The Association of CEP135 rs4865047 and NPY2R rs1902491 Single Nucleotide Polymorphisms (SNPs) with Rapid Progression of Proliferative Diabetic Retinopathy in Patients with Type 1 Diabetes Mellitus.
BACKGROUND Diabetic retinopathy has a varied prevalence, severity, and rate of progression. The aim of this study was to determine whether the single nucleotide polymorphisms (SNPs) of the gene encoding a 135-kD centrosomal protein CEP135 rs4865047 and the gene encoding the type 2 NPY protein NPY2R rs1902491 were associated with the development of rapidly progressive proliferative diabetic retinopathy in patients with type 1 diabetes mellitus. MATERIAL AND METHODS Patients with rapidly progressive proliferative diabetic retinopathy (n=48) were included in the study group. The control group (n=84) consisted of diabetes mellitus patients who had no proliferative diabetic retinopathy up to 15 years of diabetes duration. The reference group (n=90) included non-diabetic individuals who matched the study group by age and gender. The SNPs in the three groups were analyzed using real-time polymerase chain reaction (PCR) amplification. RESULTS The analysis of the distribution of genotypes in CEP135 rs4865047 and NPY2R rs1902491 detected significant differences only in the single nucleotide polymorphism rs4865047 genotype between the case and control group in comparison to the reference group. The co-dominant model showed that CEP135 rs4865047 was significantly associated with patients with rapidly progressive proliferative diabetic retinopathy (OR 7.2, 95% CI, 2.28-22.74, p=0.001). No significant association was found for the NPY2R SNP rs1902491 genotype. CONCLUSIONS Our study reports a significant association of the CEP135 single nucleotide polymorphism rs4865047 genotype with rapidly progressive proliferative diabetic retinopathy and the control group. No significant association was found of the NPY2R single nucleotide polymorphism rs1902491 genotype.


Cesium blockade of delayed outward currents and electrically induced pacemaker activity in mammalian ventricular myocardium.
The effects of Cs+, 5-25 mM, were studied in cat and guinea pig papillary muscles using voltage clamp and current clamp techniques. In solutions containing normal K+, the major effects of Cs+ were depolarization of the resting potential and reduction of the delayed outward current (ixl) between -80 and -20 mV. Both inward and outward portions of the isochronal current voltage relation (l-s clamps) were reduced by extracellular Cs+. This resulted in a substantial reduction of inward rectification and, by subtraction from the normal I-V relationship, the definition of a Cs+-sensitive component of current. Under current clamp conditions, 5-10 mM Cs+ produced a dose-dependent slowing of repetitive firing induced by depolarization. At higher concentrations (25 mM) the resting potential was depolarized and repetitive activity could not be induced by further depolarization. However, release of hyperpolarizing pulses was followed by prolonged bursts of repetitive action potentials, suggesting partial reversal of blockade or participation of another pacemaker process. The experimental results and a numerical simulation show that under readily attainable conditions, reduction in an outward pacemaker current may slow pacemaker activity.


Expression of the dominant-negative regulator Id4 is induced during adipocyte differentiation.
Expression of the Id4 gene was investigated during differentiation of 3T3-L1 preadipocytes into mature adipocytes. Id4 is a member of a family encoding non-DNA binding helix-loop-helix proteins proposed to inhibit the activity of basic HLH (bHLH) proteins important in many developmental processes. We show here that Id4 expression is low in confluent preadipocytes and rapidly induced by treatment with the combination of hormones which causes differentiation into mature adipocytes. Id4 expression is also induced by treatment with individual hormones, especially dexamathasone. Id4 mRNA can be detected in mouse and human adipose tissue. Genes encoding E-proteins (bHLH proteins known to interact with and be regulated by Id proteins) are expressed and regulated during differentiation in 3T3-L1 cells. These data suggest that the Id4 transcriptional regulator is playing a role in adipose cell differentiation and suggest that DNA-binding HLH proteins may also be important in regulation of differentiation of these cells.


Growth pattern of the maxillary sinus in the Japanese macaque (Macaca fuscata): reflections on the structural role of the paranasal sinuses.
To investigate the claim that the primate paranasal sinuses possess not a functional but a structural role associated with the skull architecture (Blaney, 1990), the relationship between the maxillary sinus and the skull architecture was studied ontogenetically in 30 skulls of male and female Japanese macaques (Macaca fuscata). Coronal CT scan series and computerised 3-dimensional images served to evaluate the maxillary sinus. The definitive hemispherical shape of the sinus was already achieved after the completion of the primary dentition. Sinus volume increased with a trend indicating positive allometry. When compared with an ontogenetic data set of orang-utan (Koppe et al. 1995), however, the growth rate of the maxillary sinus of M. fuscata was significantly less. The maxillary sinus both of male and female macaques enlarged according to a common growth pattern. However, no sexual dimorphism could be established for the maxillary sinus size. Although the volume of the right maxillary sinus was normally bigger than that of the left side, the results suggested that asymmetry in maxillary sinus volume is related neither to skull size nor sex. Whereas a correlation analysis showed close relationships between the maxillary sinus volume and external cranial dimensions, the partial correlation coefficients revealed that these relationships were highly influenced by skull size. Although it cannot be ruled out that the paranasal sinuses are to some extent linked to the skull architecture, this study does not support a solely structural role for these air cavities.


Fetal bilateral obstructive uropathy: a series of nine cases.
Bilateral obstructive uropathy is increasingly diagnosed in early pregnancy by ultrasound examination. Termination of pregnancy presented an opportunity to study uropathy in nine cases between 18 and 24 weeks of gestation. En bloc dissection of the urinary tract and subserial sectioning of the urethra revealed obstruction at the level of the membraneous urethra in all cases. No structural obstruction could be demonstrated in three cases, and urethral valves caused partial obstruction in two cases. The urethra was distorted by a fibrous band in one case. In three cases overriding urethral lumens appeared to represent incomplete or faulty canalization at the angled junction of the developing posterior and anterior urethra. Urethral obstruction is considered the major etiologic factor in the development of bilateral fetal uropathy and presumably the prune-belly phenotype.


CCORT/CCS quality indicators for congestive heart failure care.
Quality indicators are measurement tools for assessing the structure, processes and outcomes of care. Although quality indicators have been developed in other countries, Canadian cardiovascular disease indicators do not exist. To develop quality indicators for measuring and improving congestive heart failure (CHF) care in Canada. An 11-member multidisciplinary national expert panel was selected from nominees from national medical organizations. Potential quality indicators were identified by a detailed search of published guidelines, randomized trials and outcomes studies. A two-step modified Delphi process was employed with an initial screening round of indicator ratings, followed by a national quality indicator panel meeting, where definitions of the indicators were developed using consensus methods. Indicators were designed to be measurable, using retrospective chart review and linking existing administrative databases. The case definition criterion was developed based on a discharge diagnosis of CHF (International Classification of Diseases, 9th revision [ICD-9] code 428.x), with diagnostic confirmation using clinical criteria. In total, 29 indicators and five test indicators were recommended. Process indicators included prescription for angiotensin-converting enzyme inhibitors, beta-blockers or warfarin (for atrial fibrillation) at hospital discharge. Nonpharmacological in hospital process indicators included evaluation of left ventricular function, weight measurement and selected patient education counselling instructions. Process indicators in the ambulatory setting included prescription and adherence to drug therapies and physician follow-up. Outcome indicators included mortality, readmissions and emergency visits. A set of Canadian quality indicators for CHF care encompassing organizational attributes, pharmacotherapy, investigations, counselling, continuity of care and disease outcomes has been developed. These quality indicators will serve as a foundation for future studies evaluating the quality of CHF care in Canada.


Effects of prolonged treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor.
In vitro marrow hemopoietic cultures were utilized to determine the possible efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) for treating the refractory cytopenias present in the myelodysplastic syndromes (MDS). Our studies showed responsiveness of enriched hemopoietic precursors in vitro to the proliferative and granulocytic differentiative stimuli of G-CSF, generally without increased clonal self-generation. These in vitro parameters correlated with in vivo hematologic responses in our Phase I and II clinical trials. In this study 18 patients were treated for two months with s.c. administration (0.1-3 micrograms/kg/day) of G-CSF, escalating doses every two weeks. This study indicated normalization of neutrophil courses in 16 patients and reticulocyte responses with decreased red blood cell (RBC) transfusion requirements in three of 12 transfusion-dependent patients. Marrow myeloid maturation improved in the responding patients. Extended treatment for additional six- to 16-month periods has indicated persisting neutrophil responses. The relative risk of developing bacterial infections was significantly decreased in patients whose neutrophil level normalized (absolute neutrophil count greater than 1,500/mm3) during G-CSF therapy, compared to such episodes in their pretreatment neutropenic period. This therapy was well-tolerated, without serious toxicity being noted. In vitro neutrophil function (chemotaxis and phagocytosis) remained normal or improved in six of the eight tested patients. Transformation to acute myelogenous leukemia occurred in two patients with refractory anemia with excess blasts in transformation (RAEB-T) during or within a month of the treatment period. Marrow cytogenetic studies indicate persistence of the initial normal and/or abnormal clones.(ABSTRACT TRUNCATED AT 250 WORDS)


cFLIP regulates death receptor-mediated apoptosis in an ovarian granulosa cell line by inhibiting procaspase-8 cleavage.
More than 99% of follicles in mammalian ovaries undergo atresia, but the mechanisms regulating the strict selection process are still unclear. Granulosa cell apoptosis is considered the trigger of follicular atresia, which occurs in advance of the death of an oocyte. Cellular FLICE-like inhibitory protein (cFLIP), a homologue of procaspase-8 (also called FLICE), is an intracellular anti-apoptotic protein. It is expressed in granulosa cells of porcine ovaries, where its levels decreases during follicular atresia. We hypothesized that cFLIP regulates granulosa cell apoptosis by acting as a pro-survival factor. In the present study, to further reveal the function of cFLIP in granulosa cells, we examined the anti-apoptotic mechanism of cFLIP using KGN, a human granulosa tumor cell line. Fas-mediated apoptosis was induced by co-treatment with anti-Fas antibody (CH-11), which acts as an agonist of Fas-ligand, and cycloheximide (CHX). When cFLIP was stably expressed in KGN cells following transfection of an expression vector, the Fas-mediated apoptosis was inhibited. Suppression of cFLIP by small interfering RNA (siRNA) spontaneously induced cell death. Silencing of cFLIP promoted cleavage of procaspase-8, and the cell death caused by cFLIP siRNA was completely blocked by a caspase-8 inhibitor (Z-IETD-FMK), indicating that cFLIP regulates apoptosis in KGN cells by inhibiting cleavage of procaspase-8. In conclusion, cFLIP is an essential pro-survival factor for granulosa cells, and it prevents granulosa cell apoptosis by inhibiting procaspase-8 activation.


Detecting traumatic internal carotid artery dissection using transcranial Doppler in head-injured patients.
The early diagnosis of traumatic internal carotid artery dissection (TICAD) is essential for initiating appropriate treatment and improving outcome. We searched for criteria from transcranial Doppler (TCD) measurements on admission that could be associated with subsequent TICAD diagnosis in patients with traumatic brain injury (TBI). We conducted a retrospective 1:4 matched (age, mean arterial blood pressure) cohort study of 11 TBI patients with TICAD and absent or mild brain lesions on initial CT scan, 22 TBI controls with comparable brain CT scan lesions (controls 1), and 22 TBI controls with more severe brain CT scan lesions (controls 2) on admission. TCD measurements were obtained on admission from both middle cerebral arteries (MCA). All patients had subsequent CT angiography to diagnose TICAD. A >25% asymmetry in the systolic blood flow velocity between the two MCA was found in 9/11 patients with TICAD versus 0/22 in controls 1 and 5/22 in controls 2 (p < 0.01). The combination of this asymmetry with an ipsilateral pulsatility index < or =0.80 was found in 9/11 patients with TICAD versus none in the two groups of controls (p < 0.01). Our results suggest that significant asymmetry in the systolic blood flow velocity between the MCAs and a reduced ipsilateral pulsatility index could be criteria from TCD measurements associated with the occurrence of TICAD in head-injured patients. If prospectively validated, these findings could be incorporated in screening protocols for TICAD in patients with TBI.


Platelet factor XIII. The collagen receptor?
We have studied the binding of collagen fibers with platelet proteins using affinity chromatography on collagen-Sepharose. Only a few proteins from a platelet lysate were trapped by this column. When denatured collagen (gelatin) was used as the affinity ligand, the major protein did not bind and was identified as platelet Factor XIII by polyacrylamide gel electrophoresis, immunoprecipitation, and enzymic activity. This is a zymogen form of transglutaminase, which corresponds to the "a" subunit of the coagulation factor in plasma. Immunoglobulins specific for platelet Factor XIII obtained from antiserum raised against plasma Factor XIII were able to initiate platelet aggregation by themselves, in strong contrast to nonspecific antibodies. This specific immunoglobulin-mediated platelet aggregation required the presence of Ca2+. It was inhibited by aspirin and prostacyclin, but not by specific inhibitors for other agonists. These data suggest the possibility that the zymogen form of Factor XIII is located on the surface of platelets and may play a key role as the receptor for collagen-induced platelet aggregation.


TAK1 is an essential regulator of BMP signalling in cartilage.
TGFbeta activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1(col2) mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage.


Biogeography of Triatoma sanguisuga (Hemiptera: Reduviidae) on two barrier islands off the coast of Georgia, United States.
Thirty-three Triatoma sanguisuga (LeConte) adults and nymphs were collected during June and July 2009, at five sites on Cumberland Island and two sites on Sapelo Island, Georgia, to assess genetic diversity within and between sites. All but three specimens were found in a peridomestic habitat. The entire length (699 bp) of the cytochrome oxidase II mitochondrial gene was sequenced for each specimen. Twelve haplotypes were identified, nine from Cumberland Island and three from Sapelo Island. No haplotypes were shared between the two islands, indicating there is limited or no movement of gene flow between the islands. Phylogenetic relationships among the haplotypes were determined using both neighbor-joining and maximum parsimony analyses. The phylogenetic trees from both analyses were similar, with no distinct clades on either tree devoted to haplotypes from a single island. A haplotype network structure was determined using nested clade analysis, which produced two haplotype networks, one containing only specimens found on Cumberland Island. The second network included specimens from both islands, with the ancestral haplotype from Sapelo Island. This pilot study is the first to highlight triatomine populations in the southeastern United States using the cytochrome oxidase II mitochondrial gene, and indicates strong population structuring along the Georgia Coast.


Influence of age and sodium intake on plasma renin activity of normal subjects.
Supine and upright plasma renin activity (PRA) were measured i 104 normal subjects (age range 13-74 years, 71 males and 33 females) on a constant diet of normal potassium (60-80 mEq/day) and of varying but constant, sodium content (range 10-260 mEq/day). Both supine and upright PRA values were inversely related to the 24-hour urinary sodium excretion, while only upright PRA values showed a significant inverse correlation with age. Through a multiple regression analysis it was shown that age increased the significance of the PRA/sodium relationship by about 10%. Besides posture, two other factors seem to influence the PRA-age relationship: the age range and the sodium intake. In fact, the PRA-age relationship was not detectable either when subjects below 20 and above 50 were excluded, or when sodium intake was increased above 140 mEq/day. These data can explain the contrasting reports on the age influence on renin secretion. The relationship between PRA and urinary sodium confirms the dependance of PRA on the state of sodium balance. Age significantly influences the PRA/sodium relationship of normal subjects on normal or low sodium intake and in the upright position. Therefore, the decline of PRA with age may be explained by the decrease either of renin storage or of sympathetic nervous system activity on renin release.


Evaluation of the effects of compression stockings using venous plethysmography in persons with spinal cord injury.
To examine the effect of graduated compression stockings (GCS) on the properties of the venous vascular system, as characterized by venous capacitance (VC) and venous outflow (VO), in the lower extremities of individuals with spinal cord injury (SCI), according to injury level. Nine male subjects with SCI (5 with low paraplegia [LP], 4 with high paraplegia [HP]) performed 2 plethysmography tests: with and without graduated compression knee-length stockings (pressure of 21 mm/Hg). The VC, VO, and cardiovascular parameters (heart rate and blood pressure) were evaluated with and without GCS. The VC and VO were lower in patients with HP than in those with LP. For all subjects, VC was significantly lower (-14%) with GCS than without (1.77 +/- 1.18 vs 1.53 +/- 1.09 vol%, P < 0.01). On the contrary, VO did not differ significantly when wearing or not wearing GCS. This study demonstrated that 21-mm/Hg knee-length GCS are sufficient to prevent venous distension in individuals with SCI, even those with longstanding paraplegia, by significantly decreasing venous capacitance. This intervention may help to prevent deep vein thrombosis.


Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes.
Elevated production of prostaglandin E2 (PGE2) plays an important role in the pathogenesis of arthritis. Recently, an inducible microsomal prostaglandin E synthase-1 (mPGES-1) was identified. This enzyme is functionally coupled with cyclooxygenase-2 (COX-2) and converts the COX product PGH2 to PGE2. We analyzed expression of mPGES-1 in human normal and osteoarthritic (OA) cartilage and determined the effect of different inflammatory agonists on the expression of mPGES-1 in OA chondrocytes. Expression of mPGES-1 mRNA and protein in cartilage was determined by quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. OA chondrocytes were treated with different inflammatory agents, and mPGES-1 protein expression was evaluated by Western blot. Activation of the mPGES-1 promoter was assessed in transient transfection experiments. Levels of mPGES-1 mRNA and protein were markedly elevated in OA versus normal cartilage. Treatment of chondrocytes with interleukin 1beta (IL-1beta) induced expression of mPGES-1 protein in a dose- and time-dependent manner. This appears to occur at the transcriptional level, as IL-1beta induced expression of mPGES-1 mRNA and the activity of this gene promoter. Tumor necrosis factor-alpha (TNF-alpha) and IL-17 also upregulated expression of mPGES-1 protein and displayed a synergistic effect with IL-1beta. Peroxisome proliferator-activated receptor-gamma ligands, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone, inhibited IL-1beta-induced mPGES-1 protein expression, an effect that was reversed by exogenous PGE2. Our study shows that mPGES-1 expression is upregulated in OA versus normal cartilage and that proinflammatory cytokines increased mPGES-1 expression in chondrocytes. These data suggest that mPGES-1 may prove to be an interesting therapeutic target for controlling PGE2 synthesis.


Notch Signaling Regulates Mouse Perivascular Adipose Tissue Function via Mitochondrial Pathways.
Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used the Adiponectin-Cre (Adipoq-Cre) strain to activate a ligand-independent Notch1 intracellular domain transgene (N1ICD) to drive constitutive Notch signaling in the adipose tissues (N1ICD;Adipoq-Cre). We previously found that constitutive activation of Notch1 signaling in the PVAT phenocopied the effects of diet-induced obesity. To understand the downstream pathways activated by Notch signaling, we performed a proteomic analysis of the PVAT from control versus N1ICD;Adipoq-Cre mice. This comparison identified prominent changes in the protein signatures related to metabolism, adipocyte homeostasis, mitochondrial function, and ferroptosis. PVAT-derived stromal vascular fraction cells were derived from our mouse strains to study the cellular and molecular phenotypes during adipogenic induction. We found that cells with activated Notch signaling displayed decreased mitochondrial respiration despite similar levels of adipogenesis and mitochondrial number. We observed variable regulation of the proteins related to mitochondrial dynamics and ferroptosis, including PHB3, PINK1, pDRP1, and the phospholipid hydroperoxidase GPX4. Mitochondria regulate some forms of ferroptosis, which is a regulated process of cell death driven by lipid peroxidation. Accordingly, we found that Notch activation promoted lipid peroxidation and ferroptosis in PVAT-derived adipocytes. Because the PVAT phenotype is a regulator of vascular reactivity, we tested the effect of Notch activation in PVAT on vasoreactivity using wire myography. The aortae from the N1ICD;Adipoq-Cre mice had increased vasocontraction and decreased vasorelaxation in a PVAT-dependent and age-dependent manner. Our data provide support for the novel concept that increased Notch signaling in the adipose tissue leads to PVAT whitening, impaired mitochondrial function, increased ferroptosis, and loss of a protective vasodilatory signal. Our study advances our understanding of how Notch signaling in adipocytes affects mitochondrial dynamics, which impacts vascular physiology.


Comparison of two methods of service delivery for students with learning disabilities.
Both the process and outcome of providing occupational and physical therapy services in the public school system to students with learning disabilities were examined. A therapist-directed group received a combination of large and small group therapy while a consultation group received large group therapy and teacher-led follow-up sessions. Group progress on three standardized tests was compared by analysis of covariance. The result indicated that the consultation group made a greater change in mean standard score on the Bruininks-Oseretsky Test of Motor Proficiency (p <.01). The therapist-directed group made a mean change in standard score of 19.4 on the Test of Visual-Perceptual Skills compared to 7.5 for the consultation group, a difference that was clinically but not statistically significant (p=.07). Both groups made comparable progress on the Test of Visual-Motor Skills. Progress within each group was examined by the proportional change index score for each test subscale and the results were favorable for both groups. Based on student progress, the therapy needs of each group, teacher satisfaction, and utilization of available resources, each method of service delivery was effective for the particular group of students served.


The proportional work of lifting the center of mass during walking.
The present study determined the proportion of energy consumption used to lift the center of mass vertically during walking. By assuming that the vertical oscillations of the trunk were identical to those of the center of mass, the complexity of studying the human gait was simplified. The work performed on the center of mass, defined as lift work, was calculated using the subject's mass and the vertical displacement of the trunk. Compensating for the fact that human muscles are approximately 25% efficient in performing external work, the mechanical work was compared with the total energy expenditure, determined using an expired air analysis. At 1.34 and 1.79 m/s, 53.2 +/- 9.3% and 62.8 +/- 8.6%, respectively, of the total energy can be explained by lift work. At 0.45 and 0.90 m/s, the proportions are considerably less, 21.6 +/- 6.6% and 37.6 +/- 8.2%, respectively. These findings provide a rationale for why the metabolic energy cost per unit distance is greater at slower speeds than comfortable or fast speeds of walking. The total energy consumption can be accounted for by changes in the potential and kinetic energies and internal muscular work, defined as the less readily observable work probably needed for balance. The present study demonstrated that the metabolic energy cost of changing the potential energy of the center of mass during walking is significantly less relative to the total energy consumption at slower speeds than at higher speeds. Because kinetic energy is proportional to the square of the velocity, the metabolic energy cost of changing this energy is relatively small at slower speeds. Internal muscular work must therefore play a large role in total energy consumption at slow speeds of walking.


Development and preliminary validation of the Salzburg Stress Eating Scale.
Stress-related eating has long been a focus of study in several disciplines. Currently available psychometric scales conflate stress-related eating with emotional eating despite that not all stress states can be subsumed under some form of specific emotion. Moreover, existing measures primarily assess increased food intake in response to emotions and stress, thus ignoring evidence of decreased food intake in response to stress. Therefore, we drew from established stress concepts to develop the first genuine stress-related eating scale (Salzburg Stress Eating Scale [SSES]) in both German and English versions. In the SSES higher scores indicate eating more when stressed and lower scores indicate eating less when stressed. In study 1 (n = 340), the German SSES was found to have a one-factor structure (α = 0.89). SSES scores were weakly or moderately correlated with other eating-related constructs (e.g., emotional eating, body mass index [BMI]), and weakly correlated or uncorrelated with non-eating-related constructs (e.g., impulsivity, perceived stress); in addition, women had higher scores than men. Perceived stress moderated the association between stress eating and BMI, such that higher SSES scores were significantly related to higher BMI in individuals with high perceived stress, but not in individuals with low perceived stress. In studies 2 (n = 790) and 3 (n = 331), factor structure, internal consistency, and associations with sex and BMI were replicated for both German and English versions of the SSES. Hence, the SSES represents a psychometrically sound tool for the measurement of stress-related eating.


Cholesterol-Mediated Anchoring of Phospholipids onto Proteinosomes for Switching Membrane Permeability.
Modulated membrane functionalization is a necessary and overarching step for hollow microcompartments toward their application as nanoreactors or artificial cells. In this study, we show a way to generate phospholipid hybrid proteinosomes that could show superposed virtues of liposomes and proteinosomes. In comparison to pure proteinosomes, both the membrane fluidity and permeability are improved obviously after forming the phospholipid hybrid proteinosomes. Specifically, the integration of phospholipids also endows the hybrid proteinosomes demonstrating a stepwise release of the encapsulants of FITC-dextran (70 and 150 kDa) triggered sequentially by phospholipase and protease, and then a modulated cascaded enzymatic reaction between two different populations of proteinosomes are achieved. Therefore, it is anticipated that such constructed phospholipid hybrid proteinosomes could be employed as an improved microcompartmental model for further advanced artificial cell design toward achieving logic signal communication within the various artificial cellular populations as well as potential applications in the field of microreactors.


The metabolic alteration and apparent preservation of the zombie ant brain.
Some parasites can manipulate the behavior of their animal hosts to increase transmission. An interesting area of research is understanding how host neurobiology is manipulated by microbes to the point of displaying such aberrant behaviors. Here, we characterize the metabolic profile of the brain of an insect at the moment of the behavioral manipulation by a parasitic microbe. Our model system are ants infected with the parasitic fungus Ophiocordyceps kimflemingiae (=unilateralis), which manipulates ants to climb and bite into plant substrates, before killing the host (i.e. zombie ants). At the moment of the behavioral manipulation by the fungus, the host's brain is not invaded by the fungus which is known to extensively invade muscle tissue. We found that, despite not being invaded by the parasite, the brains of manipulated ants are notably different, showing alterations in neuromodulatory substances, signs of neurodegeneration, changes in energy use, and antioxidant compound that signal stress reactions by the host. Ergothionine, a fungal derived compound with known neuronal cytoprotection functions was found to be highly elevated in zombie ant brains suggesting the fungus, which does not invade the central nervous system, is preserving the brain.


3-D structure, volume, and DNA content of erythrocyte nuclei of polyploid fish.
We have explored the potential relationship between ploidy level, DNA content (pg DNA nucleus(-1)), and dimensional characteristics, such as volume (μm(3)), surface area (μm(2)), and 3-D structure of erythrocyte nuclei in a series of fish ploidy level models using Feulgen image analysis densitometry, flow cytometry, and confocal laser scanning microscopy. The species were diploid tench (Tinca tinca) (2n), Cuban gar (Atractosteus tristoechus) (2n), triploid tench (3n), evolutionary tetraploid sterlet (Acipenser ruthenus) (4n), evolutionary octaploid Siberian sturgeon (A. baerii) (8n), triploid Siberian sturgeon exhibiting dodecaploidy (12n), evolutionary 12n shortnose sturgeon (A. brevirostrum), and experimentally obtained sturgeon hybrids that were tetraploid, hexaploid (6n), heptaploid (7n), octaploid, decaploid (10n), dodecaploid and/or tetradecaploid (14n). Increase in ploidy was accompanied by growth of the nucleus and an increase in the number of flattened ellipsoid nuclei with increased transverse diameter. The volume (Vvoxel ) of erythrocyte nuclei, as the sum of voxels calculated from live cells, seems more accurate than volume (Vaxis ) calculated from measuring the major and minor axis, especially at higher and odd ploidy levels. Data of absolute and relative DNA content were in agreement with previously published reports. Species of the same ploidy level, but differing in DNA content, had a similar mean erythrocyte nuclear volume (Vvoxel ), as demonstrated in sterlet and a hybrid of sterlet and beluga (48.3 and 48.9 μm(3), respectively), with a respective mean DNA content of 3.74 and 3.10 pg DNA nucleus(-1). A similar relationship was found for the ploidy 6n, 10n, 12n. The surface-to-volume ratio decreased non-linearly with increasing ploidy. The DNA in erythrocyte nuclei appeared to be more densely packed with increase in ploidy level.


Redox properties of structural Fe in clay minerals. 2. Electrochemical and spectroscopic characterization of electron transfer irreversibility in ferruginous smectite, SWa-1.
Structural Fe in clay minerals is an important, albeit poorly characterized, redox-active phase found in many natural and engineered environments. This work develops an experimental approach to directly assess the redox properties of a natural Fe-bearing smectite (ferruginous smectite, SWa-1, 12.6 wt % Fe) with mediated electrochemical reduction (MER) and oxidation (MEO). By utilizing a suite of one-electron-transfer mediating compounds to facilitate electron transfer between structural Fe in SWa-1 and a working electrode, we show that the Fe2+/Fe3+ couple in SWa-1 is redox-active over a large range of potentials (from E(H) = -0.63 V to +0.61 V vs SHE). Electrochemical and spectroscopic analyses of SWa-1 samples that were subject to reduction and re-oxidation cycling revealed both reversible and irreversible structural Fe rearrangements that altered the observed apparent standard reduction potential (E(H)(ø)) of structural Fe. E(H)(ø)-values vary by as much as 0.56 V between SWa-1 samples with different redox histories. The wide range of E(H)-values over which SWa-1 is redox-active and redox history-dependent E(H)(ø)-values underscore the importance of Fe-bearing clay minerals as redox-active phases in a wide range of redox regimes.


Neurobehavioural and cognitive development in infants born to mothers with eating disorders.
Although recent research has focused on the effects of maternal eating disorders (EDs) on children, little is known about the effect of maternal EDs on neurobiological outcomes in newborns and infants. This study is the first to investigate neurobehavioural regulation and cognitive development in newborns and infants of mothers with EDs. Women with an active and past ED and healthy controls were recruited to a prospective longitudinal study during their first trimester or second trimester of pregnancy. Newborns and infants of mothers with ED were compared with newborns and infants of healthy controls on (a) neurobehavioural dysregulation using the Brazelton Neonatal Behavioural Assessment Scale at 8 days postpartum (active ED, n = 15; past ED, n = 20; healthy controls, n = 28); and (b) cognitive development using the Bayley Scales of Infant and Toddler Development at 1-year postpartum (active ED, n = 18; past ED, n = 19; healthy controls, n = 28). In order to maintain the largest possible sample at each time point, sample size varied across time points. Newborns of mothers with an active ED had worse autonomic stability when compared with newborns of healthy controls [B = -0.34 (-1.81, -0.26)]. Infants of mothers with a past ED had poorer language [B = -0.33 (-13.6, -1.9)] and motor development [B = -0.32 (-18.4, -1.3)] compared with healthy controls. Children of mothers with ED display neurobehavioural dysregulation early after birth and poorer language and motor development at 1 year. These characteristics suggest evidence of early neurobiological markers in children at risk. Differential outcomes in children of women with active versus past ED suggest that active symptomatology during pregnancy might have an effect on physiological reactivity while cognitive characteristics might be more stable markers of risk for ED.


Cross-sectional study of intraocular cataract lens replacement, circadian rest-activity rhythms, and sleep quality in older adults.
Age-related cataract decreases light transmission at the most sensitive spectrum for circadian photoentrainment, with negative ramifications for human health. Here, we assessed whether intraocular lens replacement (IOL) in older patients with previous cataract was associated with increased stability and amplitude of circadian rest-activity rhythms, and improved sleep quality. Our cross-sectional study included sixteen healthy older individuals without ocular diseases (controls; 55-80 years; 63.6 ± 5.6y; 8 women) and 13 patients with previous cataract and bilateral IOL (eight with blue-blocking [BB] lens and five with ultraviolet-only [UV] blocking lens; 55-80 years; 69.9 ± 5.2y; 9 women). The study comprised three weeks of at home rest-activity assessments using wrist-worn actigraphs, and each week preceded a laboratory protocol. Primary outcomes were actigraphy-derived interdaily stability, intradaily variability, and relative amplitude of circadian rest-activity rhythms. Secondary outcomes were actigraphy-assessed sleep quality (i.e. time in bed, sleep duration, sleep efficiency, mean wake bout time and fragmentation index). Patients with IOL had significantly higher interdaily stability ("Group" effect: pFDR =.001), but not intradaily variability ("Group" effect: pFDR = n.s.), and significantly higher relative amplitude of rest-activity rhythms ("Group" effect: pFDR < .001). Moreover, patients with IOL had significantly higher activity levels during the day and lower levels during the evening, as compared to healthy older controls ("Group" effect: pFDR = .03). Analyses of actigraphy-derived sleep parameters yielded no significant differences across groups ("Group" effect: all pFDR > .1). Our cross-sectional study suggests that enhancing spectral lens transmission in patients with cataract may benefit their circadian health.


An evolution-based machine learning to identify cancer type-specific driver mutations.
Identifying cancer type-specific driver mutations is crucial for illuminating distinct pathologic mechanisms across various tumors and providing opportunities of patient-specific treatment. However, although many computational methods were developed to predict driver mutations in a type-specific manner, the methods still have room to improve. Here, we devise a novel feature based on sequence co-evolution analysis to identify cancer type-specific driver mutations and construct a machine learning (ML) model with state-of-the-art performance. Specifically, relying on 28 000 tumor samples across 66 cancer types, our ML framework outperformed current leading methods of detecting cancer driver mutations. Interestingly, the cancer mutations identified by sequence co-evolution feature are frequently observed in interfaces mediating tissue-specific protein-protein interactions that are known to associate with shaping tissue-specific oncogenesis. Moreover, we provide pre-calculated potential oncogenicity on available human proteins with prediction scores of all possible residue alterations through user-friendly website (http://sbi.postech.ac.kr/w/cancerCE). This work will facilitate the identification of cancer type-specific driver mutations in newly sequenced tumor samples.


Distribution of postsynaptic density (PSD)-95 and Ca2+/calmodulin-dependent protein kinase II at the PSD.
Postsynaptic densities (PSDs) contain proteins that regulate synaptic transmission. We determined the positions of calcium/calmodulin-dependent protein kinase II (CaMKII) and PSD-95 within the three-dimensional structure of isolated PSDs using immunogold labeling, rotary shadowing, and electron microscopic tomography. The results show that all PSDs contain a central mesh immediately underlying the postsynaptic membrane. Label for PSD-95 is found on both the cytoplasmic and cleft sides of this mesh, averaging 12 nm from the cleft side. All PSDs label for PSD-95. The properties of CaMKII labeling are quite different. Label is virtually absent on the cleft sides of PSDs, but can be heavy on the cytoplasmic side at a mean distance of 25 nm from the cleft. In tomograms, CaMKII holoenzymes can be visualized directly, appearing as labeled, tower-like structures reflecting the 20 nm diameter of the holoenzyme. These towers protrude from the cytoplasmic side of the central mesh. There appears to be a local organization of CaMKII, as judged by fact that the nearest-neighbor distances are nearly invariant over a wide range of labeling density for CaMKII. The average density of CaMKII holoenzymes is highly variable, ranging from zero to values approaching a tightly packed state. This variability is significantly higher than that for PSD-95 and is consistent with an information storage role for CaMKII.


Modulation of iris sphincter and ciliary muscles by urocortin 2.
Urocortin 2 (UCN2) is a peptide related to corticotropin-releasing factor, capable of activating CRF-R2. Among its multisystemic effects, it has actions in all 3 muscle subtypes. This study's aim was to determine its potential role in two of the intrinsic eye muscle kinetics. Strips of iris sphincter (rabbit) and ciliary (bovine) muscles were dissected and mounted in isometric force-transducer systems filled with aerated-solutions. Contraction was elicited using carbachol (10(-6) M for iris sphincter, 10(-5) M for ciliary muscle), prior adding to all testing substances. UCN2 induced relaxation in iris sphincter muscle, being the effect maximal at 10(-7) M concentrations (-12.2 % variation vs. control). This effect was abolished with incubation of indomethacin, antisauvagine-30, chelerytrine and SQ22536, but preserved with L-nitro-L-arginine. In carbachol pre-stimulated ciliary muscle, UCN2 (10(-5) M) enhanced contraction (maximal effect of 18.2 % increase vs. control). UCN2 is a new modulator of iris sphincter relaxation, dependent of CRF-R2 activation, synthesis of prostaglandins (COX pathway) and both adenylate cyclase and PKC signaling pathways, but independent of nitric oxide production. Regarding ciliary muscle, UCN2 enhances carbachol-induced contraction, in higher doses.


Process-Oriented Instrument and Taxonomy for Teaching Surgical Procedures in Medical Training: The Ultrasound-Guided Insertion of Central Venous Catheter.
Procedural training is relevant for physicians who perform surgical procedures. In the medical education field, instructors who teach surgical procedures need to understand how their students are learning to give them feedback and assess them objectively. The sequence of steps of surgical procedures is an aspect rarely considered in medical education, and state-of-the-art tools for giving feedback and assessing students do not focus on this perspective. Process Mining can help to include this perspective in this field since it has recently been used successfully in some applications. However, these previous developments are more centred on students than on instructors. This paper presents the use of Process Mining to fill this gap, generating a taxonomy of activities and a process-oriented instrument. We evaluated both tools with instructors who teach central venous catheter insertion. The results show that the instructors found both tools useful to provide objective feedback and objective assessment. We concluded that the instructors understood the information provided by the instrument since it provides helpful information to understand students' performance regarding the sequence of steps followed.


Hypomagnesemia and hypocalcemia after thyroidectomy: prospective study.
Hypomagnesemia after total thyroidectomy has not been studied extensively. Our anecdotal experience suggests that it may be important in some patients after thyroid excision. The hypomagnesemic hypocalcemic syndrome has been described in other disease states in which a state of functional hypoparathyroidism exists. This study was designed to determine the incidence of hypomagnesemia after total thyroidectomy and relate it to hypocalcemia and symptoms during the postoperative period. A prospective study of all patients undergoing total thyroidectomy between September 1994 and July 1996 was performed. Patient data, thyroid function, retrosternal extension, initial versus reoperative surgery, operative details, parathyroid resection, and pathology were recorded. Calcium, magnesium, electrolytes, blood count, liver function tests, and albumin were measured prior to surgery and twice daily during the postoperative period. Fifty patients underwent total thyroidectomy: 68% were hypocalcemic, 72% were hypomagnesemic, and 36% were symptomatic during the postoperative period. Hypomagnesemia and gender were associated with hypocalcemia. Volume of fluid and neck dissection were associated with low magnesium levels. Hypomagnesemia and parathyroid resection were risk factors for symptoms after thyroidectomy. No patients developed permanent hypoparathyroidism. Transient hypocalcemia and hypomagnesemia occur frequently after total thyroidectomy. The etiology of this phenomenon is probably multifactorial. Patients are more likely to be symptomatic when both cations are low, and attempting to correct only hypocalcemia may prolong symptoms. It is important to monitor both calcium and magnesium levels after total thyroidectomy and to correct deficiencies to facilitate prompt resolution of symptoms.


Pedestrian Detection During Vehicle Backing Maneuvers Using Ultrasonic Parking Sensors.
Ultrasonic parking sensors are an active technology designed to alert drivers to the presence of objects behind their vehicle but not the presence of a human. The purpose of this study was therefore to ascertain if these sensor systems can successfully detect a human subject. We accordingly conducted experiments using four vehicles equipped with both rear-facing center and corner ultrasonic parking sensor systems to determine the detection distance between the vehicle and a 1-m tall, 75-mm diameter pipe, a child, an adult woman, and an adult man. The detection of human subjects was evaluated under front-facing and side-facing conditions behind each vehicle. The results indicate that for a front-facing and side-facing child, the center sensor detection distances were 50-84% and 32-64%, respectively, shorter than that of the pipe. For front-facing and side-facing adults, the center sensor detection distances were just less than or roughly equivalent to that of the pipe at 89-102% and 78-97%, respectively. A similar trend was seen for the corner sensors. Notably, under the side-facing condition, the sensor detection distances were slightly shorter for all subjects than under the front-facing condition. These results reveal that ultrasonic parking sensor systems can not only detect objects but also humans, indicating that ultrasonic sensors are an available countermeasure to prevent backover accidents involving pedestrians. To address the shorter detection distance of children, a combination of ultrasonic parking sensors with other systems, such as backup cameras, may be more effective for avoiding backover collisions.


Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.
Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.


Behavioral phenotype of individuals with Down syndrome.
Evidence is reviewed for a developmentally-emerging behavioral phenotype in individuals with Down syndrome that includes significant delay in nonverbal cognitive development accompanied by additional, specific deficits in speech, language production, and auditory short-term memory in infancy and childhood, but fewer adaptive behavior problems than individuals with other cognitive disabilities. Evidence of dementia emerges for up to half the individuals studied after age 50. Research issues affecting control group selection in establishing phenotypic characteristics are discussed, as well as the possible genetic mechanisms underlying variation in general cognitive delay, specific language impairment, and adult dementia. MRDD Research Reviews 2000;6:84-95. Wiley-Liss, Inc.


Possible role of a copper complex in the pathogenesis of rheumatoid arthritis.
Clinical and experimental evidence suggest that rheumatoid arthritis may be due to a deficiency in joint fluid of an inhibitor of protein denaturation. This inhibitor may be a histidine-cystine-copper complex. A deficiency of this inhibitor may permit the nonimmunological alteration of joint fluid IgG to a pseudoimmune complex which could initiate the inflammation and immunological abnormalities of rheumatoid arthritis.


Biopsy Quantitative Patohistology and Seral Values of Prostate Specific Antigen-Alpha (1) Antichymotrypsine Complex in Prediction of Adverse Pathology Findings after Radical Prostatectomy.
In this prospective study we examined the utility of parameters obtained on prostate needle biopsy and prostate specific antigen-alpha(1)-antichymotripsine complex (PSA-ACT) to predict adverse pathologic findings after radical prostatectomy. 45 consecutive patients assigned for radical prostatectomy due to clinically localized prostate cancer were included in the study. Prostate biopsy parameters such as number of positive cores, the greatest percentage of tumor in the positive cores, Gleason score, perineural invasion, unilaterality or bilaterality of the tumor were recorded. PSA-ACT was determined using sandwich immunoassay chemiluminiscent method (Bayer, Tarrytown, New York). We analyzed relationship of preoperative PSA, PSA-ACTand quantitative biopsy parameters with final pathology after prostatectomy. Adverse findings were considered when extracapsular extension of cancer (pT3) was noted. Postoperatively, 29 (64.4%) patients were diagnosed with pT2 disease and 16 (35.6%) with pT3 disease. There was a significant difference in localized vs. locally advanced disease in number of positive biopsy cores (p<0.001), greatest percentage of tumor in the core (p=0.008), localization of the tumor (p=0.003) and perineural invasion (p=0.004). Logistic regression was used to develop a model on the multivariate level. It included number of positive cores and PSA-ACT and was significant on our cohort with the reliability of 82.22%. The combination of PSA-ACT and a large scale of biopsy parameters could be used in prediction of adverse pathologic findings after radical prostatectomy. Clinical decisions and patients counselling could be influenced by these predictors but further confirmation on a larger population is necessary.


Chemometric characterization of fruit juices from Spanish cultivars according to their phenolic compound contents: I. Citrus fruits.
The data set composed by phenolic compound profiles of 83 Citrus juices (determined by HPLC-DAD-MS/MS) was evaluated by chemometrics to differentiate them according to Citrus species (sweet orange, tangerine, lemon, and grapefruit). Cluster analysis (CA) and principal component analysis (PCA) showed natural sample grouping among Citrus species and even the Citrus subclass. Most of the information contained in the full data set can be captured if only 15 phenolic compounds (concentration ≥10 mg/L), which can be quantified with fast and accurate methods in real samples, are introduced in the models; a good classification which allows the confirmation of the authenticity of juices is achieved by linear discriminant analysis. Using this reduced data set, fast and routine methods have been developed for predicting the percentage of grapefruit in adulterated sweet orange juices using principal component regression (PCR) and partial least-squares regression (PLS). The PLS model has provided suitable estimation errors.


Multivalent binding of p53 to the STAGA complex mediates coactivator recruitment after UV damage.
The recruitment of transcriptional coactivators, including histone modifying enzymes, is an important step in transcription regulation. A typical activator is thought to interact with several cofactors, presumably in a sequential manner. The common use of several cofactors raises the question of how activators achieve both cofactor selectivity and diversity. Human STAGA is a multiprotein complex with the acetyltransferase GCN5L as the catalytic subunit. Here, we first show, through RNA interference-mediated knock-down and chromatin immunoprecipitation assays, that GCN5 plays a role in p53-dependent gene activation. We then employ p53 mutagenesis, in vitro binding, protein-protein cross-linking, and chromatin immunoprecipitation assays to establish a novel role for the second p53 activation subdomain (AD2) in STAGA recruitment and, further, to demonstrate that optimal binding of STAGA to p53 involves interactions of STAGA subunits TAF9, GCN5, and ADA2b, respectively, with AD1, AD2, and carboxy-terminal domains of p53. These results provide concrete evidence for mediation of transcription factor binding to coactivator complexes through multiple interactions. Based on our data, we propose a cooperative and modular binding mode for the recruitment of coactivator complexes to promoters.


Proinflammatory phenotype with imbalance of KLF2 and RelA: risk of childhood stroke with sickle cell anemia.
Altered inflammation signaling within the cerebral vasculature may be an important risk factor for stroke in children with sickle cell anemia (SCA). This study examines how differential expression of NFkappaB/p65 (RelA), KLF2, and other transcription factors may act as switches in inflammation signaling leading to observed differences between non-SCA (NS) African Americans and African Americans with SCA who are either at risk (AR) or not at risk (NAR) of childhood stroke based on occurrence of Circle of Willis disease. Clover/Transfac analysis was used to identify overrepresented transcription factor binding motifs on genes associated with inflammation. Transcription factor binding motifs for the NFkappaB family and RFX1 were overrepresented on inflammation signaling gene set analysis. Variations in protein expression were determined by flow cytometry of blood outgrowth endothelial cells (BOECs) from NS, AR, and NAR donors and Western blots of protein extracts from both unstimulated and TNFalpha/IL1beta-stimulated BOECs. BOECs from patients with SCA had more cytoplasmic-derived RelA compared with NS BOECs. Sickle BOECs also had heightened responses to inflammatory stimuli compared with NS BOECs, as shown by increased nuclear RelA, and intracellular adhesion molecule (ICAM) response to TNFalpha/IL1beta stimulation. Multiple control points in RelA signaling were associated with risk of childhood stroke. The ratio of proinflammatory factor RelA to anti-inflammatory factor KLF2 was greater in BOECs from AR donors than NS donors. Group risk of childhood stroke with SCA was greatest among individuals who exhibited increased expression of proinflammatory transcription factors and decreased expression of transcription factors that suppress inflammation.


Estimating prokaryotic diversity and its limits.
The absolute diversity of prokaryotes is widely held to be unknown and unknowable at any scale in any environment. However, it is not necessary to count every species in a community to estimate the number of different taxa therein. It is sufficient to estimate the area under the species abundance curve for that environment. Log-normal species abundance curves are thought to characterize communities, such as bacteria, which exhibit highly dynamic and random growth. Thus, we are able to show that the diversity of prokaryotic communities may be related to the ratio of two measurable variables: the total number of individuals in the community and the abundance of the most abundant members of that community. We assume that either the least abundant species has an abundance of 1 or Preston's canonical hypothesis is valid. Consequently, we can estimate the bacterial diversity on a small scale (oceans 160 per ml; soil 6,400-38,000 per g; sewage works 70 per ml). We are also able to speculate about diversity at a larger scale, thus the entire bacterial diversity of the sea may be unlikely to exceed 2 x 10(6), while a ton of soil could contain 4 x 10(6) different taxa. These are preliminary estimates that may change as we gain a greater understanding of the nature of prokaryotic species abundance curves. Nevertheless, it is evident that local and global prokaryotic diversity can be understood through species abundance curves and purely experimental approaches to solving this conundrum will be fruitless.


Marennine, promising blue pigments from a widespread Haslea diatom species complex.
In diatoms, the main photosynthetic pigments are chlorophylls a and c, fucoxanthin, diadinoxanthin and diatoxanthin. The marine pennate diatom Haslea ostrearia has long been known for producing, in addition to these generic pigments, a water-soluble blue pigment, marennine. This pigment, responsible for the greening of oysters in western France, presents different biological activities: allelopathic, antioxidant, antibacterial, antiviral, and growth-inhibiting. A method to extract and purify marennine has been developed, but its chemical structure could hitherto not be resolved. For decades, H. ostrearia was the only organism known to produce marennine, and can be found worldwide. Our knowledge about H. ostrearia-like diatom biodiversity has recently been extended with the discovery of several new species of blue diatoms, the recently described H. karadagensis, H. silbo sp. inedit. and H. provincialis sp. inedit. These blue diatoms produce different marennine-like pigments, which belong to the same chemical family and present similar biological activities. Aside from being a potential source of natural blue pigments, H. ostrearia-like diatoms thus present a commercial potential for aquaculture, cosmetics, food and health industries.


Curcumin attenuates renal ischemia reperfusion injury via JNK pathway with the involvement of p300/CBP-mediated histone acetylation.
Apoptosis is proved responsible for renal damage during ischemia/reperfusion. The regulation for renal apoptosis induced by ischemia/reperfusion injury (IRI) has still been unclearly characterized to date. In the present study, we investigated the regulation of histone acetylation on IRI-induced renal apoptosis and the molecular mechanisms in rats with the application of curcumin possessing a variety of biological activities involving inhibition of apoptosis. Sprague-Dawley rats were randomized into four experimental groups (SHAM, IRI, curcumin, SP600125). Results showed that curcumin significantly decreased renal apoptosis and caspase-3/-9 expression and enhanced renal function in IRI rats. Treatment with curcumin in IRI rats also led to the decrease in expression of p300/cyclic AMP response element-binding protein (CBP) and activity of histone acetyltransferases (HATs). Reduced histone H3 lysine 9 (H3K9) acetylation was found near the promoter region of caspase-3/-9 after curcumin treatment. In a similar way, SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), also attenuated renal apoptosis and enhanced renal function in IRI rats. In addition, SP600125 suppressed the binding level of p300/CBP and H3K9 acetylation near the promoter region of caspase-3/-9, and curcumin could inhibit JNK phosphorylation like SP600125. These results indicate that curcumin could attenuate renal IRI via JNK/p300/CBP-mediated anti-apoptosis signaling.


Public and private incentives for self-protection.
Governments sometimes encourage or impose individual self-protection measures, such as wearing a protective mask in public during an epidemic. However, by reducing the risk of being infected by others, more self-protection may lead each individual to go outside the house more often. In the absence of lockdown, this creates a "collective offsetting effect", since more people outside means that the risk of infection is increased for all. However, wearing masks also creates a positive externality on others, by reducing the risk of infecting them. We show how to integrate these different effects in a simple model, and we discuss when self-protection efforts should be encouraged (or deterred) by a social planner.


Chronic nausea and orthostatic intolerance: Diagnostic utility of orthostatic challenge duration, Nausea Profile Questionnaire, and neurohumoral measures.
Chronic nausea in pediatrics is a debilitating condition with unclear etiology. We aimed to define hemodynamic and neurohumoral characteristics of chronic nausea associated with orthostatic intolerance in order to improve identification and elucidate mechanism. Children (10-18 years) meeting Rome III criteria for functional dyspepsia with nausea and symptoms of orthostatic intolerance (OI) completed a Nausea Profile Questionnaire followed by prolonged (45 minutes rather than the traditional 10 minutes) head-upright tilt (HUT) (70° tilt up) test. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured supine and after 15 minutes into HUT. Beat-to-beat heart rate and blood pressure were continuously recorded to calculate their variability and baroreflex sensitivity. Within 10 and 45 minutes of HUT, 46% and 85% of subjects, respectively, had an abnormal tilt test (orthostatic hypotension, postural orthostatic tachycardia, or syncope). At 15 and 45 minutes of HUT, nausea was elicited in 42% and 65% of subjects respectively. Higher Nausea Profile Questionnaire scores correlated with positive HUT testing at 10 minutes (P = 0.004) and baroreflex sensitivity at 15 minutes (P ≤ 0.01). Plasma vasopressin rose 33-fold in subjects with HUT-induced nausea compared to twofold in those who did not experience HUT-induced nausea (P < 0.01). In children with chronic nausea and OI, longer duration HUT elicited higher frequency of abnormal tilt testing and orthostatic-induced nausea. The Nausea Profile Questionnaire predicted the orthostatic response to tilt testing. Exaggerated vasopressin release differentiated patients with HUT-induced nausea (vs those without nausea), suggesting a possible mechanism for chronic nausea in childhood.


Comparison of Structural and Functional Properties of Wheat Starch Under Different Soil Drought Conditions.
Drought influences cereal crop yield and quality. However, little is known about changes in the structural and functional properties of wheat starch under soil drought conditions. In this study, two wheat cultivars were subjected to well-watered (WW), moderate soil-drought (MD), and severe soil-drought (SD) from 7 tillers in the main stem to maturity. The structural and functional properties of the resultant endosperm starch were investigated. In comparison with WW soil, the MD increased starch accumulation in grains, the proportion of large starch granules, amylose and amylopectin long branch chain contents, and average amylopectin branch chain length, which were accompanied by the increase in activities of granule bound starch synthase and soluble starch synthase. MD treated-starch had a lower gelatinization enthalpy, and swelling power, but a higher gelatinization temperature, retrogradation enthalpy, and retrogradation percentage when compared to WW conditions. The MD also increased starch resistance to acid hydrolysis, amylase hydrolysis, and in vitro digestion. The SD had the opposite effects to the MD in all cases. The results suggest that soil drought more severely affects amylose synthesis than amylopectin synthesis in wheat grains, and moderate soil-drought improves molecular structure and functional properties of the starch.


Hydroxyurea alters circulating monocyte subsets and dampens its inflammatory potential in sickle cell anemia patients.
Sickle cell anemia (SCA) is a hemolytic disease in which vaso-occlusion is an important pathophysiological mechanism. The treatment is based on hydroxyurea (HU), which decreases leukocyte counts and increases fetal hemoglobin synthesis. Different cell types are thought to contribute to vaso-occlusion. Nevertheless, the role of monocytes subsets remains unclear. We investigated frequencies of monocytes subsets in blood and their response to HU therapy, testing their ability to express pro-inflammatory molecules and tissue factor (TF). We identified major changes in monocyte subsets, with classical monocytes (CD14++CD16-) appearing highly frequent in who were not taking HU, whereas those with patrolling phenotype (CD14dimCD16+) were enriched in individuals undergoing therapy. Additionally, HU decreased the production of TNF-α, IL1-β, IL-6, IL-8 as well as TF by the LPS-activated monocytes. Likewise, frequency of TF-expressing monocytes is increased in patients with previous vaso-occlusion. Moreover, activated monocytes expressing TF produced several pro-inflammatory cytokines simultaneously. Such polyfunctional capacity was dramatically dampened by HU therapy. The frequency of classical monocytes subset was positively correlated with percentage cytokine producing cells upon LPS stimulation. These findings suggest that classical monocytes are the subset responsible for multiple pro-inflammatory cytokine production and possibly drive inflammation and vaso-occlusion in SCA which is damped by HU.


Elevated serum C-reactive protein as a prognostic marker in small cell lung cancer.
Elevated C-reactive protein (CRP) is associated with poor prognosis in several tumor types. The purpose of this study was to investigate serum CRP as a prognostic marker in small cell lung cancer (SCLC). The pretreatment serum CRP level was measured in 157 newly diagnosed SCLC patients, and correlation between serum CRP level and other clinical parameters was analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model. The initial CRP concentration was within the normal range in 72 (45.9%) patients and elevated in 85 (54.1%) patients. There was a significant correlation between serum CRP level and the extent of disease (p<0.001), weight loss (p=0.029) and chest radiation (p=0.001). Median overall survival (OS) in the normal CRP group was significantly longer than with the high CRP group (22.5 months vs. 11.2 months, p<0.001). Extent of disease (p<0.001), age (p=0.025), and performance status (p<0.001) were additional prognostic factors on univariate analysis. On multivariate analysis, elevated serum CRP level was an independent prognostic factor for poor survival (HR=1.8; p=0.014), regardless of the extent of disease (HR=3.7; p<0.001) and performance status (HR=2.2; p<0.001). High level of CRP was an independent poor prognostic serum marker in addition to previously well-known prognosticators in patients with SCLC.


Nonadherence in chronic obstructive pulmonary disease patients: what do we know and what should we do next?
Although nonadherence research in patients with chronic obstructive pulmonary disease (COPD) lags well behind other diseases, new evidence helps inform understanding about the degree and underlying causes of patient nonadherence, interventions that can improve adherence, and areas of research needed to further progress in improving this problem in patients with COPD. Fewer than half of treatments for COPD, including oxygen supplementation, physical rehabilitation, and medication, are taken as prescribed. Most patients abandon their treatment after an initial start. Nonadherence in turn contributes to rising rates of hospitalization, death, and healthcare costs. The reasons why patients choose not to use their COPD treatments are not fully understood, although depression is clearly a contributing factor. Although a substantial number of studies have tested adherence interventions, few have included COPD patients or addressed polypharmacy in patients with multiple comorbidities. The paucity of research does not reflect the inadequacy of available treatments. Lessons learned from the research outside of COPD and a small number of COPD studies suggest that a collaborative care approach will likely provide the most potential for improving overall care, including management of depression and enhancement of adherence. Exploitation of mobile telephone technology to engage patients in a discussion of their self-care should not be ignored as a potential intervention for COPD patients.


Hormones, mammary growth, and lactation: a 41-year perspective.
When I was a beginning graduate student 41 yr ago it had been established that estrogen caused mammary duct growth; a combination of estrogen and progesterone was required for lobule-alveolar development of the mammary glands; and prolactin and growth hormone were essential for mammary growth. In laboratory species exogenous prolactin, glucocorticoids, and estrogen would initiate secretion of milk provided the mammary glands had a well-developed lobule-alveolar system. It was not known with certainty that progesterone inhibited the process. For some species, prolactin and thyroxine had been shown to stimulate lactation, while glucocorticoids suppressed lactation. Definitive roles for growth hormone and insulin during lactation had not been established. Studies of hormonal control of mammary growth and function in cattle were few. In vitro methods to study hormonal regulation of the mammary glands were in their infancy. Quantitative measures of changes in mammary cell numbers and specific components of milk in response to hormones were rare. The concepts for quantification of hormone concentrations, hormone receptors, growth factors, and binding proteins in blood; hormonal regulation of nutrient partitioning; and hormonally induced mechanisms of action within mammary cells were waiting to be discovered. And eventually they were. However, lest we become too enamored with our current understanding of the hormones that control mammary growth and lactation, it remains a fact that the greatest physiological stimulus for milk yield is pregnancy, not some cocktail of exogenous hormones, growth factors, receptor agonists/antagonists, or gene therapies. Viva la mom!


Raymond Curtis: the prototypical hand surgeon.
Raymond Curtis was an unusual man who lived in unusual times and made unusual contributions. He promoted hand surgery, a specialty that was little known in his early time. He educated many surgeons in the science, art, and philosophy of hand surgery. He favorably impacted the course of the American Society for Surgery of the Hand (ASSH) by his prudence and desire to advance its cause. His influence has altered the topography and milieu of our specialty and contributed to its progress and prosperity. His legacy is perpetuated by many of his protégées who continued to emulate his humility, intensity, and unique craftsmanship.


Esophageal fistula after definitive concurrent chemotherapy and intensity modulated radiotherapy for esophageal squamous cell carcinoma.
The literature regarding esophageal fistula after definitive concurrent chemotherapy and intensity modulated radiotherapy (IMRT) for esophageal squamous cell carcinoma (ESCC) remains lacking. We aimed to investigate the risk factors of esophageal fistula among ESCC patients undergoing definitive concurrent chemoradiotherapy (CCRT) via IMRT technique. A total of 129 consecutive ESCC patients receiving definitive CCRT with IMRT between 2008 and 2018 were reviewed. The cumulative incidence of esophageal fistula and survival of patients were estimated by the Kaplan-Meier method and compared between groups by the log-rank test. The risk factors of esophageal fistula were determined with multivariate Cox proportional hazards regression analysis. Median follow-up was 14.9 months (IQR, 7.0-28.8). Esophageal perforation was identified in 20 (15.5%) patients, resulting in esophago-pleural fistula in nine, esophago-tracheal fistula in seven, broncho-esophageal fistula in two, and aorto-esophageal fistula in two patients. The median interval from IMRT to the occurrence of esophageal fistula was 4.4 months (IQR, 3.3-10.1). Patients with esophageal fistula had an inferior median overall survival (10.0 vs. 17.2 months, p = 0.0096). T4 (HR, 3.776; 95% CI, 1.383-10.308; p = 0.010) and esophageal stenosis (HR, 2.601; 95% CI, 1.053-6.428; p = 0.038) at baseline were the independent risk factors for esophageal fistula. The cumulative incidence of esophageal fistula was higher in patients with T4 (p = 0.018) and pre-treatment esophageal stenosis (p = 0.045). There was a trend toward better survival after esophageal fistula among patients receiving repair or stenting for the fistula than those only undergoing conservative treatments (median survival, 5.9 vs. 0.9 months, p = 0.058). T4 and esophageal stenosis at baseline independently increased the risk of esophageal fistula in ESCC treated by definitive CCRT with IMRT. There existed a trend toward improved survival after the fistula among patients receiving repair or stenting for esophageal perforation.


Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia.
Infant mortality and stillbirth rates in Bolivia are high and birth weights are low compared with other South American countries. Most Bolivians live at altitudes of 2500 m or higher. We sought to determine the impact of high altitude on the frequency of preeclampsia, gestational hypertension, and other pregnancy-related complications in Bolivia. We then asked whether increased preeclampsia and gestational hypertension at high altitude contributed to low birth weight and increased stillbirths. We performed a retrospective cohort study of women receiving prenatal care at low (300 m, Santa Cruz, n = 813) and high altitude (3600 m, La Paz, n = 1607) in Bolivia from 1996 to 1999. Compared with babies born at low altitude, high-altitude babies weighed less (3084 +/- 12 g versus 3366 +/- 18 g, p < 0.01) and had a greater occurrence of intrauterine growth restriction [16.8%; 95% confidence interval (CI): 14.9-18.6 versus 5.9%; 95% CI: 4.2-7.5; p < 0.01]. Preeclampsia and gestational hypertension were 1.7 times (95% CI: 1.3-2.3) more frequent at high altitude and 2.2 times (95% CI: 1.4-3.5) more frequent among primiparous women. Both high altitude and hypertensive complications independently reduced birth weight. All maternal, fetal, and neonatal complications surveyed were more frequent at high than low altitude, including fetal distress (odds ratio, 7.3; 95% CI: 3.9-13.6) and newborn respiratory distress (odds ratio, 7.3; 95% CI: 3.9-13.6; p < 0.01). Hypertensive complications of pregnancy raised the risk of stillbirth at high (odds ratio, 6.0; 95% CI: 2.2-16.2) but not at low altitude (odds ratio, 1.9; 95% CI: 0.2-17.5). These findings suggest that high altitude is an important factor worsening intrauterine mortality and maternal and infant health in Bolivia.


Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study.
Prognosis evaluation of advanced breast cancer and therapeutic strategy are mostly based on clinical features of advanced disease and molecular profiling of the primary tumor. Very few studies have evaluated the impact of metastatic subtyping during the initial metastatic event in a prospective study. The genomic landscape of metastatic breast cancer has mostly been described in very advanced, pretreated disease, limiting the findings transferability to clinical use. We developed a multicenter, single-arm, prospective clinical trial in order to address these issues. Between November 2010 and September 2013, 123 eligible patients were included. Patients at the first, untreated metastatic event were eligible. All matched primary tumors and metastatic samples were centrally reviewed for pathological typing. Targeted and whole-exome sequencing was applied to matched pairs of frozen tissue. A multivariate overall survival analysis was performed (median follow-up 64 months). Per central review in 84 patients (out of 130), we show that luminal A breast tumors are more prone to subtype switching. By combining targeted sequencing of a 91 gene panel (n = 67) and whole-exome sequencing (n = 30), a slight excess of mutations is observed in the metastases. Luminal A breast cancer has the most heterogeneous mutational profile and the highest number of mutational signatures, when comparing primary tumor and the matched metastatic tissue. Tumors with a subtype change have more mutations that are private. The metastasis-specific mutation load is significantly higher in late than in de novo metastases. The most frequently mutated genes were TP53 and PIK3CA. The most frequent metastasis-specific druggable genes were PIK3CA, PTEN, KDR, ALK, CDKN2A, NOTCH4, POLE, SETD2, SF3B1, and TSC2. Long-term outcome is driven by a combination of tumor load and metastasis biology. Profiling of the first, untreated, metastatic event of breast cancer reveals a profound heterogeneity mostly in luminal A tumors and in late metastases. Based on this profiling, we can derive information relevant to prognosis and therapeutic intervention, which support current guidelines recommending a biopsy at the first metastatic relapse. The trial was registered at ClinicalTrials.gov ( NCT01956552 ).


Emotional responses during repeated sprint intervals performed on level, downhill and uphill surfaces.
The purpose of this study was to test emotional responses during sprint intervals performed on a level, down and up surface. Fifty trained participants performed a maximal effort during a 60-m sprint and 10 repetitions of 60 m running sprints on a level, down and up surface on a 5.9% slope. Running speeds, emotional responses and heart rate were measured. Self-selected speeds were correlated with the rating of perceived exertion, the affective balance, the desire to stop and the resources needed for the task in all conditions whereas the pleasure, the desire to continue and the capacity to realise the task were correlated with speeds only during level and uphill running. Mean values of emotional parameters were significantly different (P < 0.05) during running on a flat surface, downhill and uphill. When the gradient of running surface is changed, the pattern of emotional responses was just translated, i.e. most of the slope between the evolution of emotional parameters and the repetitions were not significantly different whereas Y-intercepts were different. Consented effort is highly correlated with the resources needed for the task (P < 0.001, r(2) = 0.72). We propose that the difference in the resources needed for the task between level, downhill and uphill running (F 2, 1499 = 166.5, P < 0.001, Eta(2) = 0.18) is the most important key that explains our results.


Survivorship and Outcome of Hip Arthroscopy for Femoroacetabular Impingement Syndrome Performed With Modern Surgical Techniques.
Hip arthroscopy for femoroacetabular impingement syndrome (FAIS) is a rapidly growing field in sports surgery; however, factors associated with poor outcomes and identification of predictor models of inferior clinical outcomes is unclear. To analyze predictors of clinical failure and inferior clinical outcomes among patients undergoing hip arthroscopy for treatment of FAIS. Case-control study; Level of evidence, 3. Data were collected and analyzed from consecutive patients who underwent primary hip arthroscopy with routine capsular closure for the treatment of FAIS from a single fellowship-trained surgeon between January 2012 and November 2015. Baseline data, postoperative patient-reported outcomes, and rates of clinical failure and inferior clinical outcomes were recorded at 2 years postoperatively. Clinical failure was defined by revision hip arthroscopy or conversion to total hip arthroplasty. Inferior clinical outcome was defined as not reaching the minimal clinically important difference (MCID) or patient acceptable symptomatic state for Hip Outcome Score-Activities of Daily Living. A multivariate logistic regression analysis was used to identify significant predictors of clinical failure and inferior clinical outcome. Out of 1161 eligible patients, 935 (80.5%) completed 2-year postoperative patient-reported outcomes. The mean ± SD age and body mass index were 33.3 ± 12.3 years and 25.4 ± 8.2 kg/m2, respectively. The overall clinical failure rate was 3.6% (n = 34), including 23 cases (2.5%) of revision hip arthroscopy and 11 cases (1.2%) of conversion to total hip arthroplasty. Predictors of clinical failure were lower preoperative International Hip Outcome Tool score ( P = .016), chronic preoperative pain ( P = .001), and chondromalacia in the affected hip ( P = .04). The inferior clinical outcome group, consisting of those who failed to reach the MCID for Hip Outcome Score-Activities of Daily Living, included 256 patients (27.4%). Predictors of inferior clinical outcomes were Tönnis grade >1 ( P = .01), workers' compensation ( P < .001), and increased body mass index ( P = .02). This study demonstrates that 73% of all patients treated for symptomatic FAIS with primary hip arthroscopy and routine capsular closure achieved the MCID. Clinical failure is predicted by a number of modifiable and nonmodifiable factors, including chronic preoperative pain and presence of chondromalacia. The current study updates the midterm failure rates and outcomes achievable with hip arthroscopy for FAIS.


Effects of Mutations on the Aggregation Propensity of the Human Prion-Like Protein hnRNPA2B1.
Hundreds of human proteins contain prion-like domains, which are a subset of low-complexity domains with high amino acid compositional similarity to yeast prion domains. A recently characterized mutation in the prion-like domain of the human heterogeneous nuclear ribonucleoprotein hnRNPA2B1 increases the aggregation propensity of the protein and causes multisystem proteinopathy. The mutant protein forms cytoplasmic inclusions when expressed in Drosophila, the mutation accelerates aggregation in vitro, and the mutant prion-like domain can substitute for a portion of a yeast prion domain in supporting prion activity. To examine the relationship between amino acid sequence and aggregation propensity, we made a diverse set of point mutations in the hnRNPA2B1 prion-like domain. We found that the effects on prion formation in Saccharomyces cerevisiae and aggregation in vitro could be predicted entirely based on amino acid composition. However, composition was an imperfect predictor of inclusion formation in Drosophila; while most mutations showed similar behaviors in yeast, in vitro, and in Drosophila, a few showed anomalous behavior. Collectively, these results demonstrate the significant progress that has been made in predicting the effects of mutations on intrinsic aggregation propensity while also highlighting the challenges of predicting the effects of mutations in more complex organisms.


Cutting edge: critical role of inducible costimulator in germinal center reactions.
Inducible costimulator (ICOS) is a new member of the CD28/CTLA-4 family that is expressed on activated and germinal center (GC) T cells. Recently, we reported that ICOS-deficient mice exhibited profound defects in T cell activation and effector function. Ab responses in a T-dependent primary reaction and in a murine asthma model were also diminished. In the current study, we investigate the mechanism by which ICOS regulates humoral immunity and examine B cell GC reactions in the absence of ICOS. We found that ICOS(-/-) mice, when immunized with SRBC, had smaller GCs. Furthermore, IgG1 class switching in the GCs was impaired. Remarkably, GC formation in response to a secondary recall challenge was completely absent in ICOS knockout mice. These data establish a critical role of ICOS in regulation of humoral immunity.


Sex ratio and parental investment in Trypoxylon (Trypargilum) agamemnon Richards (Hymenoptera, Crabronidae).
The life history and sex ratio data of the solitary wasp Trypoxylon agamemnon nesting in trap-nests in southern Brazil was recorded from January 2002 to December 2007. Its sex ratio is strongly female-biased, being bivoltine or multivoltine with until three generations per year. It has two alternative life histories (diapause and direct development) and overlapping generations. In addition to the conflict of interest between the sexes, it is possible that local mate competition occurs between males and may cause a greater investment in the production of females.


Diet-Related Disease Prevention in a Rural Australian Setting: Understanding Barriers, Enablers, and the Role of Rural Health Services in Supporting Changes in Local Rural Food Environments.
Bold and comprehensive action is needed to prevent diet-related diseases in rural areas, which includes improving food environments to enable healthier dietary practices. Rural health services are integral to the health of rural populations, yet their role in community disease prevention is not swell understood. This study sought to understand health service, local government, and food outlet stakeholders' perspectives on (1) the drivers of unhealthy retail environments in a rural setting; (2) the role of rural health services in supporting changes in local food environments; and to (3) identify characteristics of potential interventions. Two Group Model Building workshops were held with health service and local government leaders (n = 9), and interviews were conducted with local food outlet participants (n = 13). Key themes included 'enablers to healthier food environments', 'barriers to healthier food environments', 'Rural health services are a leading broker of knowledge for healthy food environments', and 'characteristics of desirable healthy food environment interventions.'. Rural health services can play a key role in addressing the current barriers to healthy food environments in rural areas. Effective promotion of healthier diets in rural populations will require consideration of key stakeholder perspectives and the development of further evidence on the role that rural health services can play in improving the healthiness of food environments.


PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma.
Therapeutic options for patients with hepatocellular carcinoma (HCC) are limited. Transarterial chemoembolization (TACE) is an interventional procedure used to deliver chemotherapy and embolizing agents directly to the tumor and is the procedure of choice for patients with intermediate stage HCC. While effective, more than 40% of patients do not respond to therapy, highlighting the need to investigate possible mechanisms of resistance. We sought to evaluate mechanisms of TACE resistance and evaluate a potential therapeutic target to overcome this resistance. Using a prognostic gene signature which predicts TACE response (TACE Navigator) in a cohort of HCC patients who received TACE, patients were classified as responders and non-responders. Transcriptomic and gene pathway analysis were used to identify potential drivers of TACE resistance. Knockdown of the gene encoding rate limiting enzyme PKM2 using shRNA in HCC cell lines, as well as pharmacologic inhibition of PKM2 with shikonin using an in vitro TACE model measured response to chemotherapy under hypoxia. Finally, we replicated the TACE model with shikonin using patient derived cell line organoids (PDC). Functional studies were performed in vitro using immunoblotting, quantitative polymerase chain reaction, glycolysis and hypoxia assays. In patient non-responders, we identified enrichment of the glycolysis pathway, specifically of the gene encoding the rate-limiting enzyme PKM2. We identified four HCC cell lines which recapitulated a TACE responder-like and non-responder-like phenotype. PKM2 knockdown in HCC cell lines demonstrated a less proliferative and aggressive phenotype as well as improved drug sensitivity to both doxorubicin and cisplatin. In vitro TACE model demonstrated that TACE non-responder-like cells overcame therapeutic resistance and rendered them susceptible to therapy through PKM2 knockdown. Lastly, we obtained similar results using a pharmacologic PKM2 inhibitor, shikonin in both cell lines, and PDC organoids. Elevated PKM2 is associated with treatment resistance and abbreviated survival in patients receiving TACE. Elevated PKM2 in vitro is associated with increased utilization of the glycolysis pathway, resulting in oxygen independent cell metabolism. Through PKM2 knockdown as well as with pharmacologic inhibition with shikonin, non-responder cells can be reprogrammed to act as responders and could improve TACE efficacy in patients.


Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.
Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.


Psychopathological features in Noonan syndrome.
Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. The study included 27 individuals (67% males) with an average age of 10.4 years (range 6-18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52-85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19-56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS.


Concomitant polymorphism and the martensitic-like transformation of an organic crystal.
Crystalline polymorphism is a phenomenon that occurs in many molecular solids, resulting in a diverse range of possible bulk structures. Temperature and pressure can often be used to thermodynamically control which crystal form is preferred, and the associated transitions between polymorphic phases are often discontinuous and complete. N-Methyl-4-carboxypyridinium chloride is a solid that undergoes an apparent continuous temperature-dependent phase transition from an orthorhombic to a monoclinic polymorph. However, a hybrid characterization approach using single-crystal X-ray diffraction, terahertz time-domain spectroscopy, and solid-state density functional theory reveals the transformation to be actually a slowly changing ratio of the two discrete polymorphic forms. The potential energy surface of this process can be directly accessed using terahertz radiation, and the data show that a very low barrier (43.3 J mol-1) exists along the polymorph transformation coordinate.


A geometric view on early and middle level visual coding.
As opposed to dealing with the geometry of objects in the 3D world, this paper considers the geometry of the visual input itself, i.e. the geometry of the spatio-temporal hypersurface defined by image intensity as a function of two spatial coordinates and time. The results show how the Riemann curvature tensor of this hypersurface represents speed and direction of motion, and thereby allows to predict global motion percepts and properties of MT neurons. It is argued that important aspects of early and middle level visual coding may be understood as resulting from basic geometric processing of the spatio-temporal visual input. Finally, applications show that the approach can improve the computation of motion.