Physiological factors in hyperthermia.
The blood flow in normal tissues, i.e., skin and muscle, increases remarkably when heated at temperatures commonly used in hyperthermia (42 degrees -45 degrees C), whereas that in tumor appears to increase slightly when heated at temperatures below 41 degrees -42 degrees C but drastically decreases at temperatures above 42 degrees C. Histopathological studies of the heated tumors demonstrated a pronounced hyperemia, vascular occlusion, and hemorrhage. Due to the vascular occlusion, the dissipation of heat in the tumors becomes inefficient, and the temperatures in the tumor rise higher than those in normal tissues during hyperthermia at temperatures above 42 degrees C. The pH in tumors significantly decreases upon heating. The acidic conditions in the tumors enhances the thermal killing of tumor cells and inhibits the repair of thermal damage and development of tolerance to heat. The mechanism of the decrease in blood flow and pH in the heated tumors is not clear, but these two phenomena seem closely related. The preferential effect of hyperthermia on tumors may be attributed to the higher temperature relative to normal tissue temperature during heating and also to the decrease in the pH upon heating.


Training outreach workers for AIDS prevention in rural India: is it sustainable?
Through a process of community diagnosis and participation, a non-governmental organization in rural Karnataka state in India selected and trained peer outreach workers to implement and sustain AIDS prevention education activities. This activity was part of a larger AIDS education project that aimed at creating awareness and promoting risk-reducing behaviours in the community. This paper describes efforts of the project to identify and train peer educators during its implementation phase and discusses strategies used to facilitate sustainability. We evaluate the impact of these efforts by conducting an analysis in the project area 2 years after the end of the project. The findings reveal generalized interest among rural communities in HIV prevention issues. The project originally conducted an extensive survey to understand community organization and composition, which helped to identify potential partners and peer educators. Training peer educators was a multi-step process, and one with high attrition. While individual peer educators were an excellent resource during the life of the project, peer educators affiliated with village level institutions had the interest, access to resources and willingness to sustain project efforts. However, the sustainability of their efforts was associated with the quality of interactions with the project implementation team, the strength and leadership of their own institutions, the perceived benefits of implementing AIDS education activities after project life and the gender of the outreach worker. Non-sustainers did not have an organizational structure to backstop their work, were often poor and unemployed persons who later found gainful employment, and overwhelmingly, were female. We present a conceptual model based on these findings to help future projects plan for and achieve sustainability.


Müller muscle-conjunctiva resection. Technique for treatment of blepharoptosis.
A new technique for resecting the Müller muscle and the conjunctiva for correction of blepharoptosis has been developed. The operation is performed on all patients in whom a 10% phenylephrine hydrochloride solution instilled in the conjunctival cul-de-sac will elevate the blepharoptotic eyelid to a cosmetically acceptable level. The results of the surgery have been satisfactory in 27 of 28 operated eyelids.


Variation of plantar pressure in Chinese diabetes mellitus.
To investigate dynamic changes in plantar pressure in Chinese diabetes mellitus patients and to provide a basis for further preventing diabetic foot. This is a cross-sectional investigation including 649 Chinese diabetes mellitus patients (diabetes group) and 808 "normal" Chinese persons (nondiabetes group) with normal blood glucose levels. All the subjects provided a complete medical history and underwent a physical examination and a 75-g oral glucose tolerance test. All subjects walked barefoot with their usual gait, and their dynamic plantar forces were measured using the one-step method with a plantar pressure measurement instrument; 5 measurements were performed for each foot. No significant differences were found in age, height, body weight, or body mass index between the two groups. The fasting blood glucose levels, plantar contact time, maximum force, pressure-time integrals and force-time integrals in the diabetes group were significantly higher than those in the nondiabetes group (p < 0.05). However, the maximum pressure was significantly higher in the nondiabetes group than in the diabetes group (p < 0.05). No difference was found in the contact areas between the two groups (p > 0.05). The maximum plantar force distributions were essentially the same, with the highest force found for the medial heel, followed by the medial forefoot and the first toe. The peak plantar pressure was located at the medial forefoot for the nondiabetes group and at the hallucis for the diabetes group. In the diabetes group, the momentum in each plantar region was higher than that in the nondiabetes group; this difference was especially apparent in the heel, the lateral forefoot and the hallucis. The dynamic plantar pressures in diabetic patients differ from those in nondiabetic people with increased maximum force and pressure, a different distribution pattern and significantly increased momentum, which may lead to the formation of foot ulcers.


In Vitro Gut Metabolism of [U-13 C]-Quinic Acid, The Other Hydrolysis Product of Chlorogenic Acid.
Quinic acid in its free form is broadly abundant in plants, and can accumulate in copious amounts in coffee, tea, and certain fruits. However, it has been mostly studied as chlorogenic acid, an ester of caffeic and quinic acids. When chlorogenic acid reaches the colon, it is hydrolyzed by microbial esterases releasing caffeic and quinic acids. While biotransformation of chlorogenic and caffeic acids have been elucidated by in vitro and in vivo studies, the gut metabolism of quinic acid has been so far overlooked. [U-13 C]-Quinic acid is submitted to a colonic model using human fecal microbiota for assessing its metabolic fate. The metabolite profiles formed along microbial biotransformation are monitored by a combined metabolomics approach, using both 2D GC- and ultra-HPLC-MS. Six metabolic intermediates are identified by incorporation of isotopic label. Two parallel degradation pathways could be proposed: (1) an oxidative route, leading to aromatization and accumulation of protocatechuic acid, and a (2) reductive route, including dehydroxylation to cyclohexane carboxylic acid. Elucidating the biotransformation of food bioactives by the gut microbiota is of relevance for understanding nutrition, interindividual variability and potential effects on human metabolism.


Induction by carcinogens and chemoprevention by N-acetylcysteine of adducts to mitochondrial DNA in rat organs.
Damage to mitochondrial DNA (mtDNA) has been postulated to be associated with aging, cancer, and other chronic degenerative diseases which are the predominant causes of death in the population. We used molecular dosimetry techniques, i.e., 32P postlabeling and synchronous fluorescence spectrophotometry, in order to evaluate the formation of adducts to both mtDNA and nuclear DNA (nDNA) in different organs of rats exposed to genotoxic carcinogens. Adducts to mtDNA were detected following administration of benzo(a)pyrene i.p. or 2-acetylaminofluorene by gavage as well as following exposure of animals to cigarette smoke. mtDNA adduct levels were consistently higher than those to nDNA in the same cells, and qualitative differences were also pointed out in the case of the aromatic amine. The oral administration of the thiol N-acetylcysteine, one of the most promising cancer chemopreventive agents endowed with nucleophilic and antioxidant properties, produced a significant decrease of mtDNA adducts in the liver of 2-acetylaminofluorene-treated rats and, sharply, in the lung and liver of rats exposed to cigarette smoke.


The ultrastructural architecture of the adult Schistosoma japonicum tegument.
The tegument of the adult blood fluke Schistosoma japonicum is in direct contact with the host blood and immune systems. A comprehensive understanding of the ultrastructure of the tegument is crucial to the understanding of how the parasite maintains itself within the mammalian host. Important functions such as nutritional uptake and immune evasion are suspected functions of the tegument and this review discusses these aspects and presents some insights into some of these crucial functions. Transmission electron microscopy has allowed the identification of ultrastructural features of the adult S. japonicum, some of which differ from the reported features of other schistosome species. Morphological differences within the tegument of the adult S. japonicum are noted between sexes, among different regions of the worms and between aspects along the length of the parasite. Differences included variations in the ultrastructure, size and number of tegumental bodies and mitochondria within the matrix, and differences in the relative area of the apical surface of the tegument. Functions of the various components of the tegument matrix and specialised functions of different regions of the male and female parasites are discussed based on ultrastructural findings and previously reported biochemical and molecular data.


Facilitating cervical spine radiography in blunt trauma.
The interpretation of cervical spine radiographs is an important facet of the evaluation of blunt trauma victims. The diagnostic accuracy of cervical spine films is dependent upon the technical adequacy of the radiographs and the clinician's diagnostic and interpretive skills. The anxiety inherent in cervical radiographic interpretation by the nonradiologist can be minimized by coupling the use of several simple techniques aimed at enhancing visualization of all cervical spine elements and optimizing bony definitions with an unhurried, methodical radiographic evaluation utilizing a number of radiologic "pearls" in those instances in which injury is less than readily apparent but still suspect.


Critical points in heavy ion irradiated untwinned YBa(2)Cu3O(7-delta) crystals
The critical points in untwinned YBa(2)Cu(3)O(7-delta) crystals with dilute columnar defects are investigated. We find a convergence of a first order vortex melting line with an irreversibility line associated with the onset of the Bose glass critical regime at the lower critical point. In addition, we find that columnar defects raise the upper critical point, implying that vortex line meandering is a basic feature controlling its position.


Renal prostanoids after unclipping the denervated one-kidney, one-clip hypertensive rat.
The contribution of the renal nerves in maintaining blood pressure and modulating renal prostanoid synthesis was examined in established (less than 8 wk in duration) one-kidney, one-clip (1K,1C) hypertension in the rat. Systolic blood pressure was measured for 7 days after renal denervation, at which time the renal artery clip was removed. Twenty-four-hour urinary excretion of PGE2 and 6-keto-PGF1 alpha (stable degradation product of PGI2) was determined before and after denervation and unclipping. Compared with sham-denervated rats, denervation (n = 15) resulted in a small but significant fall in blood pressure (from 216 +/- 4 to 182 +/- 4 mmHg after 48 h) and an increase in urinary 6-keto-PGF1 alpha (from 31 +/- 4 to 43 +/- 5 ng/24 h after 24 h). There was no change in PGE2 excretion. Seven days after surgery, blood pressures were similar in denervated (202 +/- 4 mmHg) and sham-denervated (211 +/- 5 mmHg) rats and fell to a similar extent 24 h after unclipping (142 +/- 3 and 147 +/- 4 mmHg, respectively). Urinary 6-keto-PGF1 alpha increased from 25 +/- 5 to 74 +/- 11 in denervated and 21 +/- 2 to 72 +/- 9 ng/24 h in sham-denervated rats in the 24 h after unclipping. PGE2 excretion increased approximately twofold over this period. These findings indicate that the renal nerves have only a minor role in established hypertension in the 1K,1C rat and that the reversal of hypertension and stimulation of renal prostanoid synthesis following unclipping is not dependent on neural mechanisms.


Stealth Pathogens: The Sooty Blotch and Flyspeck Fungal Complex.
Sooty blotch and flyspeck (SBFS) fungi produce superficial, dark-colored colonies on fruits, stems, and leaves of many plant genera. These blemishes are economically damaging on fruit, primarily apple and pear, because they reduce the sale price of fresh fruit. Fungicide spray programs can control SBFS but are costly and impair human and environmental health; thus, less chemically intensive management strategies are needed. Although the scientific study of SBFS fungi began nearly 200 years ago, recent DNA-driven studies revealed an unexpectedly diverse complex: more than 100 species in 30 genera of Ascomycota and Basidiomycota. Analysis of evolutionary phylogenetics and phylogenomics indicates that the evolution of SBFS fungi from plant-penetrating ancestors to noninvasive ectophytic parasites was accompanied by a massive contraction of pathogenicity-related genes, including plant cell wall-degrading enzymes and effectors, and an expansion of cuticle-degradation genes. This article reviews progress in understanding SBFS taxonomy and ecology and improving disease management. We also highlight recent breakthroughs in reconstructing the evolutionary origins of these unusual plant pathogens and delineating adaptations to their ectophytic niche.


TREM-1 regulates macrophage polarization in ureteral obstruction.
Chronic kidney disease (CKD) is an emerging worldwide public health problem. Inflammatory cell infiltration and activation during the early stages in injured kidneys is a common pathologic feature of CKD. Here, we determined whether an important inflammatory regulator, triggering receptor expressed on myeloid cells (TREM)-1, is upregulated in renal tissues collected from mouse ureteral obstruction-induced nephritis. TREM-1 is crucial for modulating macrophage polarization, and has a pivotal role in mediating tubular injury and interstitial collagen deposition in obstructive nephritis. Lysates from nephritic kidneys triggered a TREM-1-dependent M1 polarization ex vivo, consistent with the observation that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived M1 macrophages express higher levels of TREM-1 in comparison with M-CSF-derived cells. Moreover, agonistic TREM-1 cross-link significantly strengthens the inductions of iNOS and GM-CSF in M1 cells. These observations are validated by a strong clinical correlation between infiltrating TREM-1-expressing/iNOS-positive macrophages and renal injury in human obstructive nephropathy. Thus, TREM-1 may be a potential diagnostic and therapeutic target in human kidney disease.


Discriminating outer membrane proteins with Fuzzy K-nearest Neighbor algorithms based on the general form of Chou's PseAAC.
Outer membrane proteins (OMPs) play important roles in cell biology. In addition, OMPs are targeted by multiple drugs. The identification of OMPs from genomic sequences and successful prediction of their secondary and tertiary structures is a challenging task due to short membrane-spanning regions with high variation in properties. Therefore, an effective and accurate silico method for discrimination of OMPs from their primary sequences is needed. In this paper, we have analyzed the performance of various machine learning mechanisms for discriminating OMPs such as: Genetic Programming, K-nearest Neighbor, and Fuzzy K-nearest Neighbor (Fuzzy K-NN) in conjunction with discrete methods such as: Amino acid composition, Amphiphilic Pseudo amino acid composition, Split amino acid composition (SAAC), and hybrid versions of these methods. The performance of the classifiers is evaluated by two datasets using 5-fold crossvalidation. After the simulation, we have observed that Fuzzy K-NN using SAAC based-features makes it quite effective in discriminating OMPs. Fuzzy K-NN achieves the highest success rates of 99.00% accuracy for discriminating OMPs from non-OMPs and 98.77% and 98.28% accuracies from α-helix membrane and globular proteins, respectively on dataset1. While on dataset2, Fuzzy K-NN achieves 99.55%, 99.90%, and 99.81% accuracies for discriminating OMPs from non- OMPs, α-helix membrane, and globular proteins, respectively. It is observed that the classification performance of our proposed method is satisfactory and is better than the existing methods. Thus, it might be an effective tool for high throughput innovation of OMPs.


Impact of sex on transcatheter aortic valve replacement outcomes: Results of a single-center study.
Early studies on transcatheter aortic valve replacement (TAVR) outcomes showed that female sex was associated with better survival. With increased use of new-generation valves, the impact of sex on contemporary TAVR outcomes is less well known. Retrospective analysis using institutional National Cardiovascular Data Registry STS/ACC TVT data was performed on all patients undergoing TAVR at Yale New Haven Hospital from July 2012 to August 2019. New-generation valves were Evolut PRO, Evolut R, and SAPIEN 3. Old-generation valves were CoreValve, SAPIEN, and SAPIEN XT. Log-rank test and Kaplan-Meier curves were used to compare sex differences in survival up to 1 year after TAVR. Cox modeling was used to adjust for baseline and procedural characteristic differences. 927 consecutive patients (41% women) underwent TAVR. Women were older (82.8 vs 80.6 years old; p < 0.001) with higher STS mortality scores compared with men (7.6% vs 6.4%; p < 0.001) despite lower prevalence of cardiovascular comorbidities including coronary artery disease, peripheral artery disease, and smoking. Most cases used transfemoral access (90.5%) and new-generation devices (72.3%). Women received smaller valves compared with men (20-26 mm: 78.0% vs 32.9%; 29-34 mm: 22.1% vs 67.1%; overall p < 0.0001). There were no statistically significant differences between sexes in both unadjusted and adjusted 1-year mortality. Our data show no significant difference in 1-year survival between sexes using primarily new generation valves. Further studies should reassess the impact of sex on TAVR outcomes and whether newer technologies like new valve design and sizes, and CT imaging may have eliminated sex-based disparities.


Thermodynamic controls on the kinetics of microbial low-pH Fe(II) oxidation.
Acid mine drainage (AMD) is a major worldwide environmental threat to surface and groundwater quality. Microbial low-pH Fe(II) oxidation could be exploited for cost-effective AMD treatment; however, its use is limited because of uncertainties associated with its rate and ability to remove Fe from solution. We developed a thermodynamic-based framework to evaluate the kinetics of low-pH Fe(II) oxidation. We measured the kinetics of low-pH Fe(II) oxidation at five sites in the Appalachian Coal Basin in the US and three sites in the Iberian Pyrite Belt in Spain and found that the fastest rates of Fe(II) oxidation occurred at the sites with the lowest pH values. Thermodynamic calculations showed that the Gibbs free energy of Fe(II) oxidation (ΔG(oxidation)) was also most negative at the sites with the lowest pH values. We then conducted two series of microbial Fe(II) oxidation experiments in laboratory-scale chemostatic bioreactors operated through a series of pH values (2.1-4.2) and found the same relationships between Fe(II) oxidation kinetics, ΔG(oxidation), and pH. Conditions that favored the fastest rates of Fe(II) oxidation coincided with higher Fe(III) solubility. The solubility of Fe(III) minerals, thus plays an important role on Fe(II) oxidation kinetics. Methods to incorporate microbial low-pH Fe(II) oxidation into active and passive AMD treatment systems are discussed in the context of these findings. This study presents a simplified model that describes the relationship between free energy and microbial kinetics and should be broadly applicable to many biogeochemical systems.


A Cross-National Study of the Gender Gap in Health Among Older Adults in India and China: Similarities and Disparities.
The present cross-sectional study examines gender differences in three major health measures among older adults in India and in China, and investigates whether these differences can be explained by major sociodemographic and health risk characteristics. The study included 7,150 individuals in India and 13,367 individuals in China aged 50-plus who participated in the WHO Study on Global AGEing and Adult Health in 2007-2010. Logistic regression models for self-reported health (SRH) and ordinary least square regression models for grip strength and cognitive function were used to investigate gender differences in health. A consistent female disadvantage was found in India and in China for all three health measures. Compared to their male counterparts, women in the Indian and the Chinese samples had, respectively, 38% (95% confidence interval [CI]: 1.22, 1.56) and 36% (95% CI: 1.25, 1.48) higher risk of reporting poor SRH, 9.56 kg (95% CI: 9.91, 9.22) and 11.95 kg (95% CI: 12.29, 11.62) lower grip strength, and 3.64 (95% CI: 3.96, 3.32) and 1.99 (95% CI: 2.28, 1.71) lower cognitive scores. The magnitude of the female disadvantage in poor SRH and in grip strength changed very little when adjustments were made for marital status, education, place of residence, smoking status, height, and number of chronic conditions; but these characteristics accounted for about 50% of the gender gap in cognitive function. In these study populations, major sociodemographic and health risk characteristics accounted for very small parts of the gender differences in health, except in cognition.


Dihydroceramide:sphinganine C-4-hydroxylation requires Des2 hydroxylase and the membrane form of cytochrome b5.
Des2 (degenerative spermatocyte 2) is a bifunctional enzyme that produces phytoceramide and ceramide from dihydroceramide. The molecular mechanism involved in C-4-hydroxylation has not been studied in detail. In the present paper, we report that C-4-hydroxylation requires an electron-transfer system that includes cytochrome b5 and that the hydroxylase activity is reconstituted in an in vitro assay with purified recombinant Des2. FLAG-tagged mouse Des2 was expressed in insect Sf9 cells and was purified by solubilization with digitonin and anti-FLAG antibody affinity column chromatography. The activity of dihydroceramide:sphinganine C-4-hydroxylase was reconstituted with the purified FLAG-Des2, mb5 (the membrane form of cytochrome b5) and bovine erythrocyte membrane. The apparent K(m) and V(max) of Des2 for the substrate N-octanoylsphinganine were 35 microM and 40 nmol x h(-1) x mg of protein(-1) respectively. The K(m) of the hydroxylase for mb5 was 0.8 microM. Interestingly, mb5 was not replaced with the soluble form of cytochrome b5, which lacks the C-terminal membrane-spanning domain. The erythrocyte membrane was separated into Triton X-100-soluble and -insoluble fractions, and the detergent-soluble fraction was replaced by the soluble or membrane form of b5R (NADH-cytochrome b5 reductase). The Triton-X-100-insoluble fraction contained trypsin-resistant factors. The Des2 protein is found in the endoplasmic reticulum and is assumed to have three membrane-spanning domains. The findings of the present study indicate that the hydroxylation requires complex formation between Des2 and mb5 via their membrane-spanning domains and electron transfer from NADH to the substrate via the reduction of mb5 by b5R.


[Eye involvement in circumscript scleroderma--manifestation of borreliosis?].
The circumscript cutaneous sclerosis is an inflammato-edematous erythema of the skin, usually leading to a plaque-like sclerosis and cutaneous atrophy. The etiology of this disease remains unknown, but some authors presume a systemic infection with Borrelia burgdorferi as the underlying pathological condition. We present a case of a 66-year-old male patient who suffered from episcleritis of his left eye. Funduscopy showed an unilateral papillary edema. Visual acuity was 1.0. The patient had multiple erythemata of the skin of the body-trunk and the arms. On histological examination the lesions were compatible with circumscript sclerosis. Neurological examination was normal. Brain imaging (MRI), CSF examination and serology showed no pathological findings, although the patient presented with raised antibodies against Borrelia burgdorferi (IgG positive, IGM negative). Intravenous antibiotic treatment and topical steroids for three weeks resulted in a complete recovery of the scleritis, but had no effect on the papillary edema. Inflammatory pathological findings of the eye can be associated with circumscript sclerosis, a disease, that is normally limited to the skin. The pathological mechanism remains unclear. The presumption of an underlying borreliosis could not be confirmed in this case.


Screening for psychiatric comorbidity in children with recurrent headache or recurrent abdominal pain.
Recurrent pain symptoms in children are associated with psychiatric comorbidities that could complicate treatment. We investigated the prevalence of psychiatric comorbidity in children with recurrent headache or recurrent abdominal pain and evaluated the screening potential of the Strength and Difficulties Questionnaire compared with the Development and Well-Being Assessment (DAWBA). Eighty-three outpatients aged 5-17 years attending a tertiary medical center for a primary diagnosis of migraine (n = 32), tension-type headache (n = 32), or recurrent abdominal pain (n = 19), and 33 healthy matched controls completed the brief self-reporting Strength and Difficulties Questionnaire followed by the Development and Well-Being Assessment. Findings were compared among groups and between instruments. The pain groups were characterized by a significantly higher number of Development and Well-Being Assessment diagnoses (range 0-11) than controls and a significantly greater prevalence (by category) of Development and Well-Being Assessment diagnoses (P < 0.001 for both). Anxiety and depression were the most prevalent Development and Well-Being Assessment diagnoses. Comorbidities were more severe in the headache groups than the controls (P < 0.001). In general, any diagnosis by the Development and Well-Being Assessment was associated with a significantly higher Strength and Difficulties Questionnaire score (P < 0.001). Abnormal scores on the emotional, conduct, and hyperactivity Strength and Difficulties Questionnaire scales were significantly predictive of a Development and Well-Being Assessment diagnosis (P < 0.003). Children referred to specialized outpatient pediatric units for evaluation of recurrent pain are at high risk of psychopathology. The Strength and Difficulties Questionnaire may serve as a rapid cost-effective tool for initial screening of these patients.


Up-regulation of sphingosine-1-phosphate receptors and sphingosine kinase 1 in the peri-ischemic area after transient middle cerebral artery occlusion in mice.
There is thought to be a strong relationship between sphingosine-1-phosphate (S1P) signaling and pathophysiolosy of cerebral ischemia. We examined the change of expression and distribution of S1P receptors (S1PRs) and sphingosine kinases (SphKs) after cerebral ischemia in male C57BL6/J mice using immunohistochemical analysis at 1, 5, 14, and 28 days after 30 min of transient middle cerebral artery occlusion (tMCAO). S1PR1, 3, and 5 were transiently induced in the cells, which were morphologically similar to neurons in the peri-infarct lesion with a peak seen at 1 day after tMCAO (p < 0.01 vs. sham control). S1PR2 appeared in the inner layer of vessels in the ischemic core (p < 0.01 vs. sham control) and the peri-infarct lesion (p < 0.01 vs. sham control) at the acute phase after tMCAO. However, SphK1 was strongly induced at 1 and 5 days after tMCAO (p < 0.01 vs. sham control) in the peri-infarct lesion, whereas SphK2 expression did not change. Western blot analysis at 1 and 5 days after 30 min of tMCAO revealed that the expression of S1PRs were transiently enhanced at the acute phase, which was consistent with the immunohistochemical results. Double immunofluorescent analysis revealed S1PR2/NG2- and S1PR2/CD31-, S1PR3/CD31-, and S1PR5/CD31-double positive cells in the peri-infarct lesion 1 day after tMCAO. The present results suggest that S1PRs and SphK1 may be important therapeutic targets for rescuing the peri-infarct lesion.


Expanding cerebellar lacunes due to dilatation of the perivascular space associated with Binswanger's subcortical arteriosclerotic encephalopathy.
An 80-year-old hypertensive woman developed right hemiplegia and died 24 hours after admission. Neuropathologic examination revealed multiple cerebral infarcts of various ages and diffuse subcortical arteriosclerotic encephalopathy. Clusters of asymptomatic "expanding" lacunes, due to dilatation of the perivascular spaces, were found in both dentate nuclei. These cavities, which presented as space-occupying lesions, were surrounded by a single layer of flattened cells and contained 1 or more sections of normal-looking arterioles. Such a topographic grouping of lacunes in the dentate nucleus has not been described previously. The mechanism of widening of the perivascular compartment remains unclear; its occurrence in a hypertensive patient and its association with typical Binswanger's subcortical arteriosclerotic encephalopathy and severe atherosclerosis with multiple infarcts suggest a common pathophysiologic mechanism possibly including an alteration of the blood-brain barrier.


Anti-proliferative effect and induction of apoptosis in androgen-independent human prostate cancer cells by 1,5-bis(2-hydroxyphenyl)-1,4-pentadiene-3-one.
Curcumin has poor in vivo absorption and bioavailability, highlighting a need for new curcumin analogues with better characteristics in these aspects. The aim of this study is to determine the anti-cancer properties of four selected curcumin analogues, on the cytotoxicity, proliferative and apoptotic effects on androgen-independent human prostate cancer cells (PC-3 and DU 145). Initial cytotoxicity screening showed MS17 has the highest cell inhibitory effect, with EC50 values of 4.4 ± 0.3 and 4.1 ± 0.8 µM, followed by MS13 (7.5 ± 0.1 and 7.4 ± 2.6 µM), MS49 (14.5 ± 1.2 and 12.3 ± 2.3 µM) and MS40E (28.0 ± 7.8 and 30.3 ± 1.9 µM) for PC-3 and DU 145 cells, respectively. Time-dependent analysis also revealed that MS13 and MS17 displayed a greater anti-proliferative effect than the other compounds. MS17 was chosen based on the high selectivity index value for further analysis on the morphological and biochemical hallmarks of apoptosis. Fluorescence microscopy analysis revealed apoptotic changes in both treated prostate cancer cells. Relative caspase-3 activity increased significantly at 48 h in PC-3 and 12 h in DU 145 cells. Highest enrichment of free nucleosomes was noted at 48 h after treatment with MS17. In conclusion, MS17 demonstrated anti-proliferative effect and induces apoptosis in a time and dose-dependent manner suggesting its potential for development as an anti-cancer agent for androgen-independent prostate cancer.


Importance of aspartate residues in balancing the flexibility and fine-tuning the catalysis of human 3-phosphoglycerate kinase.
The exact role of the metal ion, usually Mg(2+), in the catalysis of human 3-phosphoglycerate kinase, a well-studied two-domain enzyme, has not been clarified. Here we have prepared single and double alanine mutants of the potential metal-binding residues, D374 and D218. While all mutations weaken the catalytic interactions with Mg(2+), they surprisingly strengthen binding of both MgADP and MgATP, and the effects are even more pronounced for ADP and ATP. Thermodynamic parameters of binding indicate an increase in the binding entropy as a reason for the strengthening. In agreement with the experimental results, computer-simulated annealing calculations for the complexes of these mutants have supported the mobility of the nucleotide phosphates and, as a consequence, formation of their new interaction(s) within the active site. A similar type of mobility is suggested to be a characteristic feature of the nucleotide site of the wild-type enzyme, too, both in its inactive open conformation and in the active closed conformation. This mobility of the nucleotide phosphates that is regulated by the aspartate side chains of D218 and D374 through the complexing Mg(2+) is suggested to be essential in enzyme function.


Aerogel: Lightweight Access Control Framework for WebAssembly-Based Bare-Metal IoT Devices.
Application latency requirements, privacy, and security concerns have naturally pushed computing onto smartphone and IoT devices in a decentralized manner. In response to these demands, researchers have developed micro-runtimes for WebAssembly (Wasm) on IoT devices to enable streaming applications to a runtime that can run the target binaries that are independent of the device. However, the migration of Wasm and the associated security research has neglected the urgent needs of access control on bare-metal, memory management unit (MMU)-less IoT devices that are sensing and actuating upon the physical environment. This paper presents Aerogel, an access control framework that addresses security gaps between the bare-metal IoT devices and the Wasm execution environment concerning access control for sensors, actuators, processor energy usage, and memory usage. In particular, we treat the runtime as a multi-tenant environment, where each Wasm-based application is a tenant. We leverage the inherent sandboxing mechanisms of Wasm to enforce the access control policies to sensors and actuators without trusting the bare-metal operating system. We evaluate our approach on a representative IoT development board: a cortex-M4 based development board (nRF52840). Our results show that Aerogel can effectively enforce compute resource and peripheral access control policies while introducing as little as 0.19% to 1.04% runtime overhead and consuming only 18.8% to 45.9% extra energy.


Gene expression profiling of the irinotecan pathway in colorectal cancer.
The exact mechanism responsible for large variation of response to chemotherapy remains unclear. This study profiled the gene expression for the entire irinotecan pathway to provide insights into individualized cancer therapy. The RNA expressions of 24 irinotecan pathway genes were measured in paired tumor and normal tissues from 52 patients with Dukes' C colorectal cancer using a real-time quantitative reverse transcription-PCR assay. The relative expression levels across the 24 pathway genes varied considerably, with a 441-fold range from highest to lowest expression levels for the tumor tissues and a 934-fold range for the normal tissues. Interpatient variability was also quite large, with a 33.6 median fold change in the tumor tissue genes and a 30.1 median fold change in the normal tissue genes. Six of the 24 irinotecan pathway genes had dramatically lower expression levels in the tumor samples than did the genes in the normal tissues (median range, 1.28-4.39 folds; P = 0.001-0.029). Eight genes had significantly higher levels (median range, 1.35-2.42 folds; P = 0.001-0.011). Using hierarchical clustering, three gene clusters and three patient groups were observed with high similarity indices by the RNA expressions in colorectal tumors. The three patient groups had no unique clinical pathologic features but could be differentiated by the statistically significant differences in RNA expression level of seven genes. Our study indicates that gene expression profiling could be valuable for predicting tumor response to chemotherapy and for tailoring therapy to individual cancer patients.


[Illness in the Norwegian team during the Olympic winter games 2006 in Torino].
Illness is of major concern for elite level athletes during championships. Much was done to prevent illness in the Norwegian team during the Olympic Winter Games in Torino 2006. Nevertheless, some athletes became ill. This article discusses illness during the Games from both medical and socio-cultural perspectives. Eight athletes in a team of 74 were not able to compete in one or more competitions, while four or five probably competed with reduced levels of performance. Observations have given the impression that efforts to prevent illness and infection may have adversely affected the performers. Athletes and trainers have confirmed this observation.


High Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols (FODMAP) Consumption Among Endurance Athletes and Relationship to Gastrointestinal Symptoms.
Endurance athletes commonly experience lower gastrointestinal (GI) symptoms similar to those of irritable bowel syndrome (IBS). Previous research on the restriction of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP), a diet-based mitigation strategy initially developed for IBS, has shown promise for application in athlete populations. Athlete's dietary strategies surrounding exercise have not been formally assessed in relation to FODMAP content of foods or sports nutrition products. Additionally, the FODMAP content of athlete's habitual diets has not been examined in larger sample sizes. This research aims to investigate the FODMAP content of endurance athlete diets by examining these three areas, in conjunction with GI symptoms. Dietary habits surrounding exercise and GI symptoms were examined in 430 endurance athletes using a previously validated Endurance Athlete Questionnaire. A subset of athletes (n = 73) completed a FODMAP-specific food frequency questionnaire for habitual intake. The most commonly reported sports nutrition products were analyzed for FODMAP content using standardized analytical methods. Mean habitual intakes were compared to previous FODMAP studies and medians were compared between those with and without lower GI symptoms. Athletes commonly consumed high FODMAP foods during pre-race dinners and breakfasts, with over 60% reporting specific high FODMAP foods. More frequent nutrition product use, particularly solid, gel/gummy, and homemade products, was often related to increased frequency of GI symptoms. Of the sixteen commonly used sports nutrition products tested, seven were high FODMAP in one serving. All but one of the remaining products became high FODMAP when consumed in multiple servings, as is likely the case during endurance exercise. Average habitual FODMAP intake was 26.1 g (±15.9 g), similar to intakes classified as high FODMAP in previous research on FODMAPs and IBS or GI symptoms. Only 15.1% of athletes consumed a diet that would be considered low in FODMAP. Exploratory analyses showed higher intake of some FODMAP types among athletes exhibiting various lower GI symptoms. Overall, this study demonstrated that FODMAP intake by endurance athletes is high both surrounding exercise and habitually, and may be contributing to GI symptoms experienced during exercise. This information can be utilized when analyzing athlete diets and selecting foods to decrease GI symptoms.


Paranoia and conspiracy: group cohesion increases harmful intent attribution in the Trust Game.
Current theories argue that hyper-sensitisation of social threat perception is central to paranoia. Affected people often also report misperceptions of group cohesion (conspiracy) but little is known about the cognitive mechanisms underpinning this conspiracy thinking in live interactions. In a pre-registered experimental study, we used a large-scale game theory approach (N > 1,000) to test whether the social cohesion of an opposing group affects paranoid attributions in a mixed online and lab-based sample. Participants spanning the full population distribution of paranoia played as proposers in a modified Trust Game: they were allocated a bonus and chose how much money to send to a pair of responders which was quadrupled before reaching these responders. Responders decided how much to return to the proposers through the same process. Participants played in one of two conditions: against a cohesive group who communicated and arrived at a joint decision, or a non-cohesive group who made independent decisions. After the exchange, proposers rated the extent to which the responders' decisions were driven by (i) self-interest and (ii) intent to harm. Although the true motives are ambiguous, cohesive responders were reliably rated by participants as being more strongly motivated by intent to harm, indicating that group cohesion affects social threat perception. Highly paranoid participants attributed harmful intent more strongly overall but were equally reactive to social cohesion as other participants. This suggests that paranoia involves a generally lowered threshold for social threat detection but with an intact sensitivity for cohesion-related group characteristics.


The prevalence of overweight and obesity in British Columbian Aboriginal adults.
Overweight and obesity among Aboriginal populations has been a growing challenge within Canada. This investigation aimed to identify the prevalence of overweight and obesity within British Columbian adult Aboriginal populations including both on and off reserve individuals through direct measurement. Further, this study stratified the variations in these rates according to age, gender and geographic region. Weight, height and waist circumference (WC) were measured via standardized procedures, and body mass index (BMI) was calculated. The mean body composition indicators were above recommended for men (BMI = 30.3 ± 5.6 kg m(-2) ; WC = 104.2 ± 14.7 cm) and women (BMI = 30.9 ± 7.2 kg m(-2); WC= 99.3 ± 17.1 cm), respectively. Rates of obesity for men and women were similar, 48.4% and 48.7%, respectively, and showed significant increases with age. Abdominal obesity (AO) was significantly greater among female participants, 69.0% compared with 52.7% in men, while both genders also demonstrated significant increases in AO with age. Both obesity and AO rates were found to be significantly greater in the Northern and Interior regions of the province in comparison to the Vancouver/Lower Mainland region. Alarmingly high rates of obesity and AO were observed in this population in men and women at every age and geographic region.


Identifying alternative hyper-splicing signatures in MG-thymoma by exon arrays.
The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatibility gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches.


[Not Available].
Various factors participate to lower third molar eruption included premolar extractions. In Class II division 1 malocclusion, premolar extractions are sometimes decided to correct antero-posterior malocclusion. Alternative therapies without extractions exist such as DAC appliance. What is the influence on third molar eruption of extractions and non extractions in Class II division 1 malocclusion? We made a study with 60 subjects with Class II division 1 malocclusion: 30 were treated without extractions and 30 were treated with 4 extractions (included second lower premolars). We observed the evolution rate of third lower molars, the movement in the mandible and the modifications on lower arch. Extractions of second lower premolars increase the possibilities of third lower molars eruption (that increase from 10% to 50%). Like in others publications, extractions of second lower premolars, more than the first, may increase significantly the evolution rate of third molars. Nevertheless, inclusion risk is not reduced and is still important (50% in our study) with the probability that the treatment leads at the end to extractions of a quart of dental capital of the patients.


Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson's disease models.
Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.


Connecting occipital alpha band peak frequency, visual temporal resolution, and occipital GABA levels in healthy participants and hepatic encephalopathy patients.
Recent studies have proposed a connection between the individual alpha band peak frequency and the temporal resolution of visual perception in healthy human participants. This connection rests on animal studies describing oscillations in the alpha band as a mode of phasic thalamocortical information transfer for low-level visual stimuli, which critically relies on GABAergic interneurons. Here, we investigated the interplay of these parameters by measuring occipital alpha band peak frequency by means of magnetoencephalography, visual temporal resolution by means of behavioral testing, and occipital GABA levels by means of magnetic resonance spectroscopy. Importantly, we investigated a sample of healthy participants and patients with varying grades of hepatic encephalopathy, which are known to exhibit decreases in the investigated parameters, thus providing an increased parameter space. We found that occipital alpha band peak frequency and visual temporal resolution were positively correlated, i.e., higher occipital alpha band peak frequencies were on average related to a higher temporal resolution. Likewise, occipital alpha band peak frequency correlated positively with occipital GABA levels. However, correlations were significant only when both healthy participants and patients were included in the analysis, thereby indicating a connection of the measures on group level (instead of the individual level). These findings provide new insights into neurophysiological and neurochemical underpinnings of visual perception.


Combined mutagenesis and kinetics characterization of the bilin-binding GAF domain of the protein Slr1393 from the Cyanobacterium Synechocystis PCC6803.
The gene slr1393 from Synechocystis sp. PCC6803 encodes a protein composed of three GAF domains, a PAS domain, and a histidine kinase domain. GAF3 is the sole domain able to bind phycocyanobilin (PCB) as chromophore and to accomplish photochemistry: switching between a red-absorbing parental and a green-absorbing photoproduct state (λmax =649 and 536 nm, respectively). Conversions in both directions were followed by time-resolved absorption spectroscopy with the separately expressed GAF3 domain of Slr1393. Global fit analysis of the recorded absorbance changes yielded three lifetimes (3.2 μs, 390 μs, and 1.5 ms) for the red-to-green conversion, and 1.2 μs, 340 μs, and 1 ms for the green-to-red conversion. In addition to the wild-type (WT) protein, 24 mutated proteins were studied spectroscopically. The design of these site-directed mutations was based on sequence alignments with related proteins and by employing the crystal structure of AnPixJg2 (PDB ID: 3W2Z), a Slr1393 orthologous from Anabaena sp. PCC7120. The structure of AnPixJg2 was also used as template for model building, thus confirming the strong structural similarity between the proteins, and for identifying amino acids to target for mutagenesis. Only amino acids in close proximity to the chromophore were exchanged, as these were considered likely to have an impact on the spectral and dynamic properties. Three groups of mutants were found: some showed absorption features similar to the WT protein, a second group showed modified absorbance properties, and the third group had lost the ability to bind the chromophore. The most unexpected result was obtained for the exchange at residue 532 (N532Y). In vivo assembly yielded a red-absorbing, WT-like protein. Irradiation, however, not only converted it into the green-absorbing form, but also produced a 660 nm, further-red-shifted absorbance band. This photoproduct was fully reversible to the parental form upon green light irradiation.


Toward Multiplexed Optogenetic Circuits.
Owing to its ubiquity and easy availability in nature, light has been widely employed to control complex cellular behaviors. Light-sensitive proteins are the foundation to such diverse and multilevel adaptive regulations in a large range of organisms. Due to their remarkable properties and potential applications in engineered systems, exploration and engineering of natural light-sensitive proteins have significantly contributed to expand optogenetic toolboxes with tailor-made performances in synthetic genetic circuits. Progressively, more complex systems have been designed in which multiple photoreceptors, each sensing its dedicated wavelength, are combined to simultaneously coordinate cellular responses in a single cell. In this review, we highlight recent works and challenges on multiplexed optogenetic circuits in natural and engineered systems for a dynamic regulation breakthrough in biotechnological applications.


A multi-mechanism approach reduces length of stay in the ICU for severe COVID-19 patients.
COVID-19 pandemic has multifaceted presentations with rising evidence of immune-mediated mechanisms underplay. We sought to explore the outcomes of severe COVID-19 patients treated with a multi-mechanism approach (MMA) in addition to standard-of-care (SC) versus patients who only received SC treatment. Data were collected retrospectively for patients admitted to the intensive care unit (ICU). This observational cohort study was performed at five institutions, 3 in the United States and 2 in Honduras. Patients were stratified for MMA vs. SC treatment during ICU stay. MMA treatment consists of widely available medications started immediately upon hospitalization. These interventions target immunomodulation, anticoagulation, viral suppression, and oxygenation. Primary outcomes included in-hospital mortality and length of stay (LOS) for the index hospitalization and were measured using logistic regression. Of 86 patients admitted, 65 (76%) who had severe COVID-19 were included in the study; 30 (46%) patients were in SC group, compared with 35 (54%) patients treated with MMA group. Twelve (40%) patients in the SC group died, compared with 5 (14%) in the MMA group (p-value = 0.01, Chi squared test). After adjustment for gender, age, treatment group, Q-SOFA score, the MMA group had a mean length of stay 8.15 days, when compared with SC group with 13.55 days. ICU length of stay was reduced by a mean of 5.4 days (adjusted for a mean age of 54 years, p-value 0.03) and up to 9 days (unadjusted for mean age), with no significant reduction in overall adjusted mortality rate, where the strongest predictor of mortality was the use of mechanical ventilation. The finding that MMA decreases the average ICU length of stay by 5.4 days and up to 9 days in older patients suggests that implementation of this treatment protocol could allow a healthcare system to manage 60% more COVID-19 patients with the same number of ICU beds.


Z-scheme solar water splitting via self-assembly of photosystem I-catalyst hybrids in thylakoid membranes.
Nature's solar energy converters, the Photosystem I (PSI) and Photosystem II (PSII) reaction center proteins, flawlessly manage photon capture and conversion processes in plants, algae, and cyanobacteria to drive oxygenic water-splitting and carbon fixation. Herein, we utilize the native photosynthetic Z-scheme electron transport chain to drive hydrogen production from thylakoid membranes by directional electron transport to abiotic catalysts bound at the stromal end of PSI. Pt-nanoparticles readily self-assemble with PSI in spinach and cyanobacterial membranes as evidenced by light-driven H2 production in the presence of a mediating electron shuttle protein and the sacrificial electron donor sodium ascorbate. EPR characterization confirms placement of the Pt-nanoparticles on the acceptor end of PSI. In the absence of sacrificial reductant, H2 production at PSI occurs via coupling to light-induced PSII O2 evolution as confirmed by correlation of catalytic activity to the presence or absence of the PSII inhibitor DCMU. To create a more sustainable system, first-row transition metal molecular cobaloxime and nickel diphosphine catalysts were found to perform photocatalysis when bound in situ to cyanobacterial thylakoid membranes. Thus, the self-assembly of abiotic catalysts with photosynthetic membranes demonstrates a tenable method for accomplishing solar overall water splitting to generate H2, a renewable and clean fuel. This work benchmarks a significant advance toward improving photosynthetic efficiency for solar fuel production.


Site of digestion of starch in the gastrointestinal tract of dairy cows and its effect on milk yield and composition.
Physical and chemical processing of feed ingredients and feeding management strategies are major instruments of manipulating amount and site of starch digestion in the gastrointestinal tract. Generally, as rumen escape of starch increases, postruminal starch digestion increases, and there does not appear to be a limitation to intestinal starch digestion. However, the efficiency with which postruminal starch is digested decreases, which represents a limitation that warrants investigation. Even though digestible dietary starch is presented to the intestine, there is no net glucose absorption at the portal vein, and plasma glucose levels remain relatively unaffected. This result may be associated with the large metabolic requirement for postruminally absorbed glucose, which is preferentially used for oxidative metabolism at the visceral tissue level. In addition, peripheral glucose concentration is highly regulated. A possible implication is that the exogenous glucose supply may spare endogenously synthesized glucose for gut metabolism, allowing more to be directed to the mammary gland. Amino acids also may be spared (less metabolism of dietary and tissue amino acids in the gut). Current production studies yield no clear evidence as to the benefits of postruminal digestion of starch to enhance milk yield or to change its composition. However, studies suggest that starch digested postruminally is used more efficiently for milk synthesis than that digested in the rumen.


Impact of Multiple Reprocessing on Properties of Polyhydroxybutyrate and Polypropylene.
Biobased plastics have the potential to be sustainable, but to explore their circularity further, current end-of-life options need to be broadened. Mechanical recycling is one of the most accepted methods to bring back plastics into the loop. Polyhydroxybutyrates (PHBs) are biobased and biodegradable in nature with promising properties and varied applications in the market. This study focuses on their potential for mechanical recycling by multiple extrusion cycles (E1-E5) and multi-faceted characterization of the virgin (V) and reprocessed materials from E1 to E5. The behavior is compared to polypropylene (PP) as a reference with a similar property profile, which has also been reprocessed five times. The thermal properties of both series showed a stable melting point and thermal decomposition temperature from thermal analyses (differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)). However, a steady increase in the degree of crystallinity was observed which could counterbalance the decrease in molecular weight due to repeated extrusion measured by gel permeation chromatography and resulted in similar values of tensile strength across the cycles. The strain at break was impacted after the first extrusion, but no significant change was observed thereafter; the same was observed for impact strength. Even in scanning electron microscopy (SEM) images, virgin and E5 samples appeared similar, showing the stability of morphological characteristics. Fourier transform infrared spectroscopy (FTIR) results revealed that no new groups are being formed even on repeated processing. The deviation between the PHB and PP series was more predominant in the melt mass flow rate (MFR) and rheology studies. There was a drastic drop in the MFR values in PHB from virgin to E5, whereas not much difference was observed for PP throughout the cycles. This observation was corroborated by frequency sweeps conducted with the parallel plate method. The viscosity dropped from virgin to E1 and E2, but from E3 to E5 it presented similar values. This was in contrast to PP, where all the samples from virgin to E5 had the same values of viscosity. This paper highlights the possibilities of mechanical recycling of PHB and explains why future work with the addition of virgin material and other additives is an area to be explored.


Graphical tools for visualizing the results of network meta-analysis of multicomponent interventions.
Network meta-analysis (NMA) is an established method for assessing the comparative efficacy and safety of competing interventions. It is often the case that we deal with interventions that consist of multiple, possibly interacting, components. Examples of interventions' components include characteristics of the intervention, mode (face-to-face, remotely etc.), location (hospital, home etc.), provider (physician, nurse etc.), time of communication (synchronous, asynchronous etc.) and other context related components. Networks of multicomponent interventions are typically sparse and classical NMA inference is not straightforward and prone to confounding. Ideally, we would like to disentangle the effect of each component to find out what works (or does not work). To this aim, we propose novel ways of visualizing the NMA results, describe their use, and illustrate their application in real-life examples. We developed an R package viscomp to produce all the suggested figures.


Sleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-Analysis.
Mounting evidence implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer's disease (AD), but the extent of the risk is uncertain. We conducted a broad systematic review and meta-analysis to quantify the effect of sleep problems/disorders on cognitive impairment and AD. Original published literature assessing any association of sleep problems or disorders with cognitive impairment or AD was identified by searching PubMed, Embase, Web of Science, and the Cochrane library. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. We also estimated the population attributable risk. Twenty-seven observational studies (n = 69216 participants) that provided 52 RR estimates were included in the meta-analysis. Individuals with sleep problems had a 1.55 (95% CI: 1.25-1.93), 1.65 (95% CI: 1.45-1.86), and 3.78 (95% CI: 2.27-6.30) times higher risk of AD, cognitive impairment, and preclinical AD than individuals without sleep problems, respectively. The overall meta-analysis revealed that individuals with sleep problems had a 1.68 (95% CI: 1.51-1.87) times higher risk for the combined outcome of cognitive impairment and/or AD. Approximately 15% of AD in the population may be attributed to sleep problems. This meta-analysis confirmed the association between sleep and cognitive impairment or AD and, for the first time, consolidated the evidence to provide an "average" magnitude of effect. As sleep problems are of a growing concern in the population, these findings are of interest for potential prevention of AD.


Hiring case managers: the role of the candidate and the interviewer.
Interviewing for a job and conducting an interview are two challenging tasks nurse case managers experience at some point in their nursing career. One way to overcome such challenges is through learning more about the interview process. For the nurse case manager, the reward of interviewing well is getting hired for the job; for the interviewer, it is selecting the best candidate for the job. In this article, the author discusses the roles of the candidate and the interviewer in the interview process. It provides those interested in becoming nurse case managers with tips, skills, and strategies for assuring a successful interview. It also presents administrators of case management programs with beneficial recommendations for improving their interviewing skills. In addition, it discusses the interview process for potential candidates for nursing case management roles from the time of preparing the resume and cover letter until after the interview is completed.


Multiobjective optimization approach: thermal food processing.
The objective of this study was to utilize a multiobjective optimization technique for the thermal sterilization of packaged foods. The multiobjective optimization approach used in this study is based on the optimization of well-known aggregating functions by an adaptive random search algorithm. The applicability of the proposed approach was illustrated by solving widely used multiobjective test problems taken from the literature. The numerical results obtained for the multiobjective test problems and for the thermal processing problem show that the proposed approach can be effectively used for solving multiobjective optimization problems arising in the food engineering field.


The effect of nitrate and phosphate availability on Emiliania huxleyi (NZEH) physiology under different CO2 scenarios.
Growth and calcification of the marine coccolithophorid Emiliania huxleyi is affected by ocean acidification and macronutrients limitation and its response varies between strains. Here we investigated the physiological performance of a highly calcified E. huxleyi strain, NZEH, in a multiparametric experiment. Cells were exposed to different CO2 levels (ranging from 250 to 1314 μatm) under three nutrient conditions [nutrient replete (R), nitrate limited (-N), and phosphate limited (-P)]. We focused on calcite and organic carbon quotas and on nitrate and phosphate utilization by analyzing the activity of nitrate reductase (NRase) and alkaline phosphatase (APase), respectively. Particulate inorganic (PIC) and organic (POC) carbon quotas increased with increasing CO2 under R conditions but a different pattern was observed under nutrient limitation. The PIC:POC ratio decreased with increasing CO2 in nutrient limited cultures. Coccolith length increased with CO2 under all nutrient conditions but the coccosphere volume varied depending on the nutrient treatment. Maximum APase activity was found at 561 μatm of CO2 (pH 7.92) in -P cultures and in R conditions, NRase activity increased linearly with CO2. These results suggest that E. huxleyi's competitive ability for nutrient uptake might be altered in future high-CO2 oceans. The combined dataset will be useful in model parameterizations of the carbon cycle and ocean acidification.


Performance evaluation of the Anysis-200 platelet function analyzer in cardiac patients.
Platelet function analysis is crucial in assessing the hemostatic status to evaluate congenital and acquired platelet function defects. The Anysis-200 analyzer is a new automated lab-on-a-chip-based platelet function analyzer. We aimed to evaluate a new platelet function analyzing system, the Anysis-200 in comparison to the Platelet Function Analyzer (PFA)-200 in cardiac patients. Citrated blood was collected from 174 patients who visited the Department of Cardiology. The Anysis-200 consists of two kits, the microchips with collagen and epinephrine-coated membrane (C/EPI) or adenosine diphosphate-coated membrane (C/ADP). Platelet clogging in the Anysis-200 is measured by the blood migration distance obtained by a camera, which is compatible with the closure time in the PFA-200. We performed Anysis-200 and PFA-200 analyzers simultaneously and compared the results. The sensitivity and specificity of the Anysis-200 C/EPI kit in comparison to the PFA-200 C/EPI kit were 63.41% and 91.43%, respectively. Regarding the C/ADP kit, the sensitivity and specificity of the Anysis-200 were 58.97% and 74.29%, respectively. The agreement rate between the Anysis-200 and PFA-200 for C/EPI was 83.35% and 70.14% for C/ADP. The Anysis-200, which applies a novel method to detect platelet clogging, has shown moderate to fair agreement with the PFA-200. This test is potentially useful for screening cardiac patients with an abnormal platelet function.


Macrophages in Skeletal Muscle Dystrophies, An Entangled Partner.
While skeletal muscle remodeling happens throughout life, diseases that result in its dysfunction are accountable for many deaths. Indeed, skeletal muscle is exceptionally capable to respond to stimuli modifying its homeostasis, such as in atrophy, hypertrophy, regeneration and repair. In particular conditions such as genetic diseases (muscular dystrophies), skeletal muscle's capacity to remodel is strongly affected and undergoes continuous cycles of chronic damage. This induces scarring, fatty infiltration, as well as loss of contractibility and of the ability to generate force. In this context, inflammation, primarily mediated by macrophages, plays a central pathogenic role. Macrophages contribute as the primary regulators of inflammation during skeletal muscle regeneration, affecting tissue-resident cells such as myogenic cells and endothelial cells, but also fibro-adipogenic progenitors, which are the main source of the fibro fatty scar. During skeletal muscle regeneration their function is tightly orchestrated, while in dystrophies their fate is strongly disturbed, resulting in chronic inflammation. In this review, we will discuss the latest findings on the role of macrophages in skeletal muscle diseases, and how they are regulated.


Fracture risk associated with common medications used in treating type 2 diabetes mellitus.
Published data on the risk of bone fractures associated with medications used for the treatment of type 2 diabetes mellitus are summarized. A systematic literature search identified 108 publications on controlled trials and 6 meta-analyses addressing the potential for fractures with the use of 7 commonly used antidiabetic classes: thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, biguanides, insulin, and sulfonylureas. Among all the classes of agents evaluated, only TZDs have been clearly linked to significantly increased fracture risk (number needed to harm [NNH], 99 in one meta-analysis and 172 in another meta-analysis) and only in female patients. Interim data from an ongoing large placebo-controlled trial suggest that use of the SGLT2 inhibitor canagliflozin may be associated with an elevated rate of fractures (absolute risk increase, 1.4%; NNH, 71) and decreased total-hip bone mineral density. Published data regarding the other evaluated classes of agents generally show no effect on fracture risk; some evidence suggests a small bone-protective effect with the use of DPP-4 inhibitors. In patients with type 2 diabetes mellitus, evidence is strongest that, among antidiabetic drugs, TZDs increase the risk of bone fractures; thus, TZDs should be used with caution in women. Canagliflozin is the only SGLT2 inhibitor linked to an increased fracture rate. Metformin, sulfonylureas, insulin, DPP-4 inhibitors, and GLP-1 agonists appear to have overall neutral effects on bone fractures.


Pedicle screw fixation with translaminar facet joint screws for the treatment of thoracolumbar fracture.
To evaluate the efficacy of Cotrel-Dubeusset (CD) instrumentation combined with translaminar facet joint screw (TLS) in the treatment of thoracolumbar fracture. A total of six L(2)-L(4) spines were used to establish unstable fracture model with three-dimensional range of motion (ROM) of the spines measured. Fixation with CD and fixation with CD combined with translaminar facet joint screw were achieved to compare their stability. Thirty cases of thoracolumbar fracture, in whom the anterior edge of vertebral body was compressed to 59% and the posterior edge compressed to 88%, were treated by pedicle screw fixation combined with TLS. Among them, 19 received posterolateral or anterior-posterior bone grafting. There was significant difference in ROM between the two techniques except that in extension. In Group CD+TLS, ROM was 5.38% lower, lateral bending 4.91% lower and axial rotation 11.85% lower than those in Group CD respectively. In the clinical group, the average anterior edge restored to 97% and posterior edge to 98%. The duration of follow-up was 5-24 months (mean, 10 months). The rate of correction loss on the anterior edge was 4.5%. Among the 19 cases of bone grafting, all of them achieved bony fusion (mean fusion time, 4.3 month) with a correction loss rate of 3.4%. In the treatment of thoracolumbar fracture, pedicle screw fixation combined with TLS can strengthen the stability of pedicle screws, especially anti-rotation stability and enhance fusion rate and reduce correction loss.


Multiway frequency analysis for experimental psychologists.
Many research designs in experimental psychology generate data that are fundamentally discrete or categorical in nature, and produce multiway tables of frequencies. Despite an extensive and, more recently, accessible literature on the topic, multiway frequency analysis is rarely used in experimental psychology. A reason may be the form of exposition in the literature, with emphases and concerns far removed from those of the typical experimental psychologist. An approach to multiway frequency analysis for experimental psychologists is described that has the features we want: asymmetrical designs, factors assessed for their respective main and interactive effects in a manner analogous to ANOVA, and the ability to handle within-subject designs.


Adverse Events Associated With Synthetic Male Slings: An Analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience Database.
We sought to describe and analyze the adverse events associated with synthetic male slings reported to the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. We queried the MAUDE database for all entries including the terms "Male Sling," "InVance," "Virtue," or "Advance" from January 1st, 2009 to December 31st, 2018. We collected and analyzed information about the event type, date received, report source, source type, and manufacturer. We reviewed and categorized the event description text for each medical device report (MDR). A total of 497 adverse events related to the male sling were identified. The adverse events were classified as injury (95.4%), malfunction (4.2%), and other (0.4%). There were no deaths described. The slings involved were the Advance or Advance XP sling (69.8%), InVance (15.5%), Virtue Quadratic (12.3%), or unknown (2.4%). The 4 most common adverse events described were urinary incontinence (46.7%), sling erosion (9.1%), mechanical malfunction (8.2%), and pain/numbness (8.2%). There was no increase in the number of reports in the years following the FDA warnings for urogynecologic mesh. There was an overall modest number of MDRs related to male slings and the majority of them were reported by the manufacturer. The reporting of adverse events for male slings does not seem to be affected by the controversy and scrutiny towards transvaginal mesh and midurethral slings. Further clinical studies and more objective and detailed databases are needed to investigate the safety of these synthetic slings.


Expression of exogenous LIN28 contributes to proliferation and survival of mouse primary cortical neurons in vitro.
LIN28, an RNA-binding protein, is known to be involved in the regulation of many cellular processes, such as embryonic stem cell proliferation, cell fate succession, developmental timing, and oncogenesis. In this study, we investigated the effect of constitutively expressing exogenous LIN28 on neuronal cell proliferation and viability in vitro. Plasmids containing LIN28-green fluorescent protein (GFP) or GFP were introduced into the embryonic mouse brains at E14.5 by in utero electroporation. Two days after electroporation, embryonic cortices were harvested and cultured. It was found that transfected cells stably overexpressed LIN28 in vitro. Viability curve from live cell imaging showed that the number of GFP-expressing cells decreased over time in line with naive primary cortical neurons. In contrast, the number of LIN28-GFP-overexpressing neurons initially increased and remained high at later time-points in culture than GFP-expressing cells. Double immunofluorescence showed that at an early time in culture, the number of Ki-67/GFP double-positive cells was higher in the LIN28-GFP group than that of controls. Moreover, there were significantly lower numbers of condensed nuclei/GFP- and cleaved caspase-3/GFP-positive cells in the LIN28-GFP groups compared to control GFP. Furthermore, it was confirmed that the LIN28-GFP-expressing cells at days in vitro (DIV)13 were neuronal nuclei (NeuN)-positive mature neurons. Finally, the expression of insulin-like growth factor 2 (IGF-2) was induced in LIN28-expressing primary cortical neurons, which was not detected in controls. Taken together, our results indicate that the expression of exogenous LIN28 can promote the proliferation of neural progenitor cells and exert prosurvival effect on primary cortical neurons by inhibiting caspase-dependent apoptosis, possibly via upregulation of IGF-2.


Metabolic studies in experimental liver disease resulting from D(+)-galactosamine administration.
1. In confirmation of previous work, administration of d(+)-galactosamine (0.5-0.75g/kg body wt.) to rats caused a hepatitis with histological evidence of liver damage and a 9-fold rise in aspartate aminotransferase activity in serum. 2. There was a significant elevation of blood lactate and pyruvate concentrations in 24h-starved rats treated with galactosamine but no change in the [lactate]/[pyruvate] ratio. 3-Hydroxybutyrate and acetoacetate concentrations in blood were decreased. 3. The changes in the concentrations of lactate, pyruvate and ketone bodies in the freeze-clamped liver were parallel to those observed in the blood. 4. In the livers of 24h-starved galactosamine-treated rats there were large increases in the concentrations of alanine (3-fold), citrate (5-fold), 2-oxoglutarate (4-fold), with smaller increases in malate, glutamate and aspartate. There was a 4-fold rise in the value of the mass-action ratio of the alanine aminotransferase system in the livers of galactosamine-treated rats when compared to controls. 5. There was a significant decrease in the activities of aspartate and alanine aminotransferases in the cytoplasm and the soluble fraction of sonicated homogenates of the livers of rats treated with galactosamine. The activity of phosphoenolpyruvate carboxylase was decreased by 75% of the control value. 6. Glucose synthesis from lactate in perfused livers from galactosamine-treated rats was inhibited 39% when compared with controls. 7. The results indicate that the conversion of lactate into glucose is decreased in the livers of galactosamine-treated rats and that this decrease may be due to the loss of phosphoenolpyruvate carboxylase from damaged hepatocytes.


Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction.
In diabetes mellitus, heart failure with preserved ejection fraction (HFPEF) is a significant comorbidity. No therapy is available that improves cardiovascular outcomes. The aim of this study was to characterize myocardial function and ventricular-arterial coupling in a mouse model of diabetes and to analyse the effect of selective heart rate (HR) reduction by If-inhibition in this HFPEF-model. Control mice, diabetic mice (db/db), and db/db mice treated for 4 weeks with the If-inhibitor ivabradine (db/db-Iva) were compared. Aortic distensibility was measured by magnetic resonance imaging. Left ventricular (LV) pressure-volume analysis was performed in isolated working hearts, with biochemical and histological characterization of the cardiac and aortic phenotype. In db/db aortic stiffness and fibrosis were significantly enhanced compared with controls and were prevented by HR reduction in db/db-Iva. Left ventricular end-systolic elastance (Ees) was increased in db/db compared with controls (6.0 ± 1.3 vs. 3.4 ± 1.2 mmHg/µL, P < 0.01), whereas other contractility markers were reduced. Heart rate reduction in db/db-Iva lowered Ees (4.0 ± 1.1 mmHg/µL, P < 0.01), and improved the other contractility parameters. In db/db active relaxation was prolonged and end-diastolic capacitance was lower compared with controls (28 ± 3 vs. 48 ± 8 μL, P < 0.01). These parameters were ameliorated by HR reduction. Neither myocardial fibrosis nor hypertrophy were detected in db/db, whereas titin N2B expression was increased and phosphorylation of phospholamban was reduced both being prevented by HR reduction in db/db-Iva. In db/db, a model of HFPEF, selective HR reduction by If-inhibition improved vascular stiffness, LV contractility, and diastolic function. Therefore, If-inhibition might be a therapeutic concept for HFPEF, if confirmed in humans.


Detection of human bocavirus from children and adults with acute respiratory tract illness in Guangzhou, southern China.
Human bocavirus (HBoV) is a newly discovered parvovirus associated with acute respiratory tract illness (ARTI) and gastrointestinal illness. Our study is the first to analyze the characteristics of HBoV-positive samples from ARTI patients with a wide age distribution from Guangzhou, southern China. Throat swabs (n=2811) were collected and analyzed from children and adults with ARTI over a 13-month period. The HBoV complete genome from a 60 year-old female patient isolate was also determined. HBoV DNA was detected in 65/2811 (2.3%) samples, of which 61/1797 were from children (<18 years old) and 4/1014 from adults (≥18 years old). Seasonal peaks of 4.8% and 7.7% were detected in May and June, respectively. 28 of 65 (43.1%) HBoV-positive samples were co-detected with 11/16 other potential pathogens. Mycoplasma pneumoniae had the highest frequency of 16.9% (11/65). Upper and lower respiratory tract illness were common symptoms, with 19/65 (29.2%) patients diagnosed with pneumonia by chest radiography. All four adult patients had systemic influenza-like symptoms. Phylogenetic analysis of the complete genome revealed a close relationship with other HBoVs, and a more distant relationship with HBoV2 and HBoV3. HBoV was detected from children and adults with ARTI from Guangzhou, southern China. Elderly people were also susceptive to HBoV. A single lineage of HBoV was detected among a wide age distribution of patients with ARTI.


Gefitinib (Iressa, ZD1839): a novel targeted approach for the treatment of solid tumors.
Recent advances in cancer therapy have resulted in the development of drugs that target mechanisms involved in neoplastic change and angiogenesis. One example is gefitinib ('Iressa', ZD1839), an orally-active epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks EGFR signaling in vitro, thereby inhibiting the growth, proliferation and survival of many solid tumors. Clinical trial data show that gefitinib monotherapy is generally well tolerated in patients with a wide range of tumor types (including lung, head and neck, colon, breast, and prostate cancers). The most common adverse events (AEs) were mild and reversible skin and gastrointestinal disorders (National Cancer Institute common toxicity criteria grade 1/2). Few drug-related grade 3/4 skin and gastrointestinal disorders were observed, and drug-related hematologic AEs were uncommon. The clinical benefit of gefitinib in non-small-cell lung cancer (NSCLC), head and neck, colon, breast, and prostate cancer is being investigated, as antitumor activity has been observed in a range of solid tumors, including NSCLC. In two large phase II NSCLC trials (IDEAL ['Iressa' Dose Evaluation in Advanced Lung Cancer] 1 and 2) objective tumor responses of 18.4% and 11.8%, and disease control rates (complete and partial responses plus stable disease) of 54.4% and 42.2%, respectively, were seen in patients given 250 mg/day gefitinib. Additionally, disease-related symptoms improved in 40.3% and 43.1% of patients, and improved quality of life was experienced by 23.9% and 34.3% patients in IDEAL 1 and 2, respectively. Furthermore, the majority of patients who had an objective response also experienced symptom improvement. Gefitinib has been approved for the treatment of advanced NSCLC in Japan, the USA, and other countries. This review discusses the potential of gefitinib in a wide range of solid tumors. 'Iressa' is a trademark of the AstraZeneca group of companies.


Improved neuron protection following cortical injury in the absence of Semaphorin4B.
Injury to the central nervous system induces neuronal cell death and astrogliosis, an astrocyte-mediated response that has both a beneficial and detrimental impact on surrounding neuronal cells. The circumstance however, in which astrogliosis improves neuronal survival after an injury is not fully characterized. We have recently shown that Semaphorin4B (Sema4B) in the cortex is mostly expressed by astrocytes, and in its absence, astrocyte activation after an injury is altered. Here we find that in Sema4B knockout mice, neuronal cell death is reduced; as a result, more neurons survive near the injury site. Sema4B protein applied directly to neurons does not affect neuronal survival. In contrast, survival of wild-type neurons is increased when plated on glial culture isolated from the Sema4B knockout mice, as compared to Sema4B heterozygous cultures. Furthermore, this increased survival is also observed with conditioned medium collected from glial cultures of Sema4B knockout mice compared to heterozygous mice. This indicates that the increased survival is glial cell-dependent and mediated by a secreted factor(s). Together, our results imply that following injury, the lack of Sema4B expression in glial cells improves neuronal survival either as a result of reduced toxic factors, or perhaps increased survival factors under these conditions.


Thymoquinone exerts neuroprotective effect in animal model of Parkinson's disease.
Oxidative stress plays an important role in both the initiation and progression of Parkinson's disease (PD). Rotenone, an environmental toxin, induces oxidative stress and impact mitochondrial dynamics, including fission and fusion. Thymoquinone (TQ) has been reported to have antioxidant and anti-inflammatory characteristics in vitro and in vivo. TQ scavenges free radicals so prevents cell damage against oxidative agents. To evaluate the efficacy of TQ in the management of PD, male Wistar rats (8-10 months) received rotenone. Pre-treatment with TQ (7.5 and 15mg/kg/day, po) one hour prior to the rotenone injection, changed motor tests results (rotarod, rearing and bar tests). Dopamine levels of dopaminergic areas in the substantia nigra (SN) and striatum (ST) measured using high-performance liquid chromatography. Western blot analysis employed to determine the protein contents of Parkin and Drp1 (dynamin-related protein-1) in these areas and in order to identify tyrosine hydroxylase positive cells, Immunohistochemical assays performed. The results indicated that TQ significantly prevented rotenone-induced motor defects and changes in the Parkin, Drp1, dopamine and TH levels in both studied areas. These findings show that TQ effects on ameliorating the PD symptoms induced by rotenone might be associated with the neuroprotective and antioxidant effects of this compound.


Episodic memory function in advanced aging and early Alzheimer's disease.
Despite some well-documented differences, normal aging and Alzheimer's disease (AD) share a number of common neuropathological and neuropsychological features. Many of the reported differences are largely quantitative in nature and there is often overlap between the respective distributions of these populations. To assess the issue of overlap and distinguishing features in memory functions between these groups, and to minimize aging effects per se, samples of older individuals in good health (ages 75-95 yr) and younger patients in the early stages of AD (age < 75 yr) were selected to be similar in global cognitive functioning. Despite comparable language and visuospatial scores, these preliminary results suggest important qualitative differences in episodic memory functions between these conditions, even when "low-functioning" or "at-risk" controls are compared with early AD patients. These findings furthermore highlight some of the challenges in defining "normality" among the oldest segment of our population.


Single-molecule diffusion and conformational dynamics by spatial integration of temporal fluctuations.
Single-molecule localization and tracking has been used to translate spatiotemporal information of individual molecules to map their diffusion behaviours. However, accurate analysis of diffusion behaviours and including other parameters, such as the conformation and size of molecules, remain as limitations to the method. Here, we report a method that addresses the limitations of existing single-molecular localization methods. The method is based on temporal tracking of the cumulative area occupied by molecules. These temporal fluctuations are tied to molecular size, rates of diffusion and conformational changes. By analysing fluorescent nanospheres and double-stranded DNA molecules of different lengths and topological forms, we demonstrate that our cumulative-area method surpasses the conventional single-molecule localization method in terms of the accuracy of determined diffusion coefficients. Furthermore, the cumulative-area method provides conformational relaxation times of structurally flexible chains along with diffusion coefficients, which together are relevant to work in a wide spectrum of scientific fields.


[A problem of biological clocks. New data on the circadian rhythm of the changes in the state of the human body].
Analysis of time-dependent development of various events in man's life (diseases, traumas traffic accidents, normal delivery, death because of diseases) and physiological processes allowed to reveal the presence of intradian cycle in their dynamics with the period about 4-6 hs. At present possible mechanism(s) of this phenomenon is being discussed.


Structure of Mycobacterium tuberculosis glutamine synthetase in complex with a transition-state mimic provides functional insights.
Glutamine synthetase catalyzes the ligation of glutamate and ammonia to form glutamine, with the resulting hydrolysis of ATP. The enzyme is a central component of bacterial nitrogen metabolism and is a potential drug target. Here, we report a high-yield recombinant expression system for glutamine synthetase of Mycobacterium tuberculosis together with a simple purification. The procedure allowed the structure of a complex with a phosphorylated form of the inhibitor methionine sulfoximine, magnesium, and ADP to be solved by molecular replacement and refined at 2.1-A resolution. To our knowledge, this study provides the first reported structure for a taut form of the M. tuberculosis enzyme, similar to that observed for the Salmonella enzyme earlier. The phospho compound, generated in situ by an active enzyme, mimics the phosphorylated tetrahedral adduct at the transition state. Some differences in ligand interactions of the protein with both phosphorylated compound and nucleotide are observed compared with earlier structures; a third metal ion also is found. The importance of these differences in the catalytic mechanism is discussed; the results will help guide the search for specific inhibitors of potential therapeutic interest.


Serum nectin-2 and nectin-4 are diagnostic in lung cancer: which is superior?
Nectins are immunoglobulin-like molecules that are involved in cell to cell adhesion by forming tight junctions and homophilic/heterophilic interactions. This study aimed to analyze serum nectin‑2 and nectin‑4 levels in lung cancer patients and to evaluate the prognostic, diagnostic and predictive strengths. Data from 74 lung cancer patients were retrospectively examined and enzyme-linked immunosorbent assays (ELISA) were used to measure serum nectin‑2 and nectin‑4 concentrations. A total number of 40 age and sex-adjusted healthy controls were also enrolled in the study. The median serum nectin‑2 and nectin‑4 levels of the patients were significantly higher than those of controls (p < 0.001); however, neither biomarker was found to be associated with clinicopathological parameters, (p > 0.05), and furthermore they were found not to be correlated with either overall survival or progression-free survival (p > 0.05). Even though both markers showed high diagnostic values, serum nectin‑2 was found superior to both serum nectin‑4 and serum nectin-2 + nectin‑4 combinations in the diagnosis of lung cancer according to higher sensitivity, specificity and predictive values. Serum nectin‑2 and nectin‑4 might be used in lung cancer diagnosis but the diagnostic importance of nectin‑2 is higher. The prognostic and predictive strengths in cancer are controversial. Furthermore, the interactions with tumor microenvironments and the potentials as therapeutic targets for malignancies have yet to be elucidated.


Applications of aptasensors in clinical diagnostics.
Aptamers are artificial oligonucleotides (DNA or RNA) selected in vitro that bind a broad range of targets with high affinity and specificity; a sensitive yet simple method to utilize aptamers as recognition elements for the development of biosensors (aptasensors) is to transduce the signal electrochemically. So far, aptasensors have been applied to clinical diagnostics and several technologies are in development. Aptasensors will extend the limits of current clinical diagnostics. Although the potential diagnostic applications are unlimited, the most current applications are foreseen in the areas of biomarker detection, cancer clinical testing, detection of infectious microorganisms and viruses. This review attempts to list examples of the research progresses of aptamers in biosensor platforms that have been published in recent years; in particular, we display cases of aptasensors that are already incorporated in clinical diagnostics or have potential applications in clinical diagnostics.


Protection of recombinant mammalian antibodies from development-dependent proteolysis in leaves of Nicotiana benthamiana.
The expression of clinically useful proteins in plants has been bolstered by the development of high-yielding systems for transient protein expression using agroinfiltration. There is a need now to know more about how host plant development and metabolism influence the quantity and quality of recombinant proteins. Endogenous proteolysis is a key determinant of the stability and yield of recombinant proteins in plants. Here we characterised cysteine (C1A) and aspartate (A1) protease profiles in leaves of the widely used expression host Nicotiana benthamiana, in relation with the production of a murine IgG, C5-1, targeted to the cell secretory pathway. Agroinfiltration significantly altered the distribution of C1A and A1 proteases along the leaf age gradient, with a correlation between leaf age and the level of proteolysis in whole-cell and apoplast protein extracts. The co-expression of tomato cystatin SlCYS8, an inhibitor of C1A proteases, alongside C5-1 increased antibody yield by nearly 40% after the usual 6-days incubation period, up to ~3 mg per plant. No positive effect of SlCYS8 was observed in oldest leaves, in line with an increased level of C1A protease activity and a very low expression rate of the inhibitor. By contrast, C5-1 yield was greater by an additional 40% following 8- to 10-days incubations in younger leaves, where high SlCYS8 expression was maintained. These findings confirm that the co-expression of recombinant protease inhibitors is a promising strategy for increasing recombinant protein yields in plants, but that further opportunity exists to improve this approach by addressing the influence of leaf age and proteases of other classes.


Agricultural Soils Amended With Thermally-Dried Anaerobically-Digested Sewage Sludge Showed Increased Risk of Antibiotic Resistance Dissemination.
The application of sewage sludge (SS) to agricultural soil can help meet crop nutrient requirements and enhance soil properties, while reusing an organic by-product. However, SS can be a source of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs), resulting in an increased risk of antibiotic resistance dissemination. We studied the effect of the application of thermally-dried anaerobically-digested SS on (i) soil physicochemical and microbial properties, and (ii) the relative abundance of 85 ARGs and 10 MGE-genes in soil. Soil samples were taken from a variety of SS-amended agricultural fields differing in three factors: dose of application, dosage of application, and elapsed time after the last application. The relative abundance of both ARGs and MGE-genes was higher in SS-amended soils, compared to non-amended soils, particularly in those with a more recent SS application. Some physicochemical parameters (i.e., cation exchange capacity, copper concentration, phosphorus content) were positively correlated with the relative abundance of ARGs and MGE-genes. Sewage sludge application was the key factor to explain the distribution pattern of ARGs and MGE-genes. The 30 most abundant families within the soil prokaryotic community accounted for 66% of the total variation of ARG and MGE-gene relative abundances. Soil prokaryotic α-diversity was negatively correlated with the relative abundance of ARGs and MGE-genes. We concluded that agricultural soils amended with thermally-dried anaerobically-digested sewage sludge showed increased risk of antibiotic resistance dissemination.


Tertiary treatment of domestic wastewater using zeolite ceramics and aquatic plants.
In this study, we examined tertiary treatment of domestic wastewater using zeolite ceramics and aquatic plants, especially reeds, Phragmites australis. The experiment was made at real domestic wastewater treatment facilities, and comparison of treatment performance was made between the method with zeolite ceramics and that with pebble stones as conventional way. SEM observation of the ceramics' surface was also made to examine its possibility as the habitat of bacteria. The results obtained are as follows. Through the tertiary treatment experiment, it was suggested that the water purification system with zeolite ceramics and reeds could keep higher nitrogen removal efficiency for a long time. Zeolite ceramics would be useful when nitrogen compound, NH(4)-N in particular, in the influent was higher. Under SEM observation, bacteria-like objects were observed on the ceramics' surface. Appropriate operation and maintenance would be needed to keep long-term performance of both the NH(4) (+) absorption and nitrogen removal with use of zeolite ceramics.