Protein kinase C involvement in the regulation of angiogenesis.
Using the chick chorioallantoic membrane as a model system for the study of angiogenesis, we have shown that promoters of protein kinase C (PKC) such as 4-beta-phorbol-12-myristate-13-acetate (4-beta-PMA) and 1,2-dioctanoyl-sn-glycerol (DiC8) stimulated angiogenesis. This effect was specific since 4-alpha-PMA and 1,2-dioleoyl-sn-glycerol, which either do not activate or cannot reach PKC, were devoid of angiogenic activity. Furthermore, Ro 31-8220, a specific inhibitor of PKC, suppressed both basal and 4-beta-PMA- or DiC8-induced angiogenesis. Similar results were obtained with the commonly used inhibitor of PKC, 1-(5-isoquinoline-sulfonyl)-2-methylpiperazine and with tricyclodecan-9-yl-xanthogenate, an antitumor agent which has been suggested to be an inhibitor of PKC. Activation of PKC may be, therefore, an important signalling pathway in the initiation and control of the angiogenic response.


Gastrojejunostomy for management of acute proximal enteritis in a horse.
A 5-year-old Arabian stallion was treated medically 6 days for proximal enteritis. On the sixth day, exploratory celiotomy verified the diagnosis and ruled out other intraluminal and extraluminal gastrointestinal tract obstructions. A gastrojejunostomy was performed. The horse had trouble maintaining and gaining weight in the first year after surgery, but 8 years after surgery, the owner reported that the horse was doing well.


Facilitated endogenous repair: making tissue engineering simple, practical, and economical.
Facilitated endogenous repair is a novel approach to tissue engineering that avoids the ex vivo culture of autologous cells and the need for manufactured scaffolds, while minimizing the number and invasiveness of associated clinical procedures. The strategy relies on harnessing the intrinsic regenerative potential of endogenous tissues using molecular stimuli, such as gene transfer, to initiate reparative processes in situ. In the simplest example, direct percutaneous injection of an osteogenic vector is used to stimulate bone healing. If necessary, additional progenitor cells and space-filling scaffolds can be provided by autologous bone marrow, muscle, fat, and perhaps other tissues. These can be harvested, processed, and reimplanted by simple, expedited, intraoperative procedures. Examples of repair of experimental osseous and osteochondral lesions in laboratory animals are described. If successful, these strategies will provide methods for tissue regeneration that are not only effective but also inexpensive, safe, and clinically expeditious. Although orthopaedic examples are given here, the technology should be more generally applicable.


The pathogenesis of ovarian neoplasia.
Currently in the United States intra-abdominal neoplasia involving or originating in the ovary is responsible for the death of 11,000 women per year, or one every 50 minutes. Historically, as well as can be documented, although benign ovarian cysts were common, malignant neoplasia was rare. Furthermore, similar lesions arising in or adjacent to the testes are essentially unknown. The uniqueness of the tumors is appreciated by the recognition of the common cell of origin, but there are many different histologic varieties of neoplasia that may arise therefrom. The differences in incidence between the sexes and the apparent significance of irritants to which the female pelvic cavity may be exposed suggest that such proliferating agents may ascend from the vagina through the patent fallopian tube and into the pelvic and/or the general abdominal cavities. Since little improvement has been made in the overall five-year survival rate during the past 25 years (in spite of the widespread use of chemotherapeutic and other treatment modalities), possibly our basic thrusts should be directed at defining carcinogenic processes and thus preventing the development of such lethal disease.


[Prevalence of iodine- and thyroglobulin-negative findings in differentiated thyroid cancer.A retrospective analysis of patients treated from 1951 to 1998 in university hospital].
The prevalence of iodine- and thyroglobulin-negative findings was evaluated in all patients with differentiated thyroid cancer (DTC) treated from 1961 until 1998 at the Department of Nuclear Medicine, University Hospital Hamburg-Eppendorf. A total of 490 patients with papillary thyroid cancer (PCA) and 242 patients with follicular thyroid cancer (FCA) were analyzed retrospectively. Patients were divided into four groups: 1: no recurrence, 2: recurrent disease, 3: primary metastatic/progressive disease and 4: inconclusive follow-up. Results of iodine scan, serum-TG, and additional imaging modalities as well as histology were compared in all patients. 21/490 (4.3%) of patients with PCA and 16/242 (6.6%) with FCA suffered from recurrent disease. 62/490 (12.7%) of patients with PCA and 59/242 (24.4%) with FCA had primary metastatic/progressive disease. 12/21 patients with PCA and 12/16 with FCA showing up with recurrent disease had a negative iodinescan. 11/21 of patients with PCA and 4/16 with FCA and tumor recurrence had negative serum-TG levels. 14/62 patients with PCA and 14/59 with FCA presenting with primary metastatic/progressive disease had negative iodinescan. 14/62 patients with PCA and 6/59 with FCA had negative serum-TG. The prevalence of iodine-negative recurrent/metastatic disease is in accordance to the literature, whereas the prevalence of TG-negative recurrent/metastatic was noted higher than reported previously. Thus, the commonly used follow-up scheme of DTC is confirmed. However, iodine scan should be regularly performed in patients with high risk of recurrence.


Physiological role of dietary fiber: a ten-year review.
It is accepted nowadays that dietary fiber is an important constituent of the diet. There is growing evidence that the low fiber Western diets and the low consumption of whole grain products are important factors in several common diseases of the large bowel. Cereal fiber differs from that present in vegetables and fruit. A low intake of cereal fiber has been implicated in cancer of the large bowel, diverticular disease of the colon and coronary heart disease. High fiber diets are often prescribed for diabetes. Although fiber consumption by British and American consumers has decreased over the past century, consumption of whole wheat breads and fiber-rich breakfast cereals has received new attention during the past ten years.


[Role of echo-color Doppler in the diagnosis of breast diseases. Personal experience].
The role of color-Doppler US was investigated in the diagnosis of solid focal breast lesions. The results obtained with this method over the last two years were reviewed. Seventy-two patients with solid breast lesions were considered: conventional US scans of the nodules were performed first and color-Doppler scans followed, to depict vascularization. In benign focal lesions color-Doppler US never demonstrated more than a single vascular pole afferent to the lesion. In 92.5% of histologically malignant lesions, color-Doppler US easily demonstrated two or more feeding vessels. The analysis of our series confirmed the presence of a typical vascular pattern related to breast carcinoma which is easy to depict by means of color-Doppler US: this new technique is therefore of great value in the differentiation of benign from malignant breast masses, especially in the cases where conventional US and mammography alone failed to yield unquestionable and final results.


Genome-wide RNA-Seq of Human Motor Neurons Implicates Selective ER Stress Activation in Spinal Muscular Atrophy.
Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. Because this gene is expressed ubiquitously, it remains poorly understood why motor neurons (MNs) are one of the most affected cell types. To address this question, we carried out RNA sequencing studies using fixed, antibody-labeled, and purified MNs produced from control and SMA patient-derived induced pluripotent stem cells (iPSCs). We found SMA-specific changes in MNs, including hyper-activation of the ER stress pathway. Functional studies demonstrated that inhibition of ER stress improves MN survival in vitro even in MNs expressing low SMN. In SMA mice, systemic delivery of an ER stress inhibitor that crosses the blood-brain barrier led to the preservation of spinal cord MNs. Therefore, our study implies that selective activation of ER stress underlies MN death in SMA. Moreover, the approach we have taken would be broadly applicable to the study of disease-prone human cells in heterogeneous cultures.


The relationship of categorical and phonological verbal fluency to negative schizotypy and social functioning in a non-clinical sample.
Research suggests that levels of schizotypy are related to cognitive and social functioning, with negative schizotypy being particularly related to deficits in verbal fluency (VF) and distinct social skills. Considering the possibility that different VF tasks may involve both shared and unique underlying processes, this study sought to examine the separate contributions of categorical and phonological forms of VF to social functioning in those with varying levels of negative schizotypy. Face-to-face interviews were conducted in which 228 college students completed VF tasks, the SPQ-BR, and a social functioning questionnaire. Both phonological and categorical VF were inversely related to levels of negative schizotypy and inversely related to several social functioning domains. High and low levels of negative schizotypy groups were significantly different on elements of social engagement and interpersonal behaviour. In two instances, phonological VF appeared to moderate the relationships between negative schizotypy and specific elements of social functioning. These findings support a general link between verbal processing and social functioning among those with greater negative schizotypy. Possible avenues of future research are discussed.


Circadian rhythm of blood pressure and the relation to cardiovascular events.
Incidences of potentially life-threatening cardiovascular events display a diurnal pattern, tending to be higher in the morning than at other times of day. The recording of blood pressure at pre-defined intervals under everyday circumstances is facilitated by ambulatory blood pressure monitoring (ABPM). This technique shows that systolic and diastolic blood pressures display a circadian rhythm in most individuals. Typically, at the end of the night on arousal, blood pressure surges. This surge coincides with increased cardiovascular events. A recent prospective study conducted in Japan, where the incidence of stroke is high, provides further evidence for the link between cardiovascular events and morning blood pressure surge. Prevalence of both silent ischaemic events and multiple cerebrovascular infarcts was highest among the elderly subjects studied, with the largest increase in blood pressure on awakening. An increased risk of cardiovascular morbidity and mortality is also seen in 'non-dippers' (i.e. individuals in whom the normal nocturnal fall in blood pressure is absent or blunted). ABPM is superior to clinic blood pressure in predicting cardiovascular morbidity and mortality, and this suggests that 24-h blood pressure control may be necessary to gain complete benefit from blood pressure-lowering therapy. Antihypertensive agents with a long duration of action have the potential to provide blood pressure control throughout the dosing interval and thus cover the critical early morning period when the blood pressure surges. Clinical studies that have compared telmisartan with shorter-acting angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors demonstrate that telmisartan has a sustained duration of action, with proven efficacy over the entire 24-h period between doses, including the critical early morning period.


Use of sinoaortic denervation to study the role of baroreceptors in cardiovascular regulation.
To assess the role of arterial baroreceptors in cardiovascular regulation, many studies have used rats in which baroreceptor afferents have been surgically destroyed. However, interpretation of studies using sinoaortic-denervated (SAD) rats is complicated by variability in the extent of baroreceptor denervation. We have compared cardiovascular regulation in rats with total sinoaortic cardiovascular regulation in rats with total sinoaortic denervation, as assessed by the abolition of reflex changes in heart rate (HR) to increases and decreases in arterial pressure (AP), with rats that underwent the same denervation procedure but still had residual (although markedly blunted) reflex changes in HR to changes in AP. In totally SAD rats, the lability of AP was greatly exaggerated compared with sham-denervated rats, although the average AP was equivalent. In contrast, partially SAD rats had elevated AP, and although AP was more labile than in sham-denervated rats, it was less labile than in totally SAD rats. In addition, cardiovascular responses elicited by elimination of neural activity in the nucleus tractus solitarius (NTS) were qualitatively different between the two groups of rats; destruction of the NTS increased AP similarly in partially SAD rats and sham-denervated rats, whereas this treatment did not alter AP in totally SAD rats. Thus there are marked differences in SAD rats with no residual arterial baroreceptor reflex function compared with SAD rats with even a small degree of residual baroreceptor reflex function. These studies highlight the importance of carefully characterizing SAD rats used in studying the role of the baroreceptor reflex in cardiovascular regulation.


Pectin structure and particle size modify carotenoid bioaccessibility and uptake by Caco-2 cells in citrus juices vs. concentrates.
Citrus pectin is known to influence carotenoid bioaccessibility and absorption in humans, but limited attention has been given to the influence of pectin structure related to the particle size from differentially processed citrus food matrices. In this context, this study aims to investigate the nutritional health benefits of an innovative Citrus clementina concentrate, which is a new citrus-based food made by cross-flow microfiltration. This concentrated citrus-based food was selectively enriched 8-fold in β-cryptoxanthin (43-55 μg g-1) and β-carotene (6-9 μg g-1) as well as 6-fold in pectin (376-462 mg per 100 g). The bioaccessibility of pro-vitamin A carotenoids from commercial and fresh clementina juices versus their concentrates was assessed, including the intestinal carotenoid uptake by Caco-2 cells. Differences in particles size and pectin status resulted in a 7-fold increase in the bioaccessibility of carotenoids in industrial products versus fresh products while limiting their cellular uptake in correlation with larger micelle sizes (10.6 nm and 6.82 nm for industrial and fresh concentrates, respectively). Overall, the highest carotenoid bioaccessibility from industrial concentrate was sufficient to offset the lower carotenoid intestinal uptake related to micelle size. This study highlights that the structure of pectins, more specifically their degree of methoxylation, favors carotenoid bioaccessibility but impairs the intestinal absorption of carotenoids from citrus concentrates.


Long- and short-term selective forces on malaria parasite genomes.
Plasmodium parasites, the causal agents of malaria, result in more than 1 million deaths annually. Plasmodium are unicellular eukaryotes with small ∼23 Mb genomes encoding ∼5200 protein-coding genes. The protein-coding genes comprise about half of these genomes. Although evolutionary processes have a significant impact on malaria control, the selective pressures within Plasmodium genomes are poorly understood, particularly in the non-protein-coding portion of the genome. We use evolutionary methods to describe selective processes in both the coding and non-coding regions of these genomes. Based on genome alignments of seven Plasmodium species, we show that protein-coding, intergenic and intronic regions are all subject to purifying selection and we identify 670 conserved non-genic elements. We then use genome-wide polymorphism data from P. falciparum to describe short-term selective processes in this species and identify some candidate genes for balancing (diversifying) selection. Our analyses suggest that there are many functional elements in the non-genic regions of these genomes and that adaptive evolution has occurred more frequently in the protein-coding regions of the genome.


Behavior of Ru-bda Water-Oxidation Catalysts in Low Oxidation States.
The Ru complex [RuII (bda-κ-N2 O2 )(N-NH2 )2 ] (1; bda2- =2,2'-bipyridine-6,6'-dicarboxylate, N-NH2 =4-(pyridin-4-yl)aniline) was used as a synthetic intermediate to prepare new RuII and RuIII bda complexes that contain NO+ , MeCN, or H2 O ligands. In acidic solution complex 1 reacts with an excess of NO+ (generated in situ from sodium nitrite) to form a new Ru complex in which the aryl amine ligand N-NH2 is transformed into a diazonium salt [N-N2+ =4-(pyridin-4-yl)benzenediazonium)] together with the formation of a new Ru(NO) moiety in the equatorial zone, to generate [RuII (bda-κ-N2 O)(NO)(N-N2 )2 ]3+ (23+ ). Here the bda2- ligand binds in a κ-N2 O tridentate manner with a dangling carboxylate group. Similarly, complex 1 can also react with a coordinating solvent, such as MeCN, at room temperature to give [RuII (bda-κ-N2 O)(MeCN)(N-NH2 )2 ] (3). In acidic aqueous solutions, a related reaction occurs in which solvent water coordinates to the Ru center to form {[RuII {bda-κ-(NO)3 }(H2 O)(N-NH3 )2 ](H2 O)n }2+ (42+ ) and is strongly hydrogen-bonded with additional water molecules in the second coordination sphere. Furthermore, under acidic conditions the aniline ligands are also protonated to form the corresponding anilinium cationic ligands N-NH3+ . Additionally, the one-electron oxidized complex {[RuIII {bda-κ-(NO)3.5 }(H2 O)(N-NH3 )2 ](H2 O)n }3+ (53+ ) was characterized, in which the fractional value in the κ notation indicates the presence of an additional contact to the pseudo-octahedral geometry of the Ru center. The coordination modes of the complexes were studied in the solid state and in solution through single-crystal XRD, X-ray absorption spectroscopy, variable-temperature NMR spectroscopy, and DFT calculations. While κ-N2 O is the main coordination mode for 23+ and 3, an equilibrium that involves isomers with κ-N2 O and κ-NO2 coordination modes and neighboring hydrogen-bonded water molecules is observed for 42+ and 53+ .


Urinary markers for measuring exposure to endogenous and exogenous alkylating agents and precursors.
Noninvasive methodologies for measuring carcinogen exposure in humans, based on the use of urinary markers, are being developed and validated for use in molecular epidemiological studies. A range of 3-alkyladenines can be determined in urine samples by an immunoaffinity purification-GC/MS approach [3-methyladenine, 3-ethyladenine, 3-(2-hydroxyethyl)adenine, and 3-benzyladenine]. Using this method, recent results in human subjects suggest that urinary 3-alkyladenines are potentially useful markers of alkylating agent exposure, particularly where the backgrounds of such adducts are much lower than 3-methyladenine. Urinary excretion of S-benzylmercapturic acid has been studied in experimental animals as a marker of exposure to benzylating agents such as N-nitroso-methylbenzylamine. 3-Nitrotyrosine (NTyr) is formed in vivo in tissue or blood proteins after exposure to nitrosating and/or nitrating agents such as tetranitromethane. After turnover of proteins, NTyr is released and excreted in urine as metabolites 3-nitro-4-hydroxy-phenylacetic acid and 3-nitro-4-hydroxyphenylacetic acid, which are determined by GC with a thermal energy analyzer. The sensitivity and specificity, combined with ease of use, of these noninvasive biomonitoring approaches means that they may be readily incorporated into molecular epidemiological studies in which exposure to nitrosating and alkylating agents may be important risk factors.


Interrelationship between chronic kidney disease and risk of cardiovascular diseases.
An estimated 11% of the U.S. population has chronic kidney disease (CKD). Cardiovascular morbidity and mortality remain high among individuals with CKD and the higher mortality from cardiovascular disease persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of cardiovascular disease in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. Given the high cardiovascular morbidity and mortality, patients with CKD should be a target for aggressive cardiovascular risk reduction.


Neurocognitive and behavioral significance of periodic limb movements during sleep in adolescents with attention-deficit/hyperactivity disorder.
The purpose of this study is to examine the association of abnormal periodic limb movements during sleep (PLMS) with neurocognitive and behavioral outcomes in adolescents with attention-deficit/hyperactivity disorder (ADHD) from the general population. Four hundred twenty-one adolescents (17.0 ± 2.3 years, 53.9% male) from the Penn State Child Cohort, a random general population sample, underwent 9 hr polysomnography, clinical history, physical examination, neurocognitive evaluation, and completed the Child or Adult Behavioral Checklist (C/ABCL). The presence of ADHD was ascertained by parent- or self-report of receiving a diagnosis of ADHD. PLMS were defined as a PLM index (PLMI) of ≥5 events per hour of sleep. Adolescents with ADHD (n = 98) had a significantly higher PLMI (5.4 ± 7.3) and prevalence of PLMS (35%) when compared with controls (3.4 ± 5.6, p = 0.006 and 21%, p = 0.004). Significant interactions between ADHD and PLMS showed that adolescents with both disorders (n = 35) were characterized by deficits in control interference, as measured by Stroop test, and elevated internalizing behaviors, as measured by C/ABCL. ADHD severity and externalizing behaviors were elevated in a dose-response manner across ADHD-alone (n = 63) and ADHD + PLMS groups. The association of ADHD with other neurocognitive functions did not vary as a function of PLMS. PLMS are significantly more frequent in adolescents with ADHD. Importantly, adolescents with both disorders not only have worse neurobehavioral functioning than adolescents with ADHD-alone but specifically presented with executive deficits and anxiety symptoms. These data suggest that PLMS may be a marker of more severe underlying neurobiological deficits in adolescents with ADHD and comorbid internalizing problems.


Platelet functions and energy metabolism in a patient with hexokinase deficiency.
We have studied the regeneration of adenosine triphosphate (ATP) in the glycolytic pathway in platelets with a 75% reduction in hexokinase (HK) activity and have investigated aggregation and Ca2+ secretion. HK-deficient platelets had a normal glycolytic flux in the resting state, but responded insufficiently to stimulation with thrombin (5 U/ml). In contrast, glycogen contents and glycogenolysis were normal. When the metabolic adenine nucleotides were labeled with 14C-adenine, the patient's platelets showed a normal adenylate energy charge and a normal level of 14C-ATP. However, the inhibitor of mitochondrial energy generation, CN-, induced a weaker fall in 14C-ATP in the patient's platelets than in the controls. Analysis of secretion markers revealed decreased amounts of granule-bound ATP and secretable Ca2+, whereas granule-bound adenosine diphosphate (ADP), beta-thromboglobulin, N-acetyl-beta-D-glucosaminidase, and beta-glucuronidase were within the normal range. Aggregation and Ca2+ secretion induced by 5 U/ml thrombin were normal and were not changed in the presence of inhibitors of mitochondrial and glycogenolytic energy generation. Aggregation was also normal at 0.1 U/ml thrombin and was independent of these inhibitors, but Ca2+ secretion was greatly impaired when mitochondrial and glycogenolytic ATP resynthesis was abolished. These findings indicate that a severe reduction in HK activity causes insufficient acceleration of the glycolytic flux during stimulation with thrombin. This leads to impaired dense granule secretion in conditions where secretion depends on concurrent ATP resynthesis and glycolysis is rate limiting.


Guided tissue engineering for healing of cancellous and cortical bone using a combination of biomaterial based scaffolding and local bone active molecule delivery.
A metaphyseal bone defect due to infection, tumor or fracture leads to loss of cancellous and cortical bone. An animal model separating the cancellous and cortical healing was used with a combination of a macroporous gelatin-calcium sulphate-hydroxyapatite (Gel-CaS-HA) biomaterial as a cancellous defect filler, and a thin collagen membrane (CM) guiding cortical bone regeneration. The membrane was immobilized with bone morphogenic protein-2 (rhBMP-2) to enhance the osteoinductive properties. The Gel-CaS-HA cancellous defect filler contained both rhBMP-2 and a bisphosphonate, (zoledronate = ZA) to prevent premature callus resorption induced by the pro-osteoclast effect of rhBMP-2 alone. In the first part of the study, the CM delivering both rhBMP-2 and ZA was tested in a muscle pouch model in rats and the co-delivery of rhBMP-2 and ZA via the CM resulted in higher amounts of bone compared to rhBMP-2 alone. Secondly, an established tibia defect model in rats was used to study cortical and cancellous bone regeneration. The defect was left empty, filled with Gel-CaS-HA alone, Gel-CaS-HA immobilized with ZA or Gel-CaS-HA immobilized with rhBMP-2+ZA. Functionalization of the Gel-CaS-HA scaffold with bioactive molecules produced significantly more bone in the cancellous defect and its surroundings but cortical defect healing was delayed likely due to the protrusion of the Gel-CaS-HA into the cortical bone. To guide cortical regeneration, the cortical defect was sealed endosteally by a CM with or without rhBMP-2. Subsequently, the cancellous defect was filled with Gel-CaS-HA containing ZA and rhBMP-2+ZA. In the groups where the CM was doped with rhBMP-2, significantly higher number of cortices bridged. The approach to guide cancellous as well as cortical bone regeneration separately in a metaphyseal defect using two bioactive molecule immobilized biomaterials is promising and could improve the clinical care of patients with metaphyseal defects.


Shikonin promotes adriamycin‑induced apoptosis by upregulating caspase‑3 and caspase‑8 in osteosarcoma.
Osteosarcoma is the most common primary malignant bone tumor. Cancer cells employ a host of mechanisms to develop resistance to adriamycin (ADM) or other chemotherapeutic drugs. Shikonin (SK), an active constituent extracted from a Chinese medicinal herb, has been shown to cooperate with ADM in the treatment of osteosarcoma and certain other types of cancer by contributing to the response rate of chemotherapy and the side effects. The aim of the present study was to investigate the role and underlying mechanism of SK in chemotherapy for osteosarcoma. In the present study, a CCK-8 assay was performed to assess cell survival rate in vitro. Western blot analysis was performed to determine the expression levels of B‑cell lymphoma 2‑associated X protein (Bax), caspase‑3, caspase‑8, and poly (ADP‑ribose) polymerase (PARP). Flow cytometry was used to analyze cell cycle and cell death. The survival rate of cells decreased significantly in a dose‑ and time‑dependent manner when treated with a combination of SK and ADM. Western blot analysis revealed increased expression levels of Bax, caspase‑3, caspase‑8 and PARP in U2OS and MG63 cells 48 h following treatment with SK and ADM. Flow cytometric analysis showed that the combined treatment of SK and ADM significantly induced apoptosis in the osteosarcoma cells. Taken together SK cooperated with ADM to promote apoptosis, possibly by inducing caspase‑3‑ and caspase‑8‑dependent apoptosis. SK may be a potential enhancer in the treatment of drug‑resistant primary osteosarcoma.


Validation of two-pool model for in vivo ketone body kinetics.
Previous studies have indicated that simultaneous infusions of two ketone body tracers ([13C]acetoacetate and [14C]beta-hydroxybutyrate) provide accurate estimates of exogenous ketone body inflow when an open two-pool model is employed. In the present studies, net hepatic ketone body production was determined from surgically placed arterial, portal venous, and hepatic venous catheters in conscious diabetic (n = 6) and 4-day fasted (n = 7) dogs. [13C]acetoacetate and [14C]beta-hydroxybutyrate were infused simultaneously, and ketone body production was calculated from either acetoacetate (AcAc) single-isotope data, beta-hydroxybutyrate (beta-OHB) single-isotope data, the sum of individual fluxes, or the two-pool model. In fasted animals, both the AcAc single-isotope calculation and the sum of individual fluxes overestimated net hepatic production by approximately 50% (P less than 0.05), whereas the beta-OHB single-isotope calculation and the two-pool model gave accurate estimates. In the diabetic animals, the beta-OHB single-isotope calculation underestimated net hepatic production by approximately 30% (P less than 0.05). The sum of individual fluxes overestimated net hepatic production by approximately 46% (P less than 0.05), whereas both the AcAc single-isotope calculation and the two-pool model gave accurate estimates. In conclusion, single-isotope methods give erroneous estimates of net hepatic production of ketone bodies. In contrast, a two-pool model provided an accurate estimate of net hepatic production and thus appears to be suitable for determination of ketone body kinetics in humans.


Targeted ablation of oligodendrocytes triggers axonal damage.
Glial dysfunction has been implicated in a number of neurodegenerative diseases. In this study we investigated the consequences of glial and oligodendrocyte ablation on neuronal integrity and survival in Drosophila and adult mice, respectively. Targeted genetic ablation of glia was achieved in the adult Drosophila nervous system using the GAL80-GAL4 system. In mice, oligodendrocytes were depleted by the injection of diphtheria toxin in MOGi-Cre/iDTR double transgenic animals. Acute depletion of oligodendrocytes induced axonal injury, but did not cause neuronal cell death in mice. Ablation of glia in adult flies triggered neuronal apoptosis and resulted in a marked reduction in motor performance and lifespan. Our study shows that the targeted depletion of glia triggers secondary neurotoxicity and underscores the central contribution of glia to neuronal homeostasis. The models used in this study provide valuable systems for the investigation of therapeutic strategies to prevent axonal or neuronal damage.


Intermittent high glucose implements stress-induced senescence in human vascular endothelial cells: role of superoxide production by NADPH oxidase.
Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis. Endothelial cellular senescence is reported to precede atherosclerosis. We reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus. In the present study, we evaluated the effect of fluctuating glucose levels on human endothelial senescence. Constant high glucose increased senescence-associated-β-galactosidase (SA-β-gal) activity, a widely used marker for cellular senescence. Interestingly, in intermittent high glucose, this effect was more pronounced as well as increase of p21 and p16INK4a , senescence related proteins with DNA damage. However, telomerase was not activated and telomere length was not shortened, thus stress-induced senescence was shown. However, constant high glucose activated telomerase and shortened telomere length, which suggested replicative senescence. Intermittent but not constant high glucose strikingly up-regulated the expression of p22phox, an NADPH oxidase component, increasing superoxide. The small interfering RNA of p22phox undermined the increase in SA-β-gal activity induced by intermittent high glucose. Conclusively, intermittent high glucose can promote vascular endothelial senescence more than constant high glucose, which is in partially dependent on superoxide overproduction.


Structure of P-protein of the glycine cleavage system: implications for nonketotic hyperglycinemia.
The crystal structure of the P-protein of the glycine cleavage system from Thermus thermophilus HB8 has been determined. This is the first reported crystal structure of a P-protein, and it reveals that P-proteins do not involve the alpha(2)-type active dimer universally observed in the evolutionarily related pyridoxal 5'-phosphate (PLP)-dependent enzymes. Instead, novel alphabeta-type dimers associate to form an alpha(2)beta(2) tetramer, where the alpha- and beta-subunits are structurally similar and appear to have arisen by gene duplication and subsequent divergence with a loss of one active site. The binding of PLP to the apoenzyme induces large open-closed conformational changes, with residues moving up to 13.5 A. The structure of the complex formed by the holoenzyme bound to an inhibitor, (aminooxy)acetate, suggests residues that may be responsible for substrate recognition. The molecular surface around the lipoamide-binding channel shows conservation of positively charged residues, which are possibly involved in complex formation with the H-protein. These results provide insights into the molecular basis of nonketotic hyperglycinemia.


Optical trapping of gold microparticles using linearly polarized, centrally obstructed Gaussian beams.
Metallic microparticles larger than the illumination wavelength are commonly considered poor optical trapping candidates due to their high extinction coefficient. This paper presents a numerical and experimental study on the three-dimensional (3D) trapping of gold microparticles using a centrally obstructed Gaussian beam based on the T-matrix method. The range of particle size for stable optical trapping is determined. For the trapping numerical aperture of 1.32 and illumination wavelength of 1.064 µm, numerical analysis proves that 3D trapping of gold microparticles with a radius bigger than 1.0 µm can be readily achieved. By imprinting a digital lens to the spatial light modulator, we slightly defocus the centrally obstructed Gaussian beam to shift the trapping location to the focal plane for clear observation. Experimental results demonstrate stable trapping of gold microparticles with a radius greater than 1.4 µm at high-power illumination, agreeing well with the theoretical predictions. The presented work should be of interest to the community applying metallic microparticles to relevant research.


Spatial decorrelation in orientation-selective cortical cells.
We propose a model for the lateral connectivity of orientation-selective cells in the visual cortex. We study the properties of the input signal to the visual cortex and find new statistical structures that have not been processed in the retino-geniculate pathway. Using the idea that the system performs redundancy reduction of the incoming signals, we derive the lateral connectivity that will achieve this for a set of orientation-selective local circuits, as well as the complete spatial structure of a network composed of such circuits. We compare the results with various physiological measurements.


Resorbable Synthetic Meshes for Abdominal Wall Defects in Preclinical Setting: A Literature Review.
Prosthetic materials for the repair of abdominal wall defects have been studied extensively to improve outcome. A new approach can be the use of a slowly resorbable synthetic mesh, which aims to combine advantages of both synthetic and biological meshes. The objective of this review is to give an overview of the physicochemical characteristics and biomechanical, histological, and macroscopic outcome (recurrence, adhesion formation) of the use of resorbable synthetic meshes, for treatment and prevention of abdominal wall hernias, based on experimental studies. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only experimental studies were included. Outcome parameters were resorption, degradation, organization of connective tissue, inflammatory response, tensile strength, and amount of adhesion formation. Surgical characteristics were taken into account as well (type of defect, clean versus contaminated model, position mesh, repair of the defect, recurrences). In total, eleven articles were included. Three absorbable synthetic meshes are currently available: GORE BIO-A mesh (Gore), TIGR Matrix Surgical mesh (Novus Scientific), and Phasix mesh (Bard). Two studies concluded that, despite an early transient inflammatory reaction in the first months, remodeling was good in GORE BIO-A, 6-12 mo after augmentation or suture line reinforcement with only minimal to moderate adhesions when used intraperitoneally. The TIGR Matrix Surgical mesh shows only partial remodeling with a persistent foreign body reaction after 1 y. Phasix mesh seems to perform well in extraperitoneal implantation after 1 y in two studies, although the defect was small. Only two studies directly compared two resorbable synthetic meshes under the same circumstances. The latter also included a number of animals where the meshes were used in a contaminated nonhernia model. No hernia recurrences or deaths of animals were described in all studies. The use of resorbable synthetic meshes in the prevention or treatment of abdominal wall defects in animal experiments with small defects in clean setting seems safe, with no serious complications related to the device during short-term follow-up. However, there is no evidence available that can support the advantages of resorbable synthetic meshes over the use of synthetic or biological meshes, mostly due to lack of good data. More experimental studies are needed, followed by randomized controlled trials and prospective registries in humans with a sufficiently long follow-up period, to reveal the potential advantages in clinical practice.


Structural analysis of high-dimensional basins of attraction.
We propose an efficient Monte Carlo method for the computation of the volumes of high-dimensional bodies with arbitrary shape. We start with a region of known volume within the interior of the manifold and then use the multistate Bennett acceptance-ratio method to compute the dimensionless free-energy difference between a series of equilibrium simulations performed within this object. The method produces results that are in excellent agreement with thermodynamic integration, as well as a direct estimate of the associated statistical uncertainties. The histogram method also allows us to directly obtain an estimate of the interior radial probability density profile, thus yielding useful insight into the structural properties of such a high-dimensional body. We illustrate the method by analyzing the effect of structural disorder on the basins of attraction of mechanically stable packings of soft repulsive spheres.


Cardiac muscle ring finger-1 increases susceptibility to heart failure in vivo.
Muscle ring finger (MuRF)1 is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates and heterodimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal, whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy, indicating cooperative control of muscle mass by MuRF1 and MuRF2. To identify the unique role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg(+)) hearts exhibited a nonprogressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by transaortic constriction (TAC) induced rapid failure of MuRF1 Tg(+) hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg(+) hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg(+) mice did not differ from wild-type mice despite the depressed contractility following TAC. In comparing the level and activity of creatine kinase (CK) between wild-type and MuRF1 Tg(+) hearts, we found that mCK and CK-M/B protein levels were unaffected in MuRF1 Tg(+) hearts; however, total CK activity was significantly inhibited. We conclude that increased expression of cardiac MuRF1 results in a broad disruption of primary metabolic functions, including alterations in CK activity that leads to increased susceptibility to heart failure following TAC. This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo.


Quality of life of adult retinoblastoma survivors in the Netherlands.
To assess the quality of life (QoL) and predictors thereof in Dutch adult hereditary and non-hereditary retinoblastoma (RB) survivors. In this population-based cross-sectional study, a generic QoL questionnaire (SF-36) and a disease-specific interview were administered to 87 adult RB survivors aged 18 to 35 years. Their QoL data were compared with those of a Dutch healthy reference group. Among the RB hereditary/non-hereditary survivors, the QoL was compared and predictors for QoL were identified by linear multiple regression analyses. As a group, RB survivors scored significantly lower than the reference group on the SF-36 subscale 'mental health' (t = -27, df = 86, p < 0.01). Hereditary RB survivors scored lower on the subscale 'general health' (t = 2.6, df = 85, p < 0.01) than non-hereditary RB survivors. Having experienced bullying, as a child was a predictor for the SF-36 subscales: 'physical functioning' (p < 0.05), 'role functioning physical' (p < 0.01), 'role functioning emotional' (p < 0.05) and 'social functioning' (p < 0.01). Having experienced bullying (p < 0.01), but also subjective experience of impairment related to RB (p < 0.05), was predictors for 'general health'. Subjective experience of impairment was a predictor for 'vitality' (p < 0.01) and 'bodily pain' (p < 0.01). In this exploratory study, it appears that the group of adult RB survivors experience a relatively good overall but slightly decreased QoL compared with the reference group. However, they report more problems with regard to their mental health (anxiety, feelings of depression, and loss of control). Hereditary RB survivors differ significantly from non-hereditary RB survivors only in 'general health'. Bullying in childhood and subjective experience of impairment are the main predictors of a worse QoL. In order to prevent worsening of QoL, or perhaps to improve it, clinicians should make an inventory of these issues at an early stage. We recommend further research to assess the specific psychological factors that may lead to mental health problems in this population.


[Subarachnoidal anesthesia in patients with concomitant diseases of the cardiovascular system].
Age-related changes limit blood circulatory reserves in vital organs, by increasing the risk of ischemic and hypoxic lesions. Patients from a peripheral vascular surgery department form a high cardiac risk group. Subarachnoidal anesthesia is the most optimal anesthetic support (if there are no absolute contraindications) during operations for lower extremity varicose veins. Thirty patients operated on for this condition were examined to solve the problem associated with the effectiveness and safety of this method of anesthesia and to define the pattern of hemodynamic rearrangement more precisely. All the patients had concomitant cardiovascular diseases, which forced them to be referred to as ASA Classes III-IV. The authors monitored basic hemodynamic parameters, such as systolic blood pressure (BP), diastolic BP, mean BP (BP(mean)), heart rate, and cardiac output, by using a noninvasive procedure by means of a computer equipped with a Doppler flowmetric transducer, and ST-segment changes by ECG). The values of total and specific peripheral vascular resistance and cardiac index were estimated by a calculating method. Analysis of hemodynamic changes revealed no significant differences between the groups of elderly and senile patients. On examination, all the patients were divided into 2 groups by the type of circulation: 1) those with eukinetic circulation and 2) those with hypokinetic circulation. Hyperkinetic circulation was not found in the study groups of patients. The patients with cardiac disease were observed to have increased vascular resistance, in those with hypokinetic circulation, this increase being more marked (p < 0.05). In addition, ST-segment had a more stable position in patients with hypokinetic circulation. There was a great scatter in ST-segment changes in patients with eukinetic circulation in the presence of decreased peripheral resistance under preganglionic sympathetic block. With the described changes, noteworthy was the stability of BP(mean) values that did not decreased below the critical ones. This fact permitted the authors to state that the compensatory reserves of the cardiovascular system were preserved under subarachnoidal blockade, which in turn suggests the effectiveness and safety of the used anesthetic procedure.


Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study.
To test the hypothesis that strict control of diabetes during pregnancy can reduce the risk for neonatal hypocalcemia in infants of diabetic mothers. One hundred thirty-seven pregnant women with insulin-dependent diabetes enrolled before 9 weeks' gestation were randomized to one of two treatment groups. In 68 subjects, the goals were fasting blood glucose level less than 4.44 mmol/L (80 mg/dL) and 1.5-hour postprandial blood glucose level less than 6.66 mmol/L (120 mg/dL) (strict control), whereas in 69 the goals were fasting blood glucose level less than 5.55 mmol/L (100 mg/dL) and 1.5-hour post-prandial glucose level less than 7.77 mmol/L (140 mg/dL) (customary control). Infants in the strict control group had a significantly lower rate of hypocalcemia (mean calcium less than 8.0 mg/dL in term infants and less than 7.0 mg/dL in preterm infants) than infants in the customary control group (17.6 versus 31.9%; P < .05). Using logistic regression analysis and after adjusting for the effects of gestational age, asphyxia, and White class on hypocalcemia, the difference between groups remained significant. The lowest infant serum calcium concentration correlated significantly with maternal glycohemoglobin A1 concentration at delivery (P = .03), gestational age (P = .0001), and the lowest serum magnesium concentration (P = .0001). Strict management of diabetes in pregnancy is associated with a reduction in the rate of neonatal hypocalcemia.


The evolution of site-selection strategy during dispersal.
We propose a mathematical model that enables the evolutionary analysis of site-selection process of dispersing individuals that encounter sites of high or low quality. Since each site can be inhabited by at most one individual, all dispersers are not able to obtain a high-quality site. We study the evolutionary dynamics of the low-quality-site acceptance as a function of the time during the dispersal season using adaptive dynamics. We show that environmental changes affect the evolutionary dynamics in two ways: directly and indirectly via density-dependent factors. Direct evolutionary effects usually follow intuition, whereas indirect effects are often counter-intuitive and hence difficult to predict without mechanistic modeling. Therefore, the mechanistic derivation of the fitness function, with careful attention on density- and frequency dependence, is essential for predicting the consequences of environmental changes to site selection. For example, increasing fecundity in high-quality sites makes them more tempting for dispersers and hence the direct effect of this ecological change delays the acceptance of low-quality sites. However, increasing fecundity in high-quality sites also increases the population size, which makes the competition for sites more severe and thus, as an indirect effect, forces evolution to favor less picky individuals. Our results indicate that the indirect effects often dominate the intuitive effects, which emphasizes the need for mechanistic models of the immigration process.


Development of a Community-Based e-Health Program for Older Adults With Chronic Diseases: Pilot Pre-Post Study.
Chronic diseases may impact older adults' health outcomes, health care costs, and quality of life. Self-management is expected to encourage individuals to make autonomous decisions, adhere to treatment plans, deal with emotional and social consequences, and provide choices for healthy lifestyle. New eHealth solutions significantly increase the health literacy and empower patients in self-management of chronic conditions. This study aims to develop a Community-Based e-Health Program (CeHP) for older adults with chronic diseases and conduct a pilot evaluation. A pilot study with a 2-group pre- and posttest repeated measures design was adopted. Community-dwelling older adults with chronic diseases were recruited from senior activity centers in Singapore. A systematic 3-step process of developing CeHP was coupled with a smart-device application. The development of the CeHP intervention consists of theoretical framework, client-centric participatory action research process, content validity assessment, and pilot testing. Self-reported survey questionnaires and health outcomes were measured before and after the CeHP. The instruments used were the Self-care of Chronic Illness Inventory (SCCII), Healthy Aging Instrument (HAI), Short-Form Health Literacy Scale, 12 Items (HLS-SF 12), Patient Empowerment Scale (PES), and Social Support Questionnaire, 6 items. The following health outcomes were measured: Montreal Cognitive Assessment, Symbol Digit Modalities Test, total cholesterol (TC), high-density lipoproteins, low-density lipoproteins/very-low-density lipoproteins (LDL/VLDL), fasting glucose, glycated hemoglobin (HbA1c), and BMI. The CeHP consists of health education, monitoring, and an advisory system for older adults to manage their chronic conditions. It is an 8-week intensive program, including face-to-face and eHealth (Care4Senior App) sessions. Care4Senior App covers health education topics focusing on the management of hypertension, hyperlipidemia, and diabetes, brain health, healthy diet, lifestyle modification, medication adherence, exercise, and mindfulness practice. Content validity assessment indicated that the content of the CeHP is valid, with a content validity index (CVI) ranging 0.86-1 and a scale-CVI of 1. Eight participants in the CeHP group and 4 in the control group completed both baseline and post intervention assessments. Participants in the CeHP group showed improvements in fasting glucose, HbA1c, TC, LDL/VLDL, BMI, SCCII indices (Maintenance, Monitoring, and Management), HAI, and PES scores post intervention, although these changes were not significant. For the participants in the control group, the scores for SCCII (management and confidence) and HLS-SF 12 decreased post intervention. The CeHP is feasible, and it engages and empowers community-dwelling older adults to manage their chronic conditions. The rigorous process of program development and pilot evaluation provided valid evidence to expand the CeHP to a larger-scale implementation to encourage self-management, reduce debilitating complications of poorly controlled chronic diseases, promote healthy longevity and social support, and reduce health care costs.


Associations between neighborhood socioeconomic status, parental education, and executive system activation in youth.
Socioeconomic status (SES) can impact cognitive performance, including working memory (WM). As executive systems that support WM undergo functional neurodevelopment during adolescence, environmental stressors at both individual and community levels may influence cognitive outcomes. Here, we sought to examine how SES at the neighborhood and family level impacts task-related activation of the executive system during adolescence and determine whether this effect mediates the relationship between SES and WM performance. To address these questions, we studied 1,150 youths (age 8-23) that completed a fractal n-back WM task during functional magnetic resonance imaging at 3T as part of the Philadelphia Neurodevelopmental Cohort. We found that both higher neighborhood SES and parental education were associated with greater activation of the executive system to WM load, including the bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and precuneus. The association of neighborhood SES remained significant when controlling for task performance, or related factors like exposure to traumatic events. Furthermore, high-dimensional multivariate mediation analysis identified distinct patterns of brain activity within the executive system that significantly mediated the relationship between measures of SES and task performance. These findings underscore the importance of multilevel environmental factors in shaping executive system function and WM in youth.


Assessment of the Utility of Ictal Magnetoencephalography in the Localization of the Epileptic Seizure Onset Zone.
Literature on ictal magnetoencephalography (MEG) in clinical practice and the relationship to other modalities is limited because of the brevity of routine studies. To investigate the utility and reliability of ictal MEG in the localization of the epileptogenic zone. A retrospective medical record review and prospective analysis of a novel ictal rhythm analysis method was conducted at a tertiary epilepsy center with a wide base of referrals for epilepsy surgery evaluation and included consecutive cases of patients who experienced epileptic seizures during routine MEG studies from March 2008 to February 2012. A total of 377 studies screened. Data were analyzed from November 2011 to October 2015. Presurgical workup and interictal and ictal MEG data were reviewed. The localizing value of using extended-source localization of a narrow band identified visually at onset was analyzed. Of the 44 included patients, the mean (SD) age at the time of recording was 19.3 (14.9) years, and 25 (57%) were male. The mean duration of recording was 51.2 minutes. Seizures were provoked by known triggers in 3 patients and were spontaneous otherwise. Twenty-five patients (57%) had 1 seizure, 6 (14%) had 2, and 13 (30%) had 3 or more. Magnetoencephalography single equivalent current dipole analysis was possible in 29 patients (66%), of whom 8 (28%) had no clear interictal discharges. Sublobar concordance between ictal and interictal dipoles was seen in 18 of 21 patients (86%). Three patients (7%) showed clear ictal MEG patterns without electroencephalography changes. Ictal MEG dipoles correlated with the lobe of onset in 7 of 8 patients (88%) who underwent intracranial electroencephalography evaluations. Reasons for failure to identify ictal dipoles included diffuse or poor dipolar ictal patterns, no MEG changes, and movement artifact. Resection of areas containing a minimum-norm estimate of a narrow band at onset, not single equivalent current dipole, was associated with sustained seizure freedom. Ictal MEG data can provide reliable localization, including in cases that are difficult to localize by other modalities. These findings support the use of extended-source localization for seizures recorded during MEG.


Multiple mucosal lesions in the duodenum: exploring the potential clinical backgrounds and concurrent diseases.
Multiple mucosal lesions of the duodenum (MMLD), presenting with multiple mucosal redness and ulcers with or without blood clots in the proximal duodenum, may be occasionally discovered during gastroduodenal endoscopy. This study was undertaken to investigate the clinical implications of MMLD. Endoscopic pictures and charts of patients with MMLD were retrospectively reviewed. The endoscopic features of MMLD were recorded for both location and severity. The endoscopic severity of MMLD was defined as follows: Grade I: multiple mucosal redness; Grade II: multiple ulcers with clear base; Grade III: multiple ulcers with reddish base or fresh blood clot coating. A total of 229 (1.08%) MMLD events in 207 patients were identified out of a total of 21,223 upper gastrointestinal endoscopies. Common backgrounds of patients with MMLD included diabetes, hypertension, and some chemical exposure, such as cigarettes, alcohol, nonsteroidal anti-inflammatory drugs and anti-Helicobacter pyloric regimens. Common concurrent diseases included peptic disease, sepsis, malignancy, renal insufficiency, and portal hypertension. MMLD associated with sepsis usually involved only the second portion of the duodenum, but when associated with nonsteroidal anti-inflammatory drugs was less often only involved with the second portion. MMLD with renal insufficiency was less prone to involve the bulb alone. Diabetes-related MMLD tended to present with mild severity as defined by Grade I, H. pylori infection with Grade II, and renal insufficiency and portal hypertension with higher severity such as Grade III. Nine patients had fatal outcomes due to uncontrolled concurrent diseases, other than MMLD. MMLD, an uncommon occurrence in endoscopy, can develop from several clinical settings. When encountering MMLD while performing endoscopy, the best policy is to search and correct the concurrent diseases as early as possible.


Modeling riverine nitrate export from an East-Central Illinois watershed using SWAT.
Reliable water quality models are needed to forecast the water quality consequences of different agricultural nutrient management scenarios. In this study, the Soil and Water Assessment Tool (SWAT), version 2000, was applied to simulate streamflow, riverine nitrate (NO(3)) export, crop yield, and watershed nitrogen (N) budgets in the upper Embarras River (UER) watershed in east-central Illinois, which has extensive maize-soybean cultivation, large N fertilizer input, and extensive tile drainage. During the calibration (1994-2002) and validation (1985-1993) periods, SWAT simulated monthly and annual stream flows with Nash-Sutcliffe coefficients (E) ranging from 0.67 to 0.94 and R(2) from 0.75 to 0.95. For monthly and annual NO(3) loads, E ranged from -0.16 to 0.45 and R(2) from 0.36 to 0.74. Annual maize and soybean yields were simulated with relative errors ranging from -10 to 6%. The model was then used to predict the changes in NO(3) output with N fertilizer application rates 10 to 50% lower than original application rates in UER. The calibrated SWAT predicted a 10 to 43% decrease in NO(3) export from UER and a 6 to 38% reduction in maize yield in response to the reduction in N fertilizer. The SWAT model markedly overestimated NO(3) export during major wet periods. Moreover, SWAT estimated soybean N fixation rates considerably greater than literature values, and some simulated changes in the N cycle in response to fertilizer reduction seemed to be unrealistic. Improving these aspects of SWAT could lead to more reliable predictions in the water quality outcomes of nutrient management practices in tile-drained watersheds.


Structural characterization of a mixed-linkage glucan deficient mutant reveals alteration in cellulose microfibril orientation in rice coleoptile mesophyll cell walls.
The CELLULOSE SYNTHASE-LIKE F6 (CslF6) gene was previously shown to mediate the biosynthesis of mixed-linkage glucan (MLG), a cell wall polysaccharide that is hypothesized to be tightly associated with cellulose and also have a role in cell expansion in the primary cell wall of young seedlings in grass species. We have recently shown that loss-of-function cslf6 rice mutants do not accumulate MLG in most vegetative tissues. Despite the absence of a structurally important polymer, MLG, these mutants are unexpectedly viable and only show a moderate growth compromise compared to wild type. Therefore these mutants are ideal biological systems to test the current grass cell wall model. In order to gain a better understanding of the role of MLG in the primary wall, we performed in-depth compositional and structural analyses of the cell walls of 3 day-old rice seedlings using various biochemical and novel microspectroscopic approaches. We found that cellulose content as well as matrix polysaccharide composition was not significantly altered in the MLG deficient mutant. However, we observed a significant change in cellulose microfibril bundle organization in mesophyll cell walls of the cslf6 mutant. Using synchrotron source Fourier Transform Mid-Infrared (FTM-IR) Spectromicroscopy for high-resolution imaging, we determined that the bonds associated with cellulose and arabinoxylan, another major component of the primary cell walls of grasses, were in a lower energy configuration compared to wild type, suggesting a slightly weaker primary wall in MLG deficient mesophyll cells. Taken together, these results suggest that MLG may influence cellulose deposition in mesophyll cell walls without significantly affecting anisotropic growth thus challenging MLG importance in cell wall expansion.


Cultured human corneal epithelial stem/progenitor cells derived from the corneal limbus.
Stem/progenitor cells of the human corneal epithelium are present in the human corneal limbus, and several corneal epithelial stem/progenitor cell markers have been reported. Recently, the neurotrophin family receptors were reported to be useful markers of corneal epithelial stem/progenitor cells. Therefore, we examined an enzymatic separation method for obtaining corneal epithelial stem/progenitor cells and measuring the change in the expression of low-affinity neurotrophin receptor p75 (p75(NTR)), a receptor belonging to the neurotrophin family. As a result, it was found that our separation method preserved cell viability. Furthermore, p75(NTR) was mainly observed in epithelial basal cells as were the corneal epithelial stem/progenitor markers p63 and integrin β1. p75(NTR) was also observed in the cultured cells, but its frequency decreased with passage. In conclusion, we propose that our culture method will enable the culture of corneal stem cells and that it is a useful tool for elucidating the molecular basis of the niche that is necessary for the maintenance of epithelial stem cells in the corneal limbus. Furthermore, we conclude that p75(NTR) is a useful cell marker for evaluating the characteristics of stem/progenitor cells in culture.


Deinstitutionalization, social rejection, and the self-esteem of former mental patients.
Modified labeling theorists have long argued that the stigma of mental illness has important consequences for the lives of people with mental illness. We propose that social rejection is an enduring force in the lives of people with mental illness and that these experiences are central to understanding the poor self-concepts described by many former psychiatric patients. We explore changes in a cohort of recently deinstitutionalized mental patients' (N = 88) self-esteem and experiences with social rejection using data from a three wave panel survey conducted while institutionalized and over a two-year period following the patients' discharge from a long-term state hospital. Our results indicate that social rejection is a persistent source of social stress for the discharged patients. Moreover, these experiences increase feelings of self-deprecation that, in turn, weaken their sense of mastery. Where the patients' received their follow-up care--whether in a community setting or in another state hospital--had little impact on their self-related feelings or on their experiences of social rejection. Our results provide further support for modified labeling theory and underscore the need to consider the dynamic relationship between stigmatizing experiences and self-related changes.


Obliterative Bronchiolitis.
Obliterative bronchiolitis (OB) is a clinical syndrome marked by progressive dyspnea and cough with the absence of parenchymal lung disease on radiographic studies. Pulmonary function testing reveals an obstructive ventilatory defect that is typically not reversed by inhaled bronchodilator. Transbronchial biopsies are insufficiently sensitive to achieve diagnosis, and in most cases, clinical, physiological, and radiological data obviate the need for the increased risk associated with open lung biopsy. This diagnosis has been documented in a variety of exposures, including fumes from flavoring plants, smoke from burn pits, and environmental sulfur gas. Among lung transplant recipients, "bronchiolitis obliterans syndrome," a disorder with clinical and histopathological similarity to OB, represents the leading cause of long-term allograft dysfunction and mortality. After hematopoietic stem cell transplantation, chronic graft versus host disease of the lung manifests most frequently with similar clinical and pathological features. In all circumstances, immunologic and nonimmunologic mechanisms are thought to lead to airway epithelial dysfunction, which results in progressive airflow obstruction and debility. Augmentation of immunosuppression is occasionally effective in slowing or reversing the progression of disease though a significant number of patients will be nonresponders. Other immunomodulatory methods have been attempted in each circumstance where this pathology has been identified. Unfortunately, OB is poorly understood and often results in sufficient progression of disease to warrant evaluation for lung transplantation (or retransplantation). Here, we review what is known regarding pathophysiology and discuss clinical, pathological, radiological, and therapeutic factors associated with the spectrum of OB-related disease with a particular focus on lung transplantation.


Patterns of duodenal osmolality in young pigs fed solid food.
Duodenal hypertonicity can induce satiety, but whether duodenal osmolality varies during eating enough to influence meal size is not clear. To find out more about this, duodenal samples were taken via implanted catheters from 10 young pigs under three feeding conditions. 1) The pigs were fasted 4-5 h and then given a meal with drinking water available. Duodenal osmolality rose from a premeal level of 297 mosmol/kgH2O to a peak of 430 mosmol/kgH2O at 35 min after the meal began and then returned to the premeal level after 2.2 h. 2) When pigs were similarly fasted and then given a meal, but with no drinking water available during and after the meal, osmolality rose to 418 mosmol/kgH2O after 35 min and only returned to premeal levels after 4.2 h. 3) Finally, when pigs were allowed to eat and drink spontaneously, osmolality rose from a mean of 281 to only 308 mosmol/kgH2O after meals, in part because of water drinking in association with meals and in part because the spontaneous meals were smaller. The results demonstrate that duodenal osmolality can rise significantly after meals but that hyperosmolality is moderated by water drinking.


Molecular control of oogenesis.
Oogenesis is a complex process regulated by a vast number of intra- and extra-ovarian factors. Oogonia, which originate from primordial germ cells, proliferate by mitosis and form primary oocytes that arrest at the prophase stage of the first meiotic division until they are fully-grown. Within primary oocytes, synthesis and accumulation of RNAs and proteins throughout oogenesis are essential for oocyte growth and maturation; and moreover, crucial for developing into a viable embryo after fertilization. Oocyte meiotic and developmental competence is gained in a gradual and sequential manner during folliculogenesis and is related to the fact that the oocyte grows in interaction with its companion somatic cells. Communication between oocyte and its surrounding granulosa cells is vital, both for oocyte development and for granulosa cells differentiation. Oocytes depend on differentiated cumulus cells, which provide them with nutrients and regulatory signals needed to promote oocyte nuclear and cytoplasmic maturation and consequently the acquisition of developmental competence.The purpose of this article is to summarize recent knowledge on the molecular aspects of oogenesis and oocyte maturation, and the crucial role of cumulus-cell interactions, highlighting the valuable contribution of experimental evidences obtained in animal models. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.


Quantitative proteomics reveals unique responses to antimicrobial treatments in clinical Pseudomonas aeruginosa isolates.
Pseudomonas aeruginosa is an important pathogen often associated with hospital-acquired infections and chronic lung infections in people with cystic fibrosis. P. aeruginosa possesses a wide array of intrinsic and adaptive mechanisms of antibiotic resistance, and the regulation of these mechanisms is complex. Label-free quantitative proteomics is a powerful tool to compare susceptible and resistant strains of bacteria and their responses to antibiotic treatments. Here we compare the proteomes of three isolates of P. aeruginosa with different antibiotic resistance profiles in response to five challenge conditions. We uncover unique and shared proteome changes for the widely used laboratory strain PAO1 and two isolates of the Liverpool epidemic strain of P. aeruginosa, LESlike1 and LESB58. Our data set provides insight into antibiotic resistance in clinically relevant Pseudomonas isolates and highlights proteins, including those with uncharacterized functions, which can be further investigated for their role in adaptive responses to antibiotic treatments.


The Nicotiana attenuata LECTIN RECEPTOR KINASE 1 is involved in the perception of insect feeding.
The Nicotiana attenuata LECTIN RECEPTOR KINASE 1 (LecRK1) has been recently identified as a component of the mechanism used by plants to suppress the Manduca sexta-triggered accumulation of salicylic acid (SA). The suppression of the SA burst by LecRK1 allows for the unfettered induction of jasmonic acid (JA)-mediated defense responses against M. sexta herbivory. LecRK1 contains a multi-domain extracellular region composed of a G-type Lectin domain and a PAN-AP domain separated by a variable sequence with low similarity to an EGF domain. The LecRK1 intracellular region is composed of a single domain structure with predicted Ser/Thr protein kinase activity. The multi-domain structure of the extracellular region of LecRK1 adds a level of complexity in terms of the potential ligands that this receptor protein could recognize.


[Forming of the Pavlov pouch changes functional condition of the adherent mucosal layer in upper regions of the digestive tract].
In result of forming the Pavlov small gaster, secretion of pepsine in isolated part and, probable, in other parts of the gaster, was increased. This entailed a decrease in the pepsin sorption level on the luminal surface of adherent mucous layer of the gaster parts and intestine under study. This led to a drop of the level of structure glycoproteins and to increase in the per cent contents of polymeric glycoproteins in the whole pool of the mucous layer glycoproteins. The data obtained suggest that forming of the Pavlov small gaster indices significant changes of the adherent mucous layer structure-functional condition both in the gaster and in lower parts of the intestine.


Recurrent Cerebral Infarction Due to Moyamoya Disease Complicated With Systemic Lupus Erythematosus: A Case Report and Literature Review.
We report a rare case of moyamoya disease caused by an RNF213 mutation, complicated with systemic lupus erythematosus. A 32-year-old woman experienced 4 cerebral ischemia stroke events within 6 months. The main symptom was left limb weakness with blurred vision in the right eye. Results of digital subtraction angiography conducted at another hospital were consistent with moyamoya disease. On genetic testing, we found that the patient carried 2 mutations in the moyamoya disease-related gene RNF213 (p.R4810K, p.T1727M). On the basis of the laboratory immunologic indicators, such as positive antibodies and abnormal immunoglobulin levels and imaging examinations, the patient was finally diagnosed as moyamoya disease complicated with systemic lupus erythematosus. She was treated with aspirin, butylphthalide, urinary kallidinogenase, and sodium methylprednisolone. This was a 32-year-old young patient diagnosed with moyamoya disease carrying RNF213 gene mutation and accompanied by lupus with cerebral ischemic event as the first occurrence. The patient's condition was complex; therefore, comprehensive analysis and in-depth consideration were needed to avoid a missed diagnosis and misdiagnosis. When the primary disease cannot be identified, genetic testing can help to clarify the diagnosis of moyamoya disease.


Silencing of MBD1 reverses pancreatic cancer therapy resistance through inhibition of DNA damage repair.
High resistance to traditional chemo- and radiotherapies contributes to the poor prognosis of pancreatic cancer (PC). Methyl-CpG binding domain protein 1 (MBD1), which plays an important role in disease progression, contributes to the drug resistance of PC cells; however, the mechanism underlying the drug resistance endowed by MBD1 remains unknown. In this study, we found that MBD1 was recruited to DNA damage sites under DNA damage conditions. Silencing of MBD1 significantly impaired activation of the DNA damage checkpoint response and inhibited DNA repair capacity. MBD1 binds mediator of DNA damage checkpoint protein 1 (MDC1), which is induced by radiation and regulates NBS1 activation in the presence of DNA damage repair. Knockdown of MBD1 significantly increased the sensitivity of cells to radiation and cisplatin (diamindichloridoplatin, DDP) in vitro. Importantly, the function of MBD1 in regulating chemoradioresistance is also partially dependent on DNA damage repair. Thus, we hypothesize that MBD1 may promote PC chemoradioresistance by regulating PC cell fate in the presence of DNA damage. Collectively, these findings reveal an important function of MBD1 in DNA repair and mediation of chemoradioresistance of cancer cells. Moreover, this study suggests that MBD1 is a promising molecular target for sensitizing resistant PC tumor cells to chemoradiotherapy.


Phosphoinositide 3-kinase signalling events controlling axonal morphogenesis.
The establishment of neuronal morphology is essential for the formation of the nervous system. In general, neurons undergo a developmental programme during which their immature processes are specified into one axon and several dendrites. Extension of axons and dendrites is then critical for the establishment of appropriate connectivity. A body of work implicates the PI3K (phosphoinositide 3-kinase) signalling pathway to be crucial during the various events leading to the formation of neuronal circuit. In this review, we will focus specifically on the function of PI3K and downstream signalling cascades that control the establishment of axonal specification and elongation.


STUDIES IN RESPIROMETRY : I. A COMBINED GAS BURETTE-INTERFEROMETER RESPIROMETER.
A machine has been described which combines volumetric and refractometric means of observing changes in carbon dioxide and oxygen concentrations and amounts in a closed system suitable for containing a respiring system. A means of thermoregulation has been described briefly. The theory upon which estimation is based has been outlined in considerable detail and generality; indicating how dependence upon absorption of gases by reagents can be eliminated completely, although they may be used in certain instances as a means of independent check. An experiment of this nature has been reported as an illustration of one use of the machine. Data of other experiments in which a moist environment was employed for the respiring system will be given in another communication.


Quality of life and measures of asthma control in primary health care.
To study quality of life and asthma control in primary care. A total of 1,477 patients 15 to 45 years of age received questionnaires regarding asthma control (77% responded) and quality of life, Mini Asthma Quality of Life Questionnaire (MiniAQLQ), (74% responded). Patients using short-acting beta-agonists more than twice in the last week had clinically significant lower MiniAQLQ scores (5.17 versus 5.91). This finding was consistent for night awakenings during the previous week (4.42 versus 5.86), courses of oral corticosteroids (4.82 versus 5.69), and reported emergency consultations during the last 6 months (4.85 versus 5.71). Good asthma control is associated with better quality of life in asthma patients in primary care.


Pain management in sickle cell disease: palliative care begins at birth?
People with sickle cell disease (SCD) are living longer, but their lives are impacted even more by the unpredictable intermittent or constant pain that is often poorly managed over a lifetime. To address this problem, an interdisciplinary team approach is needed that brings the medical professionals together for optimal compassionate care that is coordinated from the beginning of life and throughout the patient's lifespan.The hematologist, whenever possible, should take the lead. Effective models that have been developed to address SCD pain, such as the Day Hospital, The Recidivism Project and various Home Care models, need to be integrated into an overarching plan on a continuum with an underpinning philosophy that will sustain such a program. While the focus of palliative care has been end of life, its philosophies fit the chronic disease model and support an integrated team approach to the SCD pain management dilemma. The patient-focused and family-oriented interventions can be modeled to fit "any place, any time," outpatient, inpatient or the home, with homecare and other support systems. Such are the needs in SCD: appropriate, timely and compassionate care to prevent or relieve suffering and to preserve dignity, meaning, value and quality of life with improvement that is translational from birth until the end of life.


Association between PNPLA3 rs738409 G variant and MRI cerebrovascular disease biomarkers.
Nonalcoholic fatty liver disease (NAFLD) has been associated with greater cerebral white matter hyperintensity (WMH) volume and microbleeds. The adiponutrin (PNPLA3) rs738409 G variant, a robust NAFLD susceptibility variant, has been variably associated with carotid atherosclerosis. We hypothesized that this variant is associated with WMH volume, microbleeds, covert brain infarction (CBI), and small perivascular spaces. We performed a cross-sectional analysis of the Northern Manhattan Study-MRI Substudy. The associations between the rs738409 G variant allele and outcomes were assessed using linear regression for WMH volume, logistic regression for microbleeds and CBI, and Poisson regression for small perivascular spaces. Models were adjusted for age, sex, principal components, diabetes, and body mass index. We included 1063 Northern Manhattan Study participants who had brain MRI and genotype data available (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%. The prevalence of any microbleeds and CBI were 8% and 18%, respectively. The median WMH volume and small perivascular space count score were 7.7 mL and 6, respectively. GG homozygosity, but not heterozygosity, was associated with WMH volume (β = 0.27; 95% CI, 0.03, 0.51) compared to non-carriers. Having at least one G allele was associated with the presence of microbleeds (Odds ratio, 1.78; 95% CI, 1.02, 3.12); the association was attenuated in other models. No associations were observed for CBI and small perivascular spaces. The PNPLA3 rs738409 G allele was associated with greater WMH volume, and inconsistent associations with microbleeds were seen.


Biomarkers and community-acquired pneumonia: tailoring management with biological data.
Community-acquired pneumonia (CAP) is the leading cause of death from infectious diseases worldwide, with an incidence of 0.3 to 0.5% in the adult population. A new diagnostic and prognostic approach relies on evaluation of biomarkers as an expression of the host's inflammatory response against the microorganism. C-reactive protein (CRP), procalcitonin (PCT), and cytokines are the most frequently studied, whereas pro-adrenomedullin (pro-ADM), pro-vasopressin (pro-VNP), and others are currently obtaining promising results. Their usefulness for diagnosis is limited, although PCT has been successfully used to guide prescription of antibiotics in patients with suspected CAP. Nevertheless, the accuracy of PCT in distinguishing between bacterial or viral infection and safely withholding antibiotics in CAP is the subject of debate. Analysis of systemic biomarkers in addition to clinical scores [Pneumonia Severity Index (PSI) or CURB-65 (confusion, urea, respiratory, blood pressure, >65 years)/CRB-65 (confusion, respiratory, blood pressure)] has been shown to improve 30 day mortality prediction and absence of severe complications. Pro-ADM is probably the biomarker that correlates most strongly with mortality prediction. During treatment, ~15% of hospitalized CAP patients develop treatment failure, and almost 6% may manifest rapidly progressive pneumonia. Initially increased and persistent raised levels of biomarkers and cytokines have been shown to identify patients at risk of treatment failure, thereby aiding clinical management. Data from the literature appear to support the use of biomarkers in routine clinical practice to improve the decision making in CAP.


[Experimental studies on inhibitory effects of radix Peucedani on hypoxic pulmonary hypertension in rats].
Light microscopic and morphometric methods along with the measurement of right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RBHI) were performed by the authors in studying the inhibitory effects of Radix Peucedani (RP) on structural remodeling of intraacinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT) in hypoxic rats. The results showed that, RP could not only antagonize IAPA contraction caused by hypoxia and lower the resistance of pulmonary circulation, inhibit the cell proliferation and hypertrophy of adventitial cells of pulmonary artery, but also reverse the change in structure and function of pulmonary artery. It suggests that RA plays a key role in inhibiting hypoxic structural remodeling of IAPA and pulmonary hypertension.


Ultrasonic Surgical Aspirate is a Reliable Source For Culturing Glioblastoma Stem Cells.
Glioma stem cells (GSCs) are thought to be the source of tumor growth and therapy resistance. To understand the biology of GSCs, and target these tumors therapeutically, we need robust strategies for in vitro expansion of primary GSCs. To date, tumor core biopsies have been the main established source of GSCs. Since these samples are used for diagnostic purposes, the available tissue for cell culture and therapeutic targeting can be limited. In addition, a core biopsy is usually taken from one part of the tumor, thus would be unlikely to represent intra-tumor heterogeneity. To overcome these problems, tissue fragments from all over the tumor can be collected using an ultrasonic aspirator during surgery, thus assembling a "global tumor biopsy". Usually, this ultrasonic aspirate (UA) sample is considered as biological waste after operations. Here, we show that UA samples offer a large and reliable source of live cells. Similar to core biopsies, UA samples enriched for GSCs that differentiated into neural lineages, showed inter-individual variation of GSC markers, and induced tumors. Molecular profiling showed that UA samples cover tumor heterogeneity better than core biopsies. These results suggest that UA samples can be used to establish large scale cultures for therapeutic applications.


Progressive Stabilization of Brain Network Dynamics during Childhood and Adolescence.
Functional brain networks require dynamic reconfiguration to support flexible cognitive function. However, the developmental principles shaping brain network dynamics remain poorly understood. Here, we report the longitudinal development of large-scale brain network dynamics during childhood and adolescence, and its connection with gene expression profiles. Using a multilayer network model, we show the temporally varying modular architecture of child brain networks, with higher network switching primarily in the association cortex and lower switching in the primary regions. This topographical profile exhibits progressive maturation, which manifests as reduced modular dynamics, particularly in the transmodal (e.g., default-mode and frontoparietal) and sensorimotor regions. These developmental refinements mediate age-related enhancements of global network segregation and are linked with the expression profiles of genes associated with the enrichment of ion transport and nucleobase-containing compound transport. These results highlight a progressive stabilization of brain dynamics, which expand our understanding of the neural mechanisms that underlie cognitive development.


Simultaneous detection and quantification of multiple pathogen targets in wastewater.
Wastewater-based epidemiology has emerged as a critical tool for public health surveillance, building on decades of environmental surveillance work for pathogens such as poliovirus. Work to date has been limited to monitoring a single pathogen or small numbers of pathogens in targeted studies; however, few studies consider simultaneous quantitative analysis of a wide variety of pathogens, which could greatly increase the utility of wastewater surveillance. We developed a novel quantitative multi-pathogen surveillance approach (35 pathogen targets including bacteria, viruses, protozoa, and helminths) using TaqMan Array Cards (TAC) and applied the method on concentrated wastewater samples collected at four wastewater treatment plants in Atlanta, GA from February to October of 2020. From sewersheds serving approximately 2 million people, we detected a wide range of targets including many we expected to find in wastewater (e.g., enterotoxigenic E. coli and Giardia in 97% of 29 samples at stable concentrations) as well as unexpected targets including Strongyloides stercoralis (a human threadworm rarely observed in the USA). Other notable detections included SARS-CoV-2, but also several pathogen targets that are not commonly included in wastewater surveillance like Acanthamoeba spp., Balantidium coli , Entamoeba histolytica , astrovirus, norovirus, and sapovirus. Our data suggest broad utility in expanding the scope of enteric pathogen surveillance in wastewaters, with potential for application in a variety of settings where pathogen quantification in fecal waste streams can inform public health surveillance and selection of control measures to limit infections.


Improving DNA vaccine performance through vector design.
DNA vaccines are a rapidly deployed next generation vaccination platform for treatment of human and animal disease. DNA delivery devices, such as electroporation and needle free jet injectors, are used to increase gene transfer. This results in higher antigen expression which correlates with improved humoral and cellular immunity in humans and animals. This review highlights recent vector and transgene design innovations that improve DNA vaccine performance. These new vectors improve antigen expression, increase plasmid manufacturing yield and quality in bioreactors, and eliminate antibiotic selection and other potential safety issues. A flowchart for designing synthetic antigen transgenes, combining antigen targeting, codon-optimization and bioinformatics, is presented. Application of improved vectors, of antibiotic free plasmid production, and cost effective manufacturing technologies will be critical to ensure safety, efficacy, and economically viable manufacturing of DNA vaccines currently under development for infectious disease, cancer, autoimmunity, immunotolerance and allergy indications.


Host plant resistance for fall armyworm management in maize: relevance, status and prospects in Africa and Asia.
Sustainable control of fall armyworm (FAW) requires implementation of effective integrated pest management (IPM) strategies, with host plant resistance as a key component. Significant opportunities exist for developing and deploying elite maize cultivars with native genetic resistance and/or transgenic resistance for FAW control in both Africa and Asia. The fall armyworm [Spodoptera frugiperda (J.E. Smith); FAW] has emerged as a serious pest since 2016 in Africa, and since 2018 in Asia, affecting the food security and livelihoods of millions of smallholder farmers, especially those growing maize. Sustainable control of FAW requires implementation of integrated pest management strategies, in which host plant resistance is one of the key components. Significant strides have been made in breeding elite maize lines and hybrids with native genetic resistance to FAW in Africa, based on the strong foundation of insect-resistant tropical germplasm developed at the International Maize and Wheat Improvement Center, Mexico. These efforts are further intensified to develop and deploy elite maize cultivars with native FAW tolerance/resistance and farmer-preferred traits suitable for diverse agro-ecologies in Africa and Asia. Independently, genetically modified Bt maize with resistance to FAW is already commercialized in South Africa, and in a few countries in Asia (Philippines and Vietnam), while efforts are being made to commercialize Bt maize events in additional countries in both Africa and Asia. In countries where Bt maize is commercialized, it is important to implement a robust insect resistance management strategy. Combinations of native genetic resistance and Bt maize also need to be explored as a path to more effective and sustainable host plant resistance options. We also highlight the critical gaps and priorities for host plant resistance research and development in maize, particularly in the context of sustainable FAW management in Africa and Asia.


[Outcomes of the treatment of acute intestinal obstruction in the middle-aged and elderly].
During 15 years (from 1959 to 1973) the author observed 753 patients operated upon for acute intestinal ileus; 161 of them aged above 60. An early diagnosis of the condition is difficult due to blurred main symptoms against the background of pronounced age changes and concomitant diseases. The most common non-blastomatous forms are the following: adhesive intestinal ileus (16.8%) and sigmoid volvulus (14.3%). Cancer of the colon with acute symptoms of intestinal ileus was noted in 23.6%. Stomach resection was carried out upon 37.9% of cases. Postoperative complications constituted 34.1% and lethality--30.4%. Elderly and senile patients usually appeal for medical aid rather late, which together with severe concomitant diseases, late surgical intervention, diagnostic and tactical errors admitted in the treatment result in a high postoperative lethality.


Human thymic stromal lymphopoietin promotes the proliferation and invasion of cervical cancer cells by downregulating microRNA-132 expression.
Thymic stromal lymphopoietin (TSLP), produced by cervical cancer (CC) cells, promotes angiogenesis, and the recruitment and functional regulation of eosinophils. It has been reported that microRNA (miR)-132 is aberrantly decreased in CC tissues. However, the function and mechanism of TSLP on the biological behaviors of CC cells is largely unknown. The aim of the present study was to investigate the effect of TSLP on the expression of miR-132 and the proliferation and invasion in vitro of CC cell lines, namely, HeLa and SiHa cells. The transcrpitional level of miR-132 was analyzed using reverse transcription-quantitative polymerase chaon reaction. The proliferation, invasion, and the expression of proliferation and invasion-related molecules in HeLa and SiHa cells in vitro were evaluated using bromodeoxyuridine cell proliferation, Matrigel invasion assays, flow cytometry and ELISA, respectively. Here, it was revealed that recombinant human TSLP (rhTSLP) downregulated the expression levels of miR-132 in HeLa and SiHa cells, and by contrast, the neutralizing antibodies for TSLP or TSLP receptor (TSLPR) upregulated miR-132 expression levels in HeLa and SiHa cells. The overexpression of miR-132 resulted in a lowered proliferation and invasiveness, decreased levels of proliferation-associated molecules marker of proliferation Ki-67 and proliferating cell nuclear antigen, and the decreased production of matrix metalloproteinase (MMP)2 and MMP9 in HeLa and SiHa cells. Compared with the control group, there was a higher level of proliferation and invasion in HeLa and SiHa cells following stimulation with rhTSLP. However, these effects induced by rhTSLP were significantly impaired in HeLa and SiHa cells with miR-132 overexpression. The results of the present study indicated that TSLP produced by CC cells downregulated miR-132 expression, and stimulated the proliferation and invasion of CC cells, thereby further promoting the development of CC.


Antidepressant Use and Cognitive Outcomes in Very Old Women.
Antidepressant use is very common in the elderly, but the effects of antidepressants on cognition in the elderly are controversial with some studies suggesting harm and others protection. We aimed to investigate the association between different antidepressant use and change in cognition and risk of mild cognitive impairment (MCI) or dementia in very old women. We examined 1,234 community-dwelling women (mean age 83.2 years) from the Study of Osteoporotic Fractures. Baseline antidepressant use was reported and verified by medication containers, and medications were coded with computerized dictionary. Cognitive status (normal, MCI, or dementia) was adjudicated by an expert clinical panel 5 years later. Change in a short-form Mini-Mental State Examination and Trails B were evaluated over 5 years. Eleven per cent of the women were taking antidepressants. Users of selective serotonin reuptake inhibitors (SSRIs) had the greatest cognitive decline over 5 years, after adjustment for demographics, medical comorbidities, benzodiazepine use, and baseline cognition. Multivariable logistic regression shows that the users of SSRIs were more than twice (OR = 2.69, 95% CI = 1.64-4.41) and trazodone users more than three times (3.48, 1.12-10.81) as likely to develop MCI or dementia compared with the nonusers. Further adjustment for baseline cognition or depressive symptoms did not appreciably alter the results, and the association remained after excluding women with high depressive symptoms. The use of tricyclic antidepressants or other antidepressants was not significantly associated with cognitive outcomes. The use of antidepressants, especially SSRIs and trazodone, was associated with an increased risk of cognitive impairment 5 years later among the oldest old women.


[Maternal-fetal transmission of Trypanosoma cruzi, a health problem slightly studied in Mexico: case Chiapas].
To determine the Trypanosoma cruzi infection prevalence in 1125 pregnant women and the transmission frequency to their children from Tapachula and Palenque, Chiapas. We determined the prevalence by serology tests and the transmission frequency by polymerase chain reaction (PCR) and T. cruzi reactivity capacity after 12 months. Total maternal infection prevalence were 23/1 125 (2.04%), 9/600 (1.5%) were from Tapachula and 14/525 (2.6%) from Palenque. The seropositive women were between 20 and 35 years old, 31.8% have Premature Rapture of Membrane and 9.1% have history of perinatal death. The total percentage of positive newborns by PCR was 9/23 (39.13%), out of those 2/9 (22.2%) are from Tapachula and 7/14 (50%) from Palenque. The Maternal Fetal transmission frequency was. 2/9 (22.2%) in Tapachula and 1/14 (7.14%) in Palenque, all positive infants were asynthomatic. The maternal-fetal transmission rate in Chiapas State is variable; the reason could be the maternal immunological status and T. cruzi strain.


Bio-inspired temporal regulation of ion-transport in nanochannels.
Temporal regulation of mass transport across the membrane is a vital feature of biological systems. Such regulatory mechanisms rely on complex biochemical reaction networks, often operating far from equilibrium. Herein, we demonstrate biochemical reaction mediated temporal regulation of mass transport in nanochannels of mesoporous silica sphere. The rationally designed nanochannels with pH responsive electrostatic gating are fabricated through a hetero-functionalization approach utilizing propylamine and carboxylic acid moieties. At basic pH, cationic small molecules can diffuse into the nanochannels which release back to the solution at acidic pH. The transient ion transport is temporally controlled using a base as fuel along with esterase enzyme as the mediator. The slow enzymatic hydrolysis of a dormant deactivator (ethyl acetate) determines the lifetime of transient encapsulated state, which can be programmed easily by modulating the enzymatic activity of esterase. This system represents a unique approach to create autonomous artificial cellular models.


Modeling 100,000-year climate fluctuations in pre-pleistocene time series.
A number of pre-Pleistocene climate records exhibit significant fluctuations at the 100,000-year (100-ky) eccentricity period, before the time of such fluctuations in global ice volume. The origin of these fluctuations has been obscure. Results reported here from a modeling study suggest that such a response can occur over low-latitude land areas involved in monsoon fluctuations. The twice yearly passage of the sun across the equator and the seasonal timing of perihelion interact to increase both 100-ky and 400-ky power in the modeled temperature field. The magnitude of the temperature response is sufficiently large to leave an imprint on the geologic record, and simulated fluctuations resemble those found in records of Triassic lake levels.