in the ratio of CS-elicited discharge to background activity, together with an increase in the number of units responding to the CS after conditioning, supported discrimination of the CS from the DS and performance of the conditioned blink response. This is the first detailed characterization of patterns of a rapidly conditioned Pavlovian response. Activation of units by the CS preceded the onset of the CR, supporting the hypothesis that the activity played a role in initiating the conditioned eye blink movement. Extinction with retention of performance of the CR was associated with perseverance of the increased unit discharge in response to the CS. Extinction with substantially reduced performance of the CR was associated with diminution of the unit response to the CS below levels found with conditioning. Averages of patterns of spike activity elicited by the CS after conditioning showed components of discharge with onsets of 8-40 msec (alpha 1), 40-72 msec (alpha 2), 72-112 msec (beta), and greater than 112 msec (gamma), corresponding to each of four separate excitatory EMG components of the compound blink CR. Each component increased in magnitude after conditioning, relative to levels found in the naive state. The finding that long- as well as short-latency components of unit activation increased after conditioning supported the hypothesis that generation of both long- and short-latency blink CRs in normal animals may depend significantly on neural circuitry and mechanisms within the motor cortex.


Aspirin-induced gastroduodenal injury and its prevention by prostaglandins.
It appears likely that aspirin injury and thus bleeding is due to both inhibition of the mucosal synthesis of protective endogenous prostanoids and to a local irritant effect. This injury can be abolished in humans by acid-inhibitory doses of prostaglandins and can probably be ameliorated by 'cytoprotective' doses. It has yet to be shown that the gastropathy seen in patients taking long-term aspirin-like drugs can be prevented or treated by prostaglandins. The clinical relevance of such protection has not yet been established.


The Role of Immunosenescence in the Development of Age-Related Diseases.
Aging is a complex phenomenon leading to numerous changes in the physiological systems of the body. One of the most important changes, called immunosenescence, occurs in the immune system. Immunosenescence covers changes in the innate and the adaptive immune systems and is associated with a low-grade inflammation called inflammaging. Aging, likely via inflammaging, is also associated with the emergence of chronic diseases including cardiovascular and neurodegenerative diseases, cancer, and diabetes mellitus type 2. The origin of this inflammaging is not known with certainty, but several concurrent contributing factors have been suggested, such as aging-associated changes in the innate and adaptive immune response, chronic antigenic stimulation, the appearance of endogenous macromolecular changes, and the presence of senescent cells exhibiting a senescence-associated secretory phenotype. A better understanding of the multiple biological phenomena leading to these diseases via the immunosenescence associated with inflammaging provides a powerful target for interventions to increase the healthspan of elderly subjects.


Simultaneous Improvement in the Thermostability and Catalytic Activity of Epoxidase Lsd18 for the Synthesis of Lasalocid A.
Enzymes used in the synthesis of natural products are potent catalysts, capable of efficient and stereoselective chemical transformations. Lsd18 catalyzes two sequential epoxidations during the biosynthesis of lasalocid A, a polyether polyketide natural product. We performed protein engineering on Lsd18 to improve its thermostability and catalytic activity. Utilizing structure-guided methods of FoldX and Rosetta-ddG, we designed 15 mutants of Lsd18. Screening of these mutants using thermal shift assay identified stabilized variants Lsd18-T189M, Lsd18-S195M, and the double mutant Lsd18-T189M-S195M. Trypsin digestion, molecular dynamic simulation, circular dichroism (CD) spectroscopy, and X-ray crystallography provided insights into the molecular basis for the improved enzyme properties. Notably, enhanced hydrophobic interaction within the enzyme core and interaction of the protein with the FAD cofactor appear to be responsible for its better thermostability.


Demographic and employment shifts: implications for benefits and economic security.
This Issue Brief examines factors affecting the population's age distribution and composition, such as mortality rates, fertility rates, and immigration. In addition, it examines factors affecting labor force composition, such as immigration, increased labor force participation of women, and retirement trends, and discusses the potential impact of these changes on publicly financed programs: Medicare, Medicaid, Social Security, and federal employee retirement systems. The discussion also highlights the implications of these population and labor force changes on employers, employees, and retirees. The elderly population--now 31.8 million, representing 12.6 percent of the population--is projected to experience tremendous growth between 2010 and 2030, when the baby boom generation reaches age 65, rising from 39.7 million, or 13.3 percent of the population, to 69.8 million, or 20.2 percent of the population. Growth in the elderly population has implications for retirement and health care systems. Population projections suggest that the traditionally pyramid-shaped work force, with a proportionately greater number of younger workers than older workers, will be replaced with a more even age distribution. Consequently, significant and continued modifications to benefit packages, such as changes in compensation structures in which earnings automatically rise with age, are likely to occur. Women's labor force participation began to accelerate in the mid-1950s, rising 75 percent among women aged 25-44 in 1991, although there is some indication that this growth may be flattening. With women comprising a greater part of the labor force, employers will be encouraged to develop and implement programs to better accommodate their needs. Increased life expectancy, a decreased percentage of entry level workers, changes in Social Security's normal retirement age from 65 to 67, and employer plans to raise the normal age of retirement or provide incentives to delay retirement, could raise the average age of retirement. However, other factors, such as poor health, other sources of retirement income, and individual preferences for retirement, could still dominate the retirement decision. The combination of increased average life expectancy guaranteeing more years of retirement to finance and rising dependency ratios increases the future cost of Social Security financing. Medicare financing is also an important policy issue because the program is projected to experience financial difficulties in the short term, resulting from explosive health care costs. In addition, Medicaid expenditures are consuming increasing amount of shrinking state budget resources--a large portion of which is used to finance nursing home care for a growing elderly population.


USNCTAM perspectives on mechanics in medicine.
Over decades, the theoretical and applied mechanics community has developed sophisticated approaches for analysing the behaviour of complex engineering systems. Most of these approaches have targeted systems in the transportation, materials, defence and energy industries. Applying and further developing engineering approaches for understanding, predicting and modulating the response of complicated biomedical processes not only holds great promise in meeting societal needs, but also poses serious challenges. This report, prepared for the US National Committee on Theoretical and Applied Mechanics, aims to identify the most pressing challenges in biological sciences and medicine that can be tackled within the broad field of mechanics. This echoes and complements a number of national and international initiatives aiming at fostering interdisciplinary biomedical research. This report also comments on cultural/educational challenges. Specifically, this report focuses on three major thrusts in which we believe mechanics has and will continue to have a substantial impact. (i) Rationally engineering injectable nano/microdevices for imaging and therapy of disease. Within this context, we discuss nanoparticle carrier design, vascular transport and adhesion, endocytosis and tumour growth in response to therapy, as well as uncertainty quantification techniques to better connect models and experiments. (ii) Design of biomedical devices, including point-of-care diagnostic systems, model organ and multi-organ microdevices, and pulsatile ventricular assistant devices. (iii) Mechanics of cellular processes, including mechanosensing and mechanotransduction, improved characterization of cellular constitutive behaviour, and microfluidic systems for single-cell studies.


The Roussy-Lévy family: from the original description to the gene.
In 1926, Roussy and Lévy described a large family whose members manifested an early onset dominantly inherited gait ataxia, pes cavus, and areflexia, which was eventually associated with distal muscle atrophy, postural tremor, and minor sensory loss. Slow nerve conduction and demyelination of nerve fibers with onion bulb formations in nerve biopsy specimens led to the Roussy-Lévy syndrome (RLS) being considered a variant of demyelinating Charcot-Marie-Tooth disease (CMT-1). In the present article, we report on the long-term follow-up, on nerve biopsy findings, and on the underlying molecular genetic defect in members of the original family studied by Roussy and Lévy. All patients were able to walk during their seventh decade of life. Morphologically, a chronic demyelinating neuropathy with the remarkable aspects of a focally hypertrophic myelin sheath and major loss of myelinated fibers was observed in nerve biopsy specimens of 3 members of this family. Molecular genetic testing identified a previously unknown heterozygous missense point mutation which yielded an Asn131Lys substitution in the extracellular domain of the myelin protein zero (P0). These findings show that the Roussy-Lévy family belongs to the CMT-1B subtype and has original morphological and genetic features.