Rab1b overexpression modifies Golgi size and gene expression in HeLa cells and modulates the thyrotrophin response in thyroid cells in culture.
Rab1b belongs to the Rab-GTPase family that regulates membrane trafficking and signal transduction systems able to control diverse cellular activities, including gene expression. Rab1b is essential for endoplasmic reticulum-Golgi transport. Although it is ubiquitously expressed, its mRNA levels vary among different tissues. This work aims to characterize the role of the high Rab1b levels detected in some secretory tissues. We report that, in HeLa cells, an increase in Rab1b levels induces changes in Golgi size and gene expression. Significantly, analyses applied to selected genes, KDELR3, GM130 (involved in membrane transport), and the proto-oncogene JUN, indicate that the Rab1b increase acts as a molecular switch to control the expression of these genes at the transcriptional level, resulting in changes at the protein level. These Rab1b-dependent changes require the activity of p38 mitogen-activated protein kinase and the cAMP-responsive element-binding protein consensus binding site in those target promoter regions. Moreover, our results reveal that, in a secretory thyroid cell line (FRTL5), Rab1b expression increases in response to thyroid-stimulating hormone (TSH). Additionally, changes in Rab1b expression in FRTL5 cells modify the specific TSH response. Our results show, for the first time, that changes in Rab1b levels modulate gene transcription and strongly suggest that a Rab1b increase is required to elicit a secretory response.


The microbiota of the respiratory tract: gatekeeper to respiratory health.
The respiratory tract is a complex organ system that is responsible for the exchange of oxygen and carbon dioxide. The human respiratory tract spans from the nostrils to the lung alveoli and is inhabited by niche-specific communities of bacteria. The microbiota of the respiratory tract probably acts as a gatekeeper that provides resistance to colonization by respiratory pathogens. The respiratory microbiota might also be involved in the maturation and maintenance of homeostasis of respiratory physiology and immunity. The ecological and environmental factors that direct the development of microbial communities in the respiratory tract and how these communities affect respiratory health are the focus of current research. Concurrently, the functions of the microbiome of the upper and lower respiratory tract in the physiology of the human host are being studied in detail. In this Review, we will discuss the epidemiological, biological and functional evidence that support the physiological role of the respiratory microbiota in the maintenance of human health.


High Plasma Levels of Soluble Talin-1 in Patients with Coronary Artery Disease.
Talin-1 is a cytoskeletal protein that binds integrin, thereby leading to integrin activation and affecting focal adhesions. Recently, talin-1 expression was reported to be downregulated in human atherosclerotic plaques. However, blood levels of soluble talin-1 (sTalin-1) in patients with atherosclerotic disease, such as coronary artery disease (CAD), have not been elucidated. We measured plasma sTalin-1 levels in 349 patients undergoing elective coronary angiography. The severity of CAD was represented as the number of stenotic coronary vessels and segments. Of the 349 study patients, CAD was found in 194 patients, of whom 88 had 1-vessel disease (1-VD), 60 had 2-vessel disease (2-VD), and 46 had 3-vessel disease (3-VD). Plasma sTalin-1 levels were higher in 194 patients with CAD than in 155 without CAD (CAD(-) group) (median 0.30 vs. 0.23 ng/mL, P < 0.005). A stepwise increase in sTalin-1 levels was found depending on the number of >50% stenotic coronary vessels: 0.23 in CAD(-), 0.29 in 1-VD, 0.30 in 2-VD, and 0.32 ng/mL in 3-VD group, respectively, (P < 0.05). High sTalin-1 level (>0.28 ng/mL) was found in 36% of CAD(-), 51% of 1-VD, 53% of 2-VD, and 59% of 3-VD group (P < 0.025). sTalin-1 levels also correlated with the number of >50% stenotic segments (r = 0.14, P < 0.02). The multivariate analysis revealed that sTalin-1 levels were independently associated with CAD. The odds ratio for CAD was 1.83 (95%CI = 1.14 - 2.93) for high sTalin-1 level (>0.28 ng/mL) (P < 0.02). Plasma sTalin-1 levels in patients with CAD were found to be high and to be associated with the presence and severity of CAD, suggesting a role of sTalin-1 in the progression of coronary atherosclerosis.


Eucalypt responses to fertilization and reduced herbivory.
We manipulated soil fertility and insect attack for two species of Eucalyptus in natural stands of subalpine woodland on shallow, infertile granitic soils. E. pauciflora and E. stellulata responded in similar ways to simultaneous insecticide and fertilizer treatments. Eliminating herbivorous insects produced the largest changes - improved plant growth, increased leaf N and P, and reduced leaf specific density. Fertilizer regime modified some leaf properties, but had little effect on tree growth. E. stellulata trees were initially shorter than E. pauciflora, but grew faster without herbivores; by the end of the experiment both species were the same size when herbivores were removed. Foliage N and P levels increased most in trees with the most balanced fertilizer addition (NPK), and increased in all trees protected from insects, regardless of fertilizer regime. In this system, herbivorous insects exacerbated the effects of nutrientpoor soils, and may affect dominance of Eucalyptus species in mature forests.


Fungal rhinosinusitis caused by Scedosporium apiospermum in a cat.
A 3-year-old neutered male Bengal cat with a history of chronic mucopurulent bilateral nasal discharge and sneezing was diagnosed with severe fungal rhinosinusitis. A diagnosis was obtained after computer tomography imaging, histopathological examination and fungal culture. The mold Scedosporium apiospermum was identified as the aetiological agent. To our knowledge, this case is the first description of a rhinitis or sinusitis caused by this agent in a cat. Aggressive surgical debridement combined with topical and systemic antifungal therapy was performed. Unfortunately, the treatment resulted only in a partial remission of signs.


Synthesis, anti-leukemia activity, and molecular docking of novel 3,16-androstenedione derivatives.
In this study, we synthesized androsta-4,14-diene-3,16-dione, 12β-hydroxyandrosta-4,14-diene-3,16-dione, and other 3,16-androstenedione derivatives from commercially available dehydroepiandrosterone as a starting material in 9-13 steps with high yields. The bioactivity of the obtained compounds was evaluated. Compounds 14a and 23a were shown to have high antitumor activity against acute lymphoblastic leukemia cell lines Nalm-6 and BALL-1, respectively. Network pharmacology analysis showed that the anti-leukemia activity of compounds 14a and 23a might be related to the JAK2, ABL1 protein, and PI3K/Akt signaling pathways. The molecular docking of compounds 14a and 23a identified possible active sites, with the lowest docking scores for PTGS2 and MAPK14, respectively. In addition, the absorption, distribution, metabolism, and excretion prediction results revealed the drug-likeness of the two compounds. Therefore, compounds 14a and 23a should be considered anti-leukemia candidates in future studies.


Anti-immunoglobulins in experimental streptococcal immunization; relation to bacterial growth conditions and Fc-receptors.
Heat-killed group A streptococci of types M12 and M22 were used for intravenous immunization of 60 rabbits. Presence of Fc-receptors binding monomeric IgG in M22 and their absence in M12 has been demonstrated previously. The strains were cultured in either Todd-Hewitt broth supplemented with 10% horse serum (TH-H) or in IsoVitaleX, a synthetic medium, supplemented with 10% autologous rabbit serum (IV-R). A mortality rate of 38% was noted in the first-mentioned group whereas no mortality was observed in the second group. Sera were examined for agglutination of red blood cells coated with either human or rabbit IgG. Antisera to strains cultured in TH-H regularly displayed anti-IgG antibodies reacting with human as well as rabbit IgG; anti-rabbit IgG titres of anti-M22 sera were significantly higher than those of anti-M12. Antisera to strains grown in IV-R displayed high levels of antibodies reacting with human but not with rabbit IgG. The levels of anti-human IgG did not differ between anti-M12 and anti-M22 sera.


Structural mechanism of LIN28B nucleosome targeting by OCT4.
Pioneer transcription factors are essential for cell fate changes by targeting closed chromatin. OCT4 is a crucial pioneer factor that can induce cell reprogramming. However, the structural basis of how pioneer factors recognize the in vivo nucleosomal DNA targets is unknown. Here, we determine the high-resolution structures of the nucleosome containing human LIN28B DNA and its complexes with the OCT4 DNA binding region. Three OCT4s bind the pre-positioned nucleosome by recognizing non-canonical DNA sequences. Two use their POUS domains while the other uses the POUS-loop-POUHD region; POUHD serves as a wedge to unwrap ∼25 base pair DNA. Our analysis of previous genomic data and determination of the ESRRB-nucleosome-OCT4 structure confirmed the generality of these structural features. Moreover, biochemical studies suggest that multiple OCT4s cooperatively open the H1-condensed nucleosome array containing the LIN28B nucleosome. Thus, our study suggests a mechanism of how OCT4 can target the nucleosome and open closed chromatin.


Primary atypical teratoid/rhabdoid tumor of the optic nerve: a rare entity in an exceptional location.
Atypical teratoid/rhabdoid tumors are rare and highly malignant central nervous system tumors. They have no specific radiological features and often present several histological components that make a problem in differential diagnosis with medulloblastoma and primitive neuroectodermal tumors. We present the case of a newborn girl complained of a gradual proptosis of the left eye secondary to an expansive lesional process of the optic nerve. The location at the optic nerve, reported only twice in the literature, and an exclusive rhabdoid appearance on biopsy added additional differential diagnosis problems. The proptosis worsened and the infant died few days after two cycles of chemotherapy. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2037718783145212 .


Stakeholder outcome prioritization in the Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile Spondyloarthritis (BACK-OFF JSpA) trial.
The Biologic Abatement and Capturing Kids' Outcomes and Flare Frequency in Juvenile Spondyloarthritis (BACK-OFF JSpA) study is a randomized, pragmatic trial investigating different tumour necrosis factor inhibitor de-escalation strategies for children with sustained inactive disease. In this project, we elicited concept rankings that aided in the selection of the patient-reported outcome (PRO) measures that should be examined as part of the BACK-OFF JSpA trial. We conducted a discrete choice experiment to evaluate individuals' preferences regarding PROs. Stakeholders assessed a discrete list of 21 outcome concepts, each of which had a Patient-Reported Outcome Measurement Information System (PROMIS) measure associated with it. PROMIS measures are self- or proxy-reported instruments that are universally applicable to the general population and all chronic conditions. Stakeholders were required to make choices instead of expressing the strength of a preference. Fourteen caregivers, 12 patients (9-22 years old), 16 rheumatologists and three executives from health insurance companies completed the exercise, which took approximately 10 min. The discrete choice experiment resulted in an estimate of the relative importance of each outcome and rank. All stakeholder groups agreed that the primary PRO should be 'Pain Interference', a measure that evaluates the effect of pain on a child's everyday activities, including its impact on social, emotional, mental and physical functioning. Patients and caregivers were mostly aligned in their top priorities, with patients valuing physical health (50% of the top 10) whereas caregivers were more interested in mental health (60% of the top 10). Rheumatologists and health insurance executives were most interested in physical health outcomes, which were ranked 80% and 60% of their top 10 PROs, respectively. Overall, the patients had the most diverse set of prioritized outcomes, including at least one of each category in their top 10 rank order of importance. Patients were also the only stakeholders to prioritize 'social' health. Patients and caregivers were mostly aligned in their outcome priority rankings. The rank-order list directly informed the creation of a profile of PRO measures for our upcoming trial. Stakeholder partners helped with acquisition of data and lead parent partners helped interpret data.


A modified quantitative whole blood clot lysis method for general laboratory analysis of fibrinolysis.
Because fibrinolysis is now recognized as an important factor in hypercoagulable states, we have developed and characterized an easily performed, rapid, and quantitative screening test that assesses a patient's fibrinolytic activity. This modification of the dilute whole blood clotting time (DWBCT) counts the number of intact erythrocytes released from the clot formed in samples obtained before and after the application of a venous occlusion cuff. Samples were corrected for the plasma volume changes that occurred during venous occlusion. This test was performed on nine healthy volunteers. Specimens were diluted 1:1 with PBS, rapidly clotted with thrombin and incubated at 37 C. Starting thirty minutes after the thrombin was added and then at twenty minute intervals until 110 minutes, the number of RBCs released from the clot were counted using a Coulter S Plus counter. There were consistently more RBCs released at each time period after venous occlusion (p less than 0.001). Aliquots were also obtained for measuring PAI activity and TPA levels. PAI activity was lower post-cuff at every point (p less than 0.001). TPA level was higher at every point (p less than 0.001) post-cuff. The addition of exogenous TPA, activated protein C, or anti-PAI antibodies increased the amount of clot lysis; while the addition of anti-TPA antibodies and EACA each prevented the post-cuff increase. Unlike the euglobulin lysis time (ELT) this modified DWBCT (mDWBCT) measures the patients intact fibrinolytic system, including PAI and erythrocytes, in a quantitative fashion. Unlike either the ELT or the DWBCT the mDWBCT can be performed within two hours, so results are rapidly available for clinical decisions. These studies have demonstrated an easily performed, inexpensive, quantitative screening test of a patient's overall fibrinolytic system that reacts appropriately to pharmacologic manipulations.


Subcloning of HIV-2 nef genes in E. coli and immunological reactivity of expressed fusion proteins.
The nef gene located in the 3' region of the HIV-2 genome encodes an N-terminally myristylated protein of 27-35 kD, likely to be involved in the regulation of viral transcription. The nef genes of HIV-2 isolates GH-1, ROD, ST, BEN, and D194.17 were inserted into E. coli pEX vectors and expression of Nef beta-galactosidase fusion proteins was detected in stained gels. All fusion proteins specifically reacted with a rabbit serum raised against bacterially expressed Nef from HIV-2D194.17. Sera from monkeys inoculated with HIV-2BEN or SIVMAC251 recognized the Nef proteins of only certain HIV-2 isolates. No cross-reactivity of these sera with HIV-1 Nef and of a rabbit anti-HIV-1-Nef serum with the described HIV-2 Nef fusion proteins was observed.


Production of Single-Domain Antibodies in Pichia pastoris.
Single-domain antibodies (sdAbs) are binders that consist of a single immunoglobulin domain. SdAbs have gained importance as therapeutics, diagnostic reagents, and research tools. Functional sdAbs are commonly produced in Escherichia coli, which is a simple and widely used host for production of recombinant proteins. However, there are drawbacks of the E. coli expression system, including the potential for misfolded recombinant proteins and pyrogenic contamination with toxic lipopolysaccharides. Pichia pastoris is an alternative host for the production of heterologous proteins because of its high recombinant protein yields and the ability to produce soluble, properly folded proteins without lipopolysaccharide contamination. Here, we describe a method to produce sdAbs in P. pastoris. We present methods for the cloning of sdAb-encoding genes into a P. pastoris expression vector, production and purification of sdAbs, and measurement of sdAb-binding kinetics. Functional sdAbs are easily and routinely obtained using these methods.


Biofeedback as therapy in Raynaud's disease.
The following dimensions of Raynaud's disease are reviewed: (a) etiological factors, particularly those of a psychological nature, (b) proposed biological mechanisms of vasospastic episodes, (c) efficacy of pharmaceutical and surgical interventions, and (d) use of biofeedback as therapy. Emotional stress appears to be wholly sufficient to induce vasopastic episodes in victims. Some authors further hypothesize that suppressed anger may be involved in the phenomenon. Vehicles proposed to account for the symptoms include local vascular pathology, sympathetic discharge, and biochemical phenomena. Sympathectomy does not produce permanent remission and vasodilator medications tend to have undesirable side effects even when successful. Documented success with feedback techniques is sparse but encouraging. Published outcome studies are often confounded by the use of additional treatment modes such as relaxation training and hypnosis. The study of Raynaud's disease has enormous potential for the understanding of psychosomatic illness in a holistic fashion. Stresses induce immediate physiological responses, and corrective conditioning is easily implemented and monitored.


Methylation of ethanolamine groups in phosphoethanolamines is relevant for L-arginine insertion in lipid membranes.
The interaction of L-arginine with membranes composed by phospholipids with different degrees of methylation of the ethanolamine group was studied by means of surface and dipole potentials and surface pressure variations. The subsequent methylation of the amine head group appears to hinder the synergic response of the adsorption observed in phosphatidylethanolamine membranes. The kinetics of the binding process denotes that the methyl groups are relevant in regulating the specific interaction of the amino acid with the interface by hydrogen bonds. This response can be put in correlation with the function of signal transduction assigned previously to methyl lipids [F. Hirata and J. Axelrod, 1980] and appears to be relevant to understand the mechanism of insertion of arginine residues in peptides of biological interest.


Roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in metastasis of hepatocellular carcinoma cells.
Chemokines are involved in human hepatocellular carcinoma (HCC) carcinogenesis. However, the exact mechanism of chemokines in HCC carcinogenesis remains unknown. Here we investigated the roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in the metastasis of HCC. We found that the expression levels of CXCR4 mRNA in HCC tissues, MHCC97 cells, and HUVEC cells were 2.52 +/- 1.13, 2.34 +/- 1.16 and 1.63 +/- 1.26, respectively and that the CXCR4 protein levels were 1.38 +/- 0.13, 1.96 +/- 0.32 and 1.86 +/- 0.21, respectively. In contrast, CXCR4 was not detected in normal hepatic tissues. In 78 HCC patients, we also found that the concentration of CXCL12 in cancerous ascitic fluid was 783-8,364 pg/ml and that CXCL12 mRNA level in HCC metastasis portal lymph nodes was 1.21 +/- 0.87 but undetectable in normal hepatic tissues. Finally we discovered that recombinant human CXCL12 could induce MHCC97 cells and HUVEC cells to migrate with chemotactic indexes (CI) of 3.9 +/- 1.1 and 4.1 +/- 1.6, respectively. Cancerous ascitic fluid could also induce the migration of MHCC97 cells with a CI of 1.9 +/- 0.8. Thus, our data suggest that CXCR4 and CXCL12 may play an important role in the metastasis of HCC by promoting the migration of tumor cells.


Emergency percutaneous treatment in surgical bile duct injury.
The aim of this study is to evaluate the efficacy of emergency percutaneous treatment in patients with surgical bile duct injury (SBDI). From May 2004 to May 2007, 11 patients (five men, six women; age range 26-80 years; mean age 58 years) with a critical clinical picture (severe jaundice, bile peritonitis, septic state) due to SBDI secondary to surgical or laparoscopic procedures were treated by percutaneous procedures. We performed four ultrasound-guided percutaneous drainages, four external-internal biliary drainages, one bilioplasty, and two plastic biliary stenting after 2 weeks of external-internal biliary drainage placement. All procedures had 100% technical success with no complications. The clinical emergencies resolved in 3-4 days in 100% of cases. All patients had a benign clinical course, and reoperation was avoided in 100% of cases. Interventional radiological procedures are effective in the emergency management of SBDI since they are minimally invasive and have a high success rate and a low incidence of complications compared to the more complex and dangerous surgical or laparoscopic options.


Prospective study of 90 arthroscopic rotator cuff repairs for isolated distal supraspinatus tear, assessing the impact of cardiovascular risk factors on tendon healing.
Cardiovascular risk factors have been shown to be relevant to onset of rotator cuff tear, but their influence on healing remains to be determined. To assess the individual and cumulative impact of cardiovascular risk factors on tendon healing after arthroscopic rotator cuff repair. A single-center prospective study included 90 patients undergoing arthroscopic repair of isolated distal supraspinatus tendon tear. Only isolated full-thickness tears without anteroposterior extension, retraction (Patte stage ≤ 2) or fatty involution were included. Tendon healing was assessed on ultrasound according to the 5 types of the Sugaya classification. Clinical and functional assessment at 12 months used Constant score. Cardiovascular comorbidities were screened for in the preoperative anesthesiology consultation and control consultation: smoking, high blood pressure, dyslipidemia, diabetes, obesity, cardiovascular history, and obstructive sleep apnea syndrome. Ninety patients with a mean age of 59.6±6.95 years were included for analysis. 77.7% of cuffs showed healing on ultrasound, without signs of retear (stage 1-3), 16.6% showed partial retear (stage 4) and 6.6% showed no healing, with tendon retraction (stage 5). Mean Constant score improved by 37.5 points (p=0.001), for a global score of 78 at 12 months. Multivariate analysis identified several significant cardiovascular factors for poor healing: active smoking (p=0.002), dyslipidemia (p=0.006), high blood pressure (p≤0.001) and obesity (p=0.02). Cumulative comorbidity was associated with poor tendon healing, with significant impact as of 2 cardiovascular risk factors. Constant score decreased significantly according to healing stage (p≤0.001). The present study confirmed the involvement of cardiovascular risk factors in bone-tendon healing disorder, with significant impact as of 2 factors. IV; low-power prospective clinical series.


Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways.
Metabolic abnormalities and uncontrolled angiogenesis are two vital features of malignant tumors. Although fibroblast growth factor 6 (FGF6) is known to promote the proliferation and migration of bladder cancer (BC) cells, its influences on aerobic glycolysis and angiogenesis in BC remain unclear. Gene expression at messenger RNA and protein levels were examined by reverse transcription-quantitative polymerase chain reaction and Western blot analyses, respectively. Lactate production and glucose uptake in BC cells were evaluated by performing aerobic glycolysis assays. A vasculogenic mimicry assay was executed for assessing the angiogenesis of BC cells. The viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) cocultured with supernatants of BC cells were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, wound healing assay, and tube formation assay. It was found that FGF6 displayed a high level in BC cell lines. Silencing of FGF6 reduced the levels of lactate production, glucose uptake, and the expression of angiogenic factors and glycolytic enzymes in BC cells, which also inhibited the viability and migration of HUVECs. In addition, FGF6 depletion or aerobic glycolysis inhibitor 2-deoxy-d-glucose treatment decreased the total branching length and intersection number of both BC cells and HUVECs. Moreover, glucose or lactate treatment reversed FGF6-induced suppression of cell viability, migration, tube formation, and vasculogenic mimicry. The activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways was blocked by silenced FGF6. Furthermore, PI3K/Akt inhibitor (LY2940002) and p38-MAPK inhibitor (SB203580) inhibited the levels of aerobic glycolysis-related proteins. In conclusion, FGF6 knockdown suppressed aerobic glycolysis, thereby inhibiting angiogenesis in BC via regulation of the PI3K/Akt and MAPK signaling pathways.


Photosynthetic adaptation of Solanum dulcamara L. to sun and shade Environments : IV. A comparison of North American and European genotypes.
Clonal replicates of six genotypes of Solanum dulcamara L. grown in eight different environments were compared for photosynthesis and growth. Four of the genotypes were native to shaded habitats, two to sun habitats. The experimental growth environments differed in light level, daily temperature amplitude and substrate moisture availability. Treatments elicited large differences in lightsaturated photosynthetic rates and growth. Genotypic differences in response to the treatments were identified. However, when genotypes native to sun and shade habitats were compared, there were no consistent differences in photosynthesis or total plant dry weight. It was concluded that previously reported differences in the photosynthetic response of genotypes native to sun and shade habitats to treatment light level may have been the result of the persistent after-effects to changes in leaf water potential and not an adaptive response to growth light level.


A machine learning approach to high-risk cardiac surgery risk scoring.
In patients undergoing high-risk cardiac surgery, the uncertainty of outcome may complicate the decision process to intervene. To augment decision-making, a machine learning approach was used to determine weighted personalized factors contributing to mortality. American College of Surgeons National Surgical Quality Improvement Program was queried for cardiac surgery patients with predicted mortality ≥10% between 2012 and 2019. Multiple machine learning models were investigated, with significant predictors ultimately used in gradient boosting machine (GBM) modeling. GBM-trained data were then used for local interpretable model-agnostic explanations (LIME) modeling to provide individual patient-specific mortality prediction. A total of 194 patient deaths among 1291 high-risk cardiac surgeries were included. GBM performance was superior to other model approaches. The top five factors contributing to mortality in LIME modeling were preoperative dialysis, emergent cases, Hispanic ethnicity, steroid use, and ventilator dependence. LIME results individualized patient factors with model probability and explanation of fit. The application of machine learning techniques provides individualized predicted mortality and identifies contributing factors in high-risk cardiac surgery. Employment of this modeling to the Society of Thoracic Surgeons database may provide individualized risk factors contributing to mortality.


Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein.
At least three different glucose transport systems exist in mammalian cells. These are: (1) the constitutively active, facilitative carrier characteristic of human erythrocytes, Hep G2 (ref. 2) cells and rat brain; (2) the Na-dependent active transporter of kidney and small intestine; and (3) the facilitative carrier of rat liver (B. Thorens and H. F. Lodish, personal communication). A fourth possible glucose transport system is the insulin-dependent carrier that may be specific to muscle and adipose tissue. This transporter resides primarily in an intracellular compartment in resting cells from where it translocates to the cell surface upon cellular insulin exposure. This raises the question of whether hormonal regulation of glucose transport is conferred by virtue of a tissue-specific signalling mechanism or a tissue-specific glucose transporter. Here we present data supporting the latter concept based upon a monoclonal antibody against the fat cell glucose transporter that identifies a unique, insulin-regulatable glucose transport protein in muscle and adipose tissue.


Psychological intervention for a child exposed to murder.
This report describes the process of psychotherapy for a 7-y-old boy who witnessed the gruesome murder of his mother by the father. Expressive therapy techniques such as play, art and storytelling were used to help the child emote, achieve independence and emotional maturity. The child was seen as an in-patient for 3 mo on a daily basis, followed by weekly and subsequently bi-monthly follow ups. During the ward stay, aggression towards other children and grandmother had reduced significantly. The child was able to verbalize the irreversibility and inevitability of death, and had developed healthy ways to resolve the grief. In the subsequent follow ups, although some behavior problems persisted, gains from therapy generalized to help him deal with challenges of real life, such as a constantly lurking fear of the father returning from prison.


A silent epidemic of major congenital malformations in Tigray, northern Ethiopia: hospital-based study.
Congenital malformations are defects of the morphogenesis of organs or body during the pregnancy period and are identifiable at pre- or postnatal. They are identified as the major cause of child mortality worldwide. There is a need to understand the prevalence of congenital malformations in Tigray and Ethiopia in general as surveillance data are lacking. Hence, this study was designed to investigate the burden of major congenital malformations in the Tigray Region, Northern Ethiopia. Hospital-based cross-sectional study was conducted to identify neonates with major congenital anomalies in the labor ward admitted at six major public hospitals of Tigray region, Ethiopia between January 2018 and 2019. All newborns/neonates delivered in all study hospitals during the study period were considered as the study population. The prevalence of major congenital anomalies and the distribution of each type of major congenital anomalies within total birth were calculated. Data on maternal, and newborn demographic characteristics was collected. Statistical analysis was done using SPSS and p value < 0.05 was considered significant. A total of 12,225 births and terminations were recorded in the six hospitals during the study period. Of total 12,225 births and terminations examined, 383 births had major congenital malformations and the overall prevalence of congenital malformations was 3.13% of the total births examined. Congenital anomalies (CAs) of the central nervous system specifically neural tube defects (NTDs) were the commonest anomalies in this study, found in 68.7% (263NTDs/383 CAs) of the neonates with CAs. The overall prevalence of NTDs was 2.15% (263/12,225 births) of the total births examined. Maternal factors such as women 20 years of age or younger (p < 0.0001) and women older than 35 years of age (p < 0.0001), abortion history (p < 0.0001), gravidity above 4 (p = 0.005), were more likely associated with an increased risk of babies with congenital anomalies. Fetal factors including gestational ages below 28 weeks (p < 0.0001) and above 40 weeks (p < 0.0001) were strongly associated with an increased risk of babies with congenital anomalies. However, these associated factors were not resulted from multivariable logistic regression analysis. Thus, the result might be affected by possible confounding factors. This study has shown a high prevalence of major congenital anomalies in the study community. Of the total congenital anomalies observed, most of neonates are affected with neural tube defects, a birth defect with well-established evidence having folic acid deficiency or insufficiency is the predominant cause of spina bifida and anencephaly. This just screams urgency to implement effective/mandatory/ programs to get all women of reproductive age an adequate folic acid to prevent spina bifida and anencephaly.


Sociality as a life-history tactic of ground squirrels.
Multi-variate analysis of life-history traits of 18 species of burrowing sciurids indicates that reproductive effort is determined by body-size energetics. Other traits, such as age adult weight reached, age of dispersal, length of time of gestation, were significantly correlated with body size. A principal component analysis suggested that the complex of life-history traits could be reduced to four components: body size (=weight), seasonality, specific reproductive effort, and maturity. The variation in the sociality index was best explained by age of first reproduction and age adult weight reached. Generally, species are more social when large body size combined with a relatively short growing season is associated with delayed dispersal and occurs in those species typically breeding for the first time at age two or older. Sociality in these species may have evolved through retention of daughters within the maternal home range as a means of continuing reproductive investment beyond weaning.


Starting and stopping mechanisms of absence epileptic seizures are revealed by hazard functions.
We show that the hazard function provides useful information about the starting and the stopping mechanisms of absence epileptic seizures. The hazard function quantifies changes in the probability that an event (respectively, the starting and the stopping of a seizure) occurs in some small time interval given that it has not occurred yet. It informs us about changes in the concentration of endogenous substances that modulate the neuronal signalling properties of (parts of) the brain. In a pharmacological experiment, we used the hazard function to study the effect of a GABA-transaminase inhibitor (vigabatrin) on the starting and the stopping mechanisms of absence epileptic seizures in a genetic rat model of absence epilepsy (the WAG/Rij rat). This experiment showed that a high GABA level changed the stopping mechanism of the absence epileptic seizures, creating much better conditions for very long seizures to develop. With respect to the starting mechanism, it was found that both with a high and a low GABA level, there was evidence for a recovery mechanism that decreases the probability that a new seizure starts. Initially, this probability is larger with a high GABA level, but gradually it converges to the same constant baseline probability as in the condition with a low GABA level.


Association between having a regular healthcare provider and pre-exposure prophylaxis use among men who have sex with men: a cross-sectional survey.
Healthcare providers whom people see regularly (e.g., primary care providers [PCPs]) are likely to interact with individuals at risk of human immunodeficiency virus (HIV). However, most PCPs report never prescribing pre-exposure prophylaxis (PrEP), a medication that prevents HIV infection. This study examined the association between having a regular healthcare provider and PrEP use among men who have sex with men (MSM). We analyzed health survey data from Black (n = 151) and White (n = 113) MSM in Atlanta, GA using log binomial regressions. Among Black MSM, the proportion who used PrEP was nearly three times higher for those with a regular provider compared to those without one (aPR 2.58; 95% CI: 0.96, 6.93). Conversely, the proportion of White MSM who used PrEP was slightly lower among those with a regular provider (aPR 0.67; 95% CI: 0.36, 1.27). Findings suggest having a regular provider may be more strongly associated with PrEP among Black MSM.


Incidence risks for subtypes of heart diseases in a Russian cohort of Mayak Production Association nuclear workers.
Heart diseases are one of the main causes of death. The incidence risks were assessed for various types of heart diseases (HDs) in a cohort of Russian nuclear workers of the Mayak Production Association (PA) who had been chronically occupationally exposed to external gamma and/ or internal alpha radiation. The study cohort included all workers (22,377 individuals) who had been hired at the Mayak PA during 1948-1982 and followed up until 31 December 2018. The mean gamma-absorbed dose to the liver (standard deviation) was 0.43 (0.63) Gy, and the mean alpha-absorbed dose to the liver was 0.25 (1.19) Gy. Excess relative risk (ERR) per unit liver-absorbed dose (Gy) was calculated based on maximum likelihood. At the end of the follow-up, 559 chronic rheumatic heart disease (CRHD), 7722 ischemic heart disease (IHD) [including 2185 acute myocardial infarction (AMI) and 3976 angina pectoris (AP)], 4939 heart failure (HF), and 3689 cardiac arrhythmia and conduction disorder (CACD) cases were verified in the study cohort. Linear model fits of the gamma dose response for HDs were best once adjustments for non-radiation factors (sex, attained age, calendar period, smoking status and alcohol consumption) and alpha dose were included. ERR/Gy in males and females was 0.17 (95% confidence intervals: 0.10, 0.26) and 0.23 (0.09, 0.38) for IHD; 0.18 (0.09, 0.29) and 0.26 (0.08, 0.49) for AP; - 0.01 (n/a, 0.1) and - 0.01 (n/a, 0.27) for AMI; 0.27 (0.16, 0.40) and 0.27 (0.10, 0.49) for HF; 0.32 (0.19, 0.46) and 0.05 (- 0.09, 0.22) for CACD; 0.73 (- 0.02, 2.40) and - 0.12 (- 0.50, 0.69) for CRHD, respectively. Sensitivity analyses demonstrated the persistence of a significant dose-response regardless of exclusion/inclusion of adjustments for known potential non-radiation confounders (smoking, alcohol consumption, body mass index, hypertension, diabetes mellitus), and it was only the magnitude of the risk estimate that varied. The risks of HD incidence were not modified with sex (except for the CACD risk). This study provides evidence for a significant association of certain types of HDs with cumulative dose of occupational chronic external exposure to gamma radiation.


Modeling ALS and FTD with iPSC-derived neurons.
Recent advances in genetics and neuropathology support the idea that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD) are two ends of a disease spectrum. Although several animal models have been developed to investigate the pathogenesis and disease progression in ALS and FTD, there are significant limitations that hamper our ability to connect these models with the neurodegenerative processes in human diseases. With the technical breakthrough in reprogramming biology, it is now possible to generate patient-specific induced pluripotent stem cells (iPSCs) and disease-relevant neuron subtypes. This review provides a comprehensive summary of studies that use iPSC-derived neurons to model ALS and FTD. We discuss the unique capabilities of iPSC-derived neurons that capture some key features of ALS and FTD, and underscore their potential roles in drug discovery. There are, however, several critical caveats that require improvements before iPSC-derived neurons can become highly effective disease models. This article is part of a Special Issue entitled SI: Exploiting human neurons.


Bariatric surgery in adolescents: preliminary 1-year results with a novel technique (Santoro III).
Bariatric surgery (BS) was recognized as the only treatment for morbid obesity in adolescents. Classic surgical procedures are based on mechanical restriction and/or malabsorption, resulting in a large number of possible complications and demanding lifelong medical attention. A novel BS design, the Santoro III procedure, relies on modifying secretion of the satiogenic hormones GLP-1 and PYY. This approach avoids common BS complications such as prostheses, narrow anastomoses, excluded segments, and malabsorption. This study describes the 1-year follow-up of the first ten adolescents operated on using the Santoro III technique in a pediatric surgical service. Ten adolescents, mean age 16.1 ± 1.7 years with body mass index (BMI) greater than 40 kg/m(2) (range 44 to 72 kg/m(2)), refractory to at least 2 years of medical weight loss treatment were selected by a multidisciplinary team to undergo BS. This operation consists of a sleeve gastrectomy with enteroomentectomy and partial gastro-ileal derivation. After 1 year, mean body weight decreased from 140.3 to 88.6 kg, and BMI decreased from 52.8 ± 9.5 kg/m(2) to 33.4 ± 7.7 kg/m(2), with percent of excess BMI lost as 83.9 ± 17.1%. Glucose, insulin, total cholesterol, LDL-cholesterol, and triglyceride levels decreased significantly, while HDL-cholesterol, hemoglobin, and albumin levels remained unchanged. There were no mortalities or reoperations. The two complications that presented during the trial (intraperitoneal abscess and polyneuritis) resolved with medical treatment without sequelae. All the patients returned to their normal activities and their BMI began to stabilize approximately 2 years following surgery. The Santoro III procedure is an attractive option for adolescent BS, with promising 1-year follow-up results. These initial studies should be monitored for long-term outcomes and confirmed on a larger group of patients.


A new method to model change in cutaneous blood flow due to mechanical skin irritation part I: comparison between experimental and numerical data.
Mechanical skin irritation creates vasodilation. Vasodilation of vascular networks induces increase in blood volume and blood velocity. Both can be measured by Laser Doppler Velocimetry. We propose in this article a method permitting comparison between experimental and numerical results. Experimental data was obtained by Laser Doppler Velocimetry. Numerical results were obtained by a continuous model of the vascular network. The model consists of three layers. First and last layer are described by anisotropic and heterogeneous porous media. They represent the irrigation and the drainage of the vascular system. The intermediate layer is described by a lumped parameter model that does not permit horizontal fluxes. All vessels are compliant. The permeabilities depend on the volumes of the specific layer. Skin irritation is modeled by a change in compliance of small arterial blood vessels. The comparison between experimental and numerical data is based on the model proposed by Bonner and Nossal [1981. Model for laser Doppler measurements of blood flow. Appl. Opt. 20, 2097-2107]. The model describes the Doppler frequency spectrum S(omega) as a function of the optical phenomena creating the frequency shift. The comparison is based on the model of the first moment M1 approximately integralomegaS(omega)domega. The variables of the first moment can be determined by results of the numerical model. We have shown, that it exists a linear relation between the change in compliance and the following increase in first moment. Using this linear relation experimental and numerical data can be compared.


Endovascular therapy in acute ischemic stroke with poor reperfusion is associated with worse outcomes compared with best medical management: a HERMES substudy.
Functional outcomes in patients with acute ischemic stroke (AIS) with large vessel occlusion (LVO) undergoing endovascular treatment (EVT) with poor reperfusion were compared with patients with AIS-LVO treated with best medical management only. Data are from the HERMES collaboration, a patient-level meta-analysis of seven randomized EVT trials. Baseline characteristics and functional outcomes (modified Rankin Scale (mRS) score at 90 days) were compared between patients with poor reperfusion (defined as modified Thrombolysis in Cerebral Infarction Score 0-1 on the final intracranial angiography run as assessed by the central imaging core laboratory) and patients in the control arm with multivariable logistic ordinal logistic regression adjusted for pre-specified baseline variables. 972 of 1764 patients from the HERMES collaboration were included in the analysis: 893 in the control arm and 79 in the EVT arm with final mTICI 0-1. Patients with poor reperfusion who underwent EVT had higher baseline National Institutes of Health Stroke Scale than controls (median 19 (IQR 15.5-21) vs 17 (13-21), P=0.011). They also had worse mRS at 90 days compared with those in the control arm in adjusted analysis (median 4 (IQR 3-6) vs median 4 (IQR 2-5), adjusted common OR 0.59 (95% CI 0.38 to 0.91)). Symptomatic intracranial hemorrhage was not different between the two groups (3.9% vs 3.5%, P=0.75, adjusted OR 0.94 (95% CI 0.23 to 3.88)). Poor reperfusion after EVT was associated with worse outcomes than best medical management, although no difference in symptomatic intracranial hemorrhage was seen. These results emphasize the need for additional efforts to further improve technical EVT success rates.


Intranasal midazolam as first-line inhospital treatment for status epilepticus: a pharmaco-EEG cohort study.
We sought to evaluate the efficacy and tolerability of intranasal midazolam (in-MDZ) as first-line inhospital therapy in patients with status epilepticus (SE) during continuous EEG recording. Data on medical history, etiology and semiology of SE, anticonvulsive medication usage, efficacy and safety of in-MDZ were retrospectively reviewed between 2015 and 2018. Time to end of SE regarding the administration of in-MDZ and ß-band effects were analyzed on EEG and with frequency analysis. In total, 42 patients (mean age: 52.7 ± 22.7 years; 23 females) were treated with a median dose of 5 mg of in-MDZ (range: 2.5-15 mg, mean: 6.4 mg, SD: 2.6) for SE. The majority of the patients suffered from nonconvulsive SE (n = 24; 55.8%). In total, 24 (57.1%) patients were responders, as SE stopped following the administration of in-MDZ without any other drugs being given. On average, SE ceased on EEG at 05:05 (minutes:seconds) after the application of in-MDZ (median: 04:56; range: 00:29-14:53; SD:03:13). Frequency analysis showed an increased ß-band on EEG after the application of in-MDZ at 04:07 on average (median: 03:50; range: 02:20-05:40; SD: 01:09). Adverse events were recorded in six patients (14.3%), with nasal irritations present in five (11.9%) and prolonged sedation occurring in one (2.6%) patient. This pharmaco-EEG-based study showed that in-MDZ is effective and well-tolerated for the acute treatment of SE. EEG and clinical effects of in-MDZ administration occurred within 04:07 and 5:05 on average. Intranasal midazolam appears to be an easily applicable and rapidly effective alternative to buccal or intramuscular application as first-line treatment if an intravenous route is not available.


[Neovascular invasion of the endothelio-descemetic interface occurring after deep anterior lamellar keratoplasty].
The endothelio-descemetic interface (EDI) of a deep anterior lamellar keratoplasty (DALK) may become the locus of a neovascular proliferation. Bevacizumab (Avastin) is an antiangiogenic alternative available for curative treatment in deep corneal neovascularization. We report the case of a 49-year-old woman who had received two arcuate relaxing incisions for high astigmatism after DALK. She developed graft rejection associated with significant neovascular stromal invasion in the EDI of the graft-host interface. Two subconjunctival injections of bevacizumab 1 month apart as well as thermocauterization of the feeding vessel were necessary and effective. No recurrence has been observed after 2 years of follow-up. Corneal neovascularization can be a cause of DALK rejection. A combination of anti-antiangiogenic and physical methods may abort graft rejection and permanently restore graft function.


Time required for indocyanine green fluorescence emission for evaluating bowel perfusion in left-sided colon and rectal cancer surgery.
Indocyanine green fluorescence imaging (ICG-FI) has been reported to be useful in reducing the incidence of anastomotic leakage (AL) in colectomy. This study aimed to investigate the correlation between the required time for ICG fluorescence emission and AL in left-sided colon and rectal cancer surgery using the double-stapling technique (DST) anastomosis. This retrospective study included 217 patients with colorectal cancer who underwent left-sided colon and rectal surgery using ICG-FI-based perfusion assessment at our department between November 2018 and July 2022. We recorded the time required to achieve maximum fluorescence emission after ICG systemic injection and assessed its correlation with the occurrence of AL. Among 217 patients, AL occurred in 21 patients (9.7%). The median time from ICG administration to maximum fluorescence emission was 32 s (range 25-58 s) in the AL group and 28 s (range 10-45 s) in the non-AL group (p < 0.001). The cut-off value for the presence of AL obtained from the ROC curve was 31 s. In 58 patients with a required time for ICG fluorescence of 31 s or longer, the following risk factors for AL were identified: low preoperative albumin [3.4 mg/dl (range 2.6-4.4) vs. 3.9 mg/dl (range 2.6-4.9), p = 0.016], absence of preoperative mechanical bowel preparation (53.8% vs. 91.1%, p = 0.005), obstructive tumor (61.5% vs. 17.8%, p = 0.004), and larger tumor diameter [65 mm (range 40-90) vs. 35 mm (range 4.0-100), p < 0.001]. The time required for ICG fluorescence emission was associated with AL.


Melanocortin agonists stimulate lipolysis in human adipose tissue explants but not in adipocytes.
The central melanocortin system is broadly involved in the regulation of mammalian nutrient utilization. However, the function of melanocortin receptors (MCRs) expressed directly in peripheral metabolic tissues is still unclear. The objective of this study was to investigate the lipolytic capacity of MC1-5R in differentiated adipocytes versus intact white adipose tissue. Non-selective MCR agonist α-MSH, MC5R-selective agonist PG-901 and MC4R-selective agonist LY2112688 significantly stimulated lipolysis in intact white adipose tissue, whereas stimulation of MCRs in differentiated adipocytes failed to do so. The lipolytic response of MC5R was decreased in intact human white adipose tissue when co-treating with β-adrenergic antagonist propranolol, suggesting that the effect may be dependent on neuronal innervation via noradrenalin release. When developing an anti-obesity therapeutic drug with selective MC4R/MC5R properties, effects on lipolysis in white adipose tissue may be physiologically relevant.


Riboflavin ameliorates pathological cardiac hypertrophy and fibrosis through the activation of short-chain acyl-CoA dehydrogenase.
Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. FAD, a coenzyme of SCAD, participates in the electron transfer of SCAD-catalyzed fatty acid β-oxidation, which plays a crucial role in maintaining the balance of myocardial energy metabolism. Insufficient riboflavin intake can lead to symptoms similar to short-chain acyl-CoA dehydrogenase (SCAD) deficiency or flavin adenine dinucleotide (FAD) gene abnormality, which can be alleviated by riboflavin supplementation. However, whether riboflavin can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of riboflavin on pathological cardiac hypertrophy and fibrosis. In vitro experiments, riboflavin increased SCAD expression and the content of ATP, decreased the free fatty acids content and improved PE-induced cardiomyocytes hypertrophy and AngⅡ-induced cardiac fibroblasts proliferation by increasing the content of FAD, which were attenuated by knocking down the expression of SCAD using small interfering RNA. In vivo experiments, riboflavin significantly increased the expression of SCAD and the energy metabolism of the heart to improve TAC induced pathological myocardial hypertrophy and fibrosis in mice. The results demonstrate that riboflavin improves pathological cardiac hypertrophy and fibrosis by increasing the content of FAD to activate SCAD, which may be a new strategy for treating pathological cardiac hypertrophy and fibrosis.


Osmoregulation of fission yeast: cloning of two distinct genes encoding glycerol-3-phosphate dehydrogenase, one of which is responsible for osmotolerance for growth.
Many types of microorganisms, including both prokaryotes and eukaryotes, have developed mechanisms to adapt to severe osmotic stress. In this study, we isolated multicopy suppressor genes for a Schizosaccharomyces pombe mutant, which exhibited the clear phenotype of being osmosensitive for growth (Osms) on agar plates containing high concentrations of either non-ionic or ionic osmotic solutes. Two genes were thus identified, and each was suggested to encode an NADH-dependent glycerol-3-phosphate dehydrogenase (GPD), which is required for glycerol synthesis. The nucleotide sequences, determined for these genes (named gpd1+ and gpd2+, respectively), revealed that S. pombe has two distinct GPD isozymes. They are only 60% identical to each other in their amino acid sequences. One such isozyme, GPD1, was shown to be directly involved in osmoregulation, based on the following observations. (i) Expression of gpd1+ was regulated at the mRNA level in response to osmotic upshift. (ii) It was demonstrated that wild-type cells markedly accumulated internal glycerol under high-osmolarity growth conditions. (iii) delta gpd1 mutants, however, failed to do so even in a high-osmolarity medium, and thus exhibited an Osms phenotype. On the other hand, the gpd2+ gene was constitutively expressed at a particular low level, regardless of the osmolarity of the medium.


Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer.
Epigenetics refers to heritable changes in gene expression that are independent of alterations in DNA sequence. It is now accepted that disruption of epigenetic mechanisms plays a key role in the pathogenesis of cancer: culminating in altered gene function and malignant cellular transformation. DNA methylation and histone modifications are the most widely studied changes but non-coding RNAs such as miRNAs are also considered part of the epigenetic machinery. The insulin-like growth factor (IGF) axis is composed of two ligands, IGF-I and -II, their receptors and six high affinity IGF binding proteins (IGFBPs). The IGF axis plays a key role in cancer development and progression. As IGFBP genes have consistently been identified among the most common to be aberrantly altered in tumours, this review will focus on epigenetic regulation of IGFBP-3 in cancer for which the majority of evidence has been obtained.


Assessment of genetic linkage and parent-of-origin effects on obesity.
Obesity is a growing health care problem worldwide and is a major underlying risk factor for common diseases such as diabetes. Parent-of-origin effect has been reported to be involved in the development of obesity. But the genes with imprinting effects related to obesity are largely unknown. The objective of the study was to identify obesity-related genetic loci, both with and without imprinting effects. We conducted genome-wide linkage analyses for obesity with and without consideration of imprinting effects in a large sample including more than 4000 individuals. In addition to body mass index (BMI), we also used a more stringent and accurate obesity definition, which simultaneously considers BMI and percentage of fat mass (PFM) in a gender-specific manner. Simulations were performed to identify the genome-wide significant and suggestive significant thresholds. In nonimprinted linkage analyses, we detected suggestive linkage at 2q31 (LOD = 2.23) and 16q22 (LOD = 1.87) for BMI and 2q37 (LOD = 2.23) for BMI and PFM. Interestingly, 2q37 also achieved a significant maternal linkage with BMI and PFM (LOD=3.34) in imprinted linkage analyses. Imprinted linkage analyses revealed suggestive linkage evidence for BMI at three additional genomic regions, including 3p14 (LOD = 2.20, paternal), 3q24 (LOD = 1.97, maternal), and 19q13 (LOD = 1.81, maternal). We reported linkage and imprinting effects for obesity on several chromosome regions and suggested the potential importance of parent-of-origin effects and phenotype definition of obesity in delineating the genetic basis of obesity.


Seeded growth of monodisperse gibbsite platelets to adjustable sizes.
Nanosized hexagonal gibbsite seeds are grown from a mixture of dissolved alumina alkoxides at 85 degrees C. Centrifugation reduces the polydispersity by 30%. The seeds can be grown further by adding them to a fresh alkoxide mixture and heating it. This procedure was repeated several times to obtain particles of 570 nm +/- 11% diameter and a thickness of 47 +/- 23%. No indications of a size limit were observed. The thus obtained particles may form easily a columnar phase. Individual gibbsite particles in solution can be seen by confocal microscope.


Molecular basis of hypokalemic myopathy caused by 17alpha-hydroxylase/17,20-lyase deficiency.
We describe a 28-year-old woman presenting with hypokalemic myopathy caused by 17alpha-hydroxylase/17,20-lyase deficiency caused by a homozygous mutation consisting of a G-to-C transition in the initiation codon in exon 1 of the CYP17 gene resulting in expression of an enzymatically inactive truncated P450c17 protein.


[Experimental-clinical substantiation of the use of atraumatic suture material "metallatravm" in the surgery of bile ducts].
High efficacy of home sutural material "Metallatravm" application while biliary anastomoses creation was proved in experiment on 180 white rats. One-layer extramucosal interrupted suture application proved as a long-term one. In 35 patients with biliary ducts obstruction high efficacy of applied material was noted. Ligature cholelithiasis and stenosis recurrences were not observed.


Adaptive variation of pelage color within and between species of the subterranean mole rat (Spalax ehrenbergi) in Israel.
Color notations of dorsal pelage were analyzed in 451 adult subterranean mole rats, comprising 19 populations and 4 chromosomal species (2n=52, 54, 58 and 60) of the Spalax ehrenbergi superspecies in Israel. In addition, the color notations of soil samples from the collection sites were measured. In an attempt to evaluate the degree of correlation between pelage color of mole rats and the local soil color, each color was compared both macro- and microgeographically. The macrogeographic comparisons were among populations of the 4 chromosomal species, and the microgeographic comparisons were among pairs of geographically neighboring subpopulations which occur under similar climatic conditions but differ in soil type and color. The results indicate that 1. no differences in pelage color notation exist between the sexes; 2. pelage of mole rats is generally characterized by an over-all grayish color, but its shades vary regionally and locally in accordance with varying soil color; 3. a positive correlation was found between pelage and local soil colors in the macrogeographic analysis and this correlation was verified in a microgeographic comparison; 4. specimens from populations of the northern chromosomal species (2n=52, 54) mainly inhabit terra rossa and basalt soils, respectively, with reddish brown tones, and they tend to have a more reddish shade, whereas animals from the central species (2n=58), which inhabits mainly dark soils including alluvial clays, terra rossa and brown rendzina and the souther species 2n=60, which occurs mainly in light soil types such as pale rendzina, sandy loams and loess, tend to have a more yellowish shade. The general appearance of specimens from 2n=58 was dark gray while that of 2n=60 specimens was light gray; 5. mole rats living in xeric environments (particularly 2n=60, but also 2n=54) are lighter than those which live in mesic environments (2n=52, 58). The results support the conclusion that pelage color of strictly subterranean mole rats is subject to selection pressures of overground predation of disharmonious types with their background soil color. The possibility that the pelage color variation and patterns also contributes to better thermoregulation while mole rats are above ground is discussed.


How to identify compounds posing problems in absorption, distribution and elimination.
Absorption problems may be regarded mainly as compound inherent characteristics and are to a certain degree predictable on the basis of physicochemical parameters of test compounds. Problems originating from interactions of the compound and/or its metabolites with biological structures or processes are system inherent problems and can only be recognized by in vivo disposition studies of the compound. The examples given demonstrate clearly that preclinical absorption and disposition studies are of great help and in some cases even indispensable in planning of toxicity studies and in interpreting toxicity data.


US Food and Drug Administration Approval Summary: Nivolumab Plus Platinum-Doublet Chemotherapy for the Neoadjuvant Treatment of Patients With Resectable Non-Small-Cell Lung Cancer.
On March 4, 2022, the US Food and Drug Administration (FDA) approved nivolumab plus platinum-doublet chemotherapy for the neoadjuvant treatment of patients with resectable non-small-cell lung cancer (NSCLC). We discuss the FDA's review of the key data and regulatory considerations supporting this approval. The approval was based on the results of CheckMate 816, an international, multiregional, active-controlled trial that randomly assigned 358 patients with resectable NSCLC, stage IB (≥4 cm) to IIIA (N2) per the American Joint Committee on Cancer seventh staging edition to receive either nivolumab plus platinum-doublet or platinum-doublet chemotherapy alone for three cycles before planned surgical resection. The major efficacy end point that supported this approval was event-free survival (EFS). At the first planned interim analysis (IA), the hazard ratio (HR) for EFS was 0.63 (95% CI, 0.45 to 0.87; P = .0052; statistical significance boundary = .0262) favoring the nivolumab plus chemotherapy arm; the median EFS was 31.6 months (95% CI, 30.2 to not reached) in the nivolumab plus chemotherapy arm versus 20.8 months (95% CI, 14.0 to 26.7) in the chemotherapy-only arm. At the time of a prespecified IA for overall survival (OS), 26% of patients had died, and the HR for OS was 0.57 (95% CI, 0.38 to 0.87; P = .0079; statistical significance boundary = .0033). Eighty-three percent of patients in the nivolumab-containing arm versus 75% in the chemotherapy-only arm received definitive surgery. This approval, the first for any regimen for the neoadjuvant treatment of NSCLC in the United States, was supported by a statistically significant and clinically meaningful improvement in EFS with no evidence of detriment in OS or negative impact on patients' receipt and timing of surgery or surgical outcomes.


Microplastics analytics: why we should not underestimate the importance of blank controls.
Recent years have seen considerable scientific attention devoted towards documenting the presence of microplastics (MPs) in environmental samples. Due to omnipresence of environmental microplastics, however, disentangling environmental MPs from sample contamination is a challenge. Hence, the environmental (collection site and laboratory) microplastics contamination of samples during processing is a reality that we must address, in order to generate reproducible and reliable data. Here we investigated published literature and have found that around 1/5 of studies failed to use blank controls in their experiments. Additionally, only 34% of the studies used a controlled air environment for their sample processing (laminar flow, fume hood, closed laboratory, clean room, etc.). In that regard, we have also shown that preparing samples in the fume hood, leads to more microplastics > 1 μm) contamination than preparing it in the laboratory bench and the laminar flow. Although it did not completely prevent microplastics contamination, the processing of sample inside the laminar flow is the best option to reduce sample contamination during processing. Overall, we showed that blank controls are a must in microplastics sample preparation, but it is often overlooked by researchers. The online version contains supplementary material available at 10.1186/s43591-023-00065-3.


Health-related quality of life after maxillectomy: obturator rehabilitation compared with flap reconstruction.
Health-related quality of life (QoL) reported by patients has the potential to improve care after ablative surgery of the midface, as existing treatment algorithms still generally revolve around outcomes assessed traditionally only by clinicians. Decisions in particular relate to reconstruction with a flap compared with rehabilitation with an obturator, the need for adjuvant treatment, and morbidity related to the size of the defect. We prospectively collected health-related QoL assessments for 39 consecutive patients treated by maxillectomy between 01 January 2010 and 31 December 2014 using the University of Washington Quality of Life Questionnaire, and who had a mean (SD) duration of follow-up of 14 (4). We made sub-group analyses using paired t tests and analysis of variance (ANOVA) to compare reconstruction with a flap with rehabilitation with obturators, size of the vertical defect, and whether adjuvant treatment with radiotherapy or chemoradiotherapy adversely affected it. Overall there was a significant decrease in health-related QoL after treatment compared with before (p<0.001), but there was no significant difference in the effects of any of the paired reconstructive and rehabilitation treatments on it. Obturators remain an important option for rehabilitation in selected patients in addition to reconstruction with a flap. We found that neither increasing the size of the vertical defect (in an attempt to ensure clear margins) nor the use of postoperative radiotherapy seemed to have any adverse effect on QoL. More patients are required before we can conclude that the potential survival benefits of such measures may outweigh any adverse effects.


[Transtracheal oxygen therapy with oxycath: introduction technic, complications, results in 12 treated patients].
Continuous oxygen therapy is essential in the treatment of advanced chronic obstructive pulmonary disease (COPD). A transtracheal oxygen administration system is more effective in the rehabilitation of these patients than are traditional systems, nasal canula or Venturi mask devices. In the present work the authors describe a simple technique for introducing the transtracheal catheter. The procedure is performed under local anesthesia and a Teflon catheter is inserted between the second and third tracheal rings. In a case study of 12 patients the complications encountered included purulent drainage of the skin tract and accidental displacement of the transtracheal catheter. No procedure related deaths were incurred. Subjectively, the patients experience a sensation of being able to breathe more easily, thus resulting in increased outdoor activity.


Flowcytometric and cytogenetic analysis of human cultured cell lines derived from high- and low-grade astrocytomas.
Five human cell lines cultured from high- and low-grade astrocytomas in cerebral hemisphere have been analyzed for DNA and protein distribution by flowcytometric (FCM) and correlated with cytogenetic profiles. Simultaneous calibration with chicken erythrocytes as a co-running standard provided an estimate of chromosomal number of predominate stem cells of each cell line by the ratio of the DNA content of the major peak (G1) to that of chicken erythrocyte (T/E ratio) of FCM. Various lines had different distributions of chromosomal number, ranging from near diploid to tetraploid. Each line had a stem-cell population and chromosomal markers indicative of clonal selection, but no common marker specific to astrocytomas. The histogram of DNA distribution obtained by FCM correlated well with the chromosomal distribution by cytogenetic analysis. In addition, simultaneous measurement of protein and DNA content in multidimensional FCM demonstrated a sigmoid configuration of the profiles, which indicated a gradual increase of protein content associated with an increase of chromosomal number or with progression of cell cycle. To avoid confusion of a bimodal chromosomal distribution with the G2/M phase of the cell cycle, and to determine chromosomal numbers associated with a DNA histogram, simultaneous cytogenetic and FCM study are required. More rapid than cytogenetic analysis, the T/E ratio allows estimation of chromosomal number of the stem-cell population associated with DNA histograms of cultured glioma-derived cell lines.


Tailored Properties of Carbon for Supercapacitors by Blending Lignin and Cellulose to Mimic Biomass as Carbonaceous Precursor.
KOH-activated carbon materials prepared from biomass-derived carbon source, cellulose and lignin, were compared. Mixtures of different ratios of cellulose and lignin were used to partially mimic biomass as carbon source. This allows tailoring and optimizing of the KOH activated carbon materials by getting rid of the restriction of the intrinsic proportion of cellulose and lignin in specific biomass. The results indicate that cellulose use results in a more porous structure, whereas lignin use leads to more partially activated graphite structure. The activated carbon material (CL1) prepared from blend of cellulose with lignin in mass ratio of 1 : 1 exhibits a high specific surface area of 2000.39 m2 g-1 , and in TEABF4 /ACN (tetraethylammonium tetrafluoroborate dissolved in acetonitrile) electrolyte it showed a maximum specific capacitance of 136.10 F g-1 , a maximum energy density of 18.11 Wh kg-1 , and a capacitance retention of 85.04 % under current density as high as 15 A g-1 .


Discovery of novel phenothiazine derivatives as new agrochemical alternatives for treating plant viral diseases.
Plant viral diseases, namely 'plant cancer', are extremely difficult to control. Even worse, few antiviral agents can effectively control and totally block viral infection. There is an urgent need to explore and discover novel agrochemicals with high activity and a unique mode of action to manage these refractory diseases. Forty-one new phenothiazine derivatives were prepared and their inhibitory activity against tobacco mosaic virus (TMV) was assessed. Compound A8 had the highest protective activity against TMV, with a half-maximal effective concentration (EC50 ) of 115.67 μg/mL, which was significantly better than that of the positive controls ningnanmycin (271.28 μg/mL) and ribavirin (557.47 μg/mL). Biochemical assays demonstrated that compound A8 could inhibit TMV replication by disrupting TMV self-assembly, but also enabled the tobacco plant to enhance its defense potency by increasing the activities of various defense enzymes. In this study, novel phenothiazine derivatives were elaborately fabricated and showed remarkable anti-TMV behavior that possessed the dual-action mechanisms of inhibiting TMV assembly and invoking the defense responses of tobacco plants. Moreover, new agrochemical alternatives based on phenothiazine were assessed for their antiviral activities and showed extended agricultural application. © 2023 Society of Chemical Industry.


Microplastics in marine mammal blubber, melon, & other tissues: Evidence of translocation.
Marine mammals consume large quantities of microplastic particles, likely via trophic transfer (i.e., through prey who have consumed plastic) and direct consumption from seawater or sediment. Microplastics have been found in the stomachs, gastro-intestinal tracts, and feces of cetaceans and pinnipeds. Translocation of ingested microplastics has been documented in other organs of several aquatic species, but has not been examined in marine mammals. Marine mammals have highly specialized lipid-rich tissues which may increase susceptibility to lipophilic microplastics. Here we demonstrate the occurrence of microplastics, ranging in size, mass concentration, and particle count concentration from 24.4 μm - 1387 μm, 0.59 μg/g - 25.20 μg/g, and 0.04 - 0.39 particles/g, respectively, in four tissues (acoustic fat pad, blubber, lung, & melon) from twelve marine mammal species inclusive of mysticetes, odontocetes, and phocids. Twenty-two individuals were examined for microplastics using a combination of Raman spectroscopy and pyrolysis gas chromatography with mass spectrometry. Overall, 68% of individuals had at least one microplastic particle in at least one of the four tissue types, with the most common polymer and shape observed being polyethylene and fibers, respectively. These findings suggest some proportion of ingested microplastics translocate throughout marine mammal bodies posing an exposure risk to both marine mammals and people. For people, exposure could be directly through consumption for those who rely on marine mammals as food and indirectly to peoples globally who consume the same prey resources as marine mammals. Some individuals examined represent samples obtained over two decades ago, suggesting that this process, and thus exposure risk, has occurred for some time.


Deinococcus radiodurans-derived membrane vesicles protect HaCaT cells against H2O2-induced oxidative stress via modulation of MAPK and Nrf2/ARE pathways.
Deinococcus radiodurans is a robust bacterium that can withstand harsh environments that cause oxidative stress to macromolecules due to its cellular structure and physiological functions. Cells release extracellular vesicles for intercellular communication and the transfer of biological information; their payload reflects the status of the source cells. Yet, the biological role and mechanism of Deinococcus radiodurans-derived extracellular vesicles remain unclear. This study investigated the protective effects of membrane vesicles derived from D. radiodurans (R1-MVs) against H2O2-induced oxidative stress in HaCaT cells. R1-MVs were identified as 322 nm spherical molecules. Pretreatment with R1-MVs inhibited H2O2-mediated apoptosis in HaCaT cells by suppressing the loss of mitochondrial membrane potential and reactive oxygen species (ROS) production. R1-MVs increased the superoxide dismutase (SOD) and catalase (CAT) activities, restored glutathione (GSH) homeostasis, and reduced malondialdehyde (MDA) production in H2O2-exposed HaCaT cells. Moreover, the protective effect of R1-MVs against H2O2-induced oxidative stress in HaCaT cells was dependent on the downregulation of mitogen-activated protein kinase (MAPK) phosphorylation and the upregulation of the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. Furthermore, the weaker protective capabilities of R1-MVs derived from ΔDR2577 mutant than that of the wild-type R1-MVs confirmed our inferences and indicated that SlpA protein plays a crucial role in R1-MVs against H2O2-induced oxidative stress. Taken together, R1-MVs exert significant protective effects against H2O2-induced oxidative stress in keratinocytes and have the potential to be applied in radiation-induced oxidative stress models.


Preoperative statin use and outcomes following cardiac surgery.
Cardiac surgery carries a 2-3% early mortality due in part to perioperative myocardial infarction (PMI), low-output syndrome (LOS), and arrhythmias. Statins attenuate thrombogenesis, normalize endothelial dysfunction, and mitigate the oxidative stress and reperfusion injury characteristic of such complications. We sought to determine whether preoperative statin use is associated with reduced early mortality and major morbidity following cardiac surgery. Patients having isolated coronary artery bypass grafting (CABG), valve, or combined CABG/valve surgery between May 1998 and June 2003 (n=5469) were identified. A logistic regression model was generated to determine the association of preoperative statin use with in-hospital mortality (IHM). Propensity score analysis was used to match two subgroups of patients (Group I, on statins, n=1443; Group II, not on statins, n=1443) on multiple factors known to impact cardiac surgical outcome. Outcomes assessed were IHM, intra-aortic balloon pump (IABP) use, PMI, prolonged (>24 h) ventilation (p-vent), stroke, and a composite end point (comp) defined as any one or more of the above. Of the 5469 patients, 3555 were on statins and 1914 were not. Unadjusted rates of IHM (2.6% vs. 5.0%), stroke (1.9% vs. 3.3%), p-vent (10.2% vs. 16.6%), and comp (12.7% vs. 19.5%) were lower (p=0.0001) in patients receiving statins. After adjustment, statin use was not associated with a reduction in IHM (OR=0.9, 95% CI=0.6-1.2, p=0.36) or comp (OR=0.9, 95% CI=0.8-1.1, p=0.31). After matching two subgroups using propensity score for statin, no significant differences were found in any of the adjusted outcomes for Group I vs. Group II: IHM (4.0% vs. 4.6%), PMI (1.5% vs. 1.1%), p-vent (15.8% vs. 15.7%), IABP use (2.0% vs. 2.3%), stroke (3.0% vs. 3.3%), and comp (19.1% vs. 18.8%). Preoperative statin use is not associated with a reduction in IHM or major morbidity following cardiac surgery.


Parents' Awareness of and Perspectives on Childhood Refractive Error and Spectacle Wear in Saudi Arabia.
This study aimed to assess parents' awareness of and perspectives on childhood refractive errors in Saudi Arabia. This cross-sectional study was conducted between October and November 2020 in public schools across different regions of Saudi Arabia. Data were collected using an online questionnaire that assessed parents' knowledge and perceptions of childhood refractive errors and spectacle wear. A total of 358 parents from different regions of Saudi Arabia completed the questionnaire and were obtained in this study (response rate: 85%). Approximately one third (38.3%) of the parents reported that they had never heard of refractive errors and one-third (33.8%) mentioned that uncorrected refractive errors did not lead to visual impairment. The majority (74.0%) cited using eyeglasses as an effective way to manage childhood refractive errors. Two-thirds (63.7%) stated that they did not receive any information about paediatric eye care. Better knowledge was associated with a higher educational level, female gender and older age (P <0.001, P = 0.008 and P = 0.024, respectively). Regarding parents' perspective on spectacle wear, 13.7% felt that using eyeglasses affected their children's chances of learning. However, 82.7% supposed that eyeglasses did not affect their children's employment opportunities. Almost a quarter of the sample (22.1%) thought that using eyeglasses would decrease the eye's power, resulting in childhood visual impairment. The level of awareness and perceptions regarding childhood refractive errors and spectacle wear was low among parents. Therefore, a policy is needed to improve the awareness and perception of the key stakeholders in this issue, including parents and teachers.


Endbulb synaptic depression within the range of presynaptic spontaneous firing and its impact on the firing reliability of cochlear nucleus bushy neurons.
The majority of auditory nerve fibers exhibit prominent spontaneous activity in the absence of sound. More than half of all auditory nerve fibers in CBA mice have spontaneous firing rates higher than 20 spikes/s, with some fibers exceeding 100 spikes/s. We tested whether and to what extent endbulb synapses are depressed by activity between 10 and 100 Hz, within the spontaneous firing rates of auditory nerve fibers. In contrast to rate-dependent depression seen at rates >100 Hz, we found that the extent of depression was essentially rate-independent (∼35%) between 10 and 100 Hz. Neither cyclothiazide nor γ-d-glutamylglycine altered the rate-independent depression, arguing against receptor desensitization and/or vesicle depletion as major contributors for the depression. When endbulb synaptic transmission was more than half-blocked with the P/Q Ca(2+) channel blocker ω-agatoxin IVA, depression during 25 and 100 Hz trains was significantly attenuated, indicating P/Q Ca(2+) channel inactivation may contribute to low frequency synaptic depression. Following conditioning with a 100 Hz Poisson train, the EPSC paired-pulse ratio was increased, suggesting a reduced release probability. This in turn should reduce subsequent depletion-based synaptic depression at higher activation rates. To probe whether this conditioning of the synapse improves the reliability of postsynaptic responses, we tested the firing reliability of bushy neurons to 200 Hz stimulation after conditioning the endbulb with a 25 Hz or 100 Hz stimulus train. Although immediately following the conditioning train, bushy cells responded to minimal suprathreshold stimulation less reliably, the firing reliability eventually settled to the same level (<50%) regardless of the presence or absence of the preconditioning. However, when multiple presynaptic fibers were activated simultaneously, the postsynaptic response reliability did not drop significantly below 90%. These results suggest that single endbulb terminals do not reliably trigger action potentials in bushy cells under "normal" operating conditions. We conclude that the endbulb synapses are chronically depressed even by low rates of spontaneous activity, and are more resistant to further depression when challenged with a higher rate of activity. However, there seems to be no beneficial effect as assessed by the firing reliability of postsynaptic neurons for transmitting information about higher rates of activity.


Quality of patient- and proxy-reported outcomes for children with impairment of the upper extremity: a systematic review using the COSMIN methodology.
As patient-reported outcome measures (PROMs) have become of significant importance in patient evaluation, adequately selecting the appropriate instrument is an integral part of pediatric orthopedic research and clinical practice. This systematic review provides a comprehensive overview of PROMs targeted at children with impairment of the upper limb, and critically appraises and summarizes the quality of their measurement properties by applying the COnsensus-based Standards for selection of health Measurement INstruments (COSMIN) methodology. A systematic search of the MEDLINE and EMBASE databases was performed to identify relevant publications reporting on the development and/or validation of PROMs used for evaluating children with impairment of the upper extremity. Data extraction and quality assessment (including a risk of bias evaluation) of the included studies was undertaken by two reviewers independently and in accordance with COSMIN guidelines. Out of 6423 screened publications, 32 original articles were eligible for inclusion in this review, reporting evidence on the measurement properties of 22 self- and/or proxy-reported questionnaires (including seven cultural adaptations) for various pediatric orthopedic conditions, including cerebral palsy (CP) and obstetric brachial plexus palsy (OBPP). The measurement property most frequently evaluated was construct validity. No studies evaluating content validity and only four PROM development studies were included. The methodological quality of these development studies was either 'doubtful' or 'inadequate'. The quantity and quality of the evidence on the other measurement properties of the included questionnaires varied substantially with insufficient sample sizes and/or poor methodological quality resulting in significant downgrading of evidence quality. This review provides a comprehensive overview of currently available PROMs for evaluation of the pediatric upper limb. Based on our findings, none of the PROMs demonstrated sufficient evidence on their measurement properties to justify recommending the use of these instruments. These findings provide room for validation studies on existing pediatric orthopedic upper limb PROMs (especially on content validity), and/or the development of new instruments.


Intra-operative assessment of fractured articular surfaces in cone beam CT image data.
The assessment of intra-operatively acquired volumetric data is a difficult and often time-consuming task, which demands a new set of skills from the surgeons. In the case of orthopedic surgeries such as the treatment of calcaneal fractures, the correctness of the reduction of the bone fragments can be verified with the help of C-arm CT volumetric images. For an accurate intra-operative assessment of the displaced fragments, an automatic segmentation of the articular surfaces and color-coded visualization was developed. Our automatic approach consists of three major steps: first, using adjusted standard planes intersecting the articular region, the joint space is localized with an intensity profile-based method. In a second step, the localized joint space is segmented on the Laplacian of Gaussian filtered volumetric image by a modified binary flood fill algorithm. Finally, a 3D surface model of the segmented joint space is analyzed and visualized with focus on critical displacements of the surface. A specifically designed human cadaver study consisting of ten lower legs of ten different donors was conducted to acquire 48 realistic C-arm CT images of misaligned bone fragments (steps of varying sizes) in the posterior talar articular surface of the calcaneus. The proposed algorithmic pipeline was verified by the acquired image data and showed very good results with no false positives and an overall correct displacement assessment of 93.8%. The proposed algorithmic pipeline can be easily integrated into the clinical workflow and qualifies for intra-operative usage. It showed very good results on the reference data set of the cadaver study. With the help of such an assistance system, the time-consuming process of 2D view adjustment and visual assessment of the gray value images can be greatly simplified.


miR-1271 inhibits growth, invasion and epithelial-mesenchymal transition by targeting ZEB1 in ovarian cancer cells.
MicroRNA-1271 (miR-1271) has a role in suppressing cell growth, cell cycle and promoting cell apoptosis in many cancers. This research was to explore the great role of miR-1271 in ovarian cancer (OC). RT-qPCR was utilized to evaluate the mRNA levels of miR-1271 and its target gene. The proliferative and invasive abilities were measured using Cell Counting Kit-8 and transwell assays. The overall survival rate of OC patients was assessed by Kaplan-Meier method. miR-1271 was downregulated in OC tissues, and downregulation of miR-1271 predicted a poor outcome of the OC patients. Zinc finger E-box binding homeobox 1 (ZEB1) was a target gene of miR-1271 and its expression was regulated by miR-1271 in OC. The expression of miR-1271 had a negative connection with the expression of ZEB1 in OC tissues. miR-1271 inhibited cell viability and invasion-mediated epithelial-mesenchymal transition in SKOV3 cells. ZEB1 reversed partial roles of miR-1271 on viability and invasion in OC. miR-1271 inhibited cell proliferation and invasion-mediated EMT in OC. The newly identified miR-1271/ZEB1 axis provides novel insight into the pathogenesis of OC.


Wave-particle interaction effects in the Van Allen belts.
Discovering such structures as the third radiation belt (or "storage ring") has been a major observational achievement of the NASA Radiation Belt Storm Probes program (renamed the "Van Allen Probes" mission in November 2012). A goal of that program was to understand more thoroughly how high-energy electrons are accelerated deep inside the radiation belts-and ultimately lost-due to various wave-particle interactions. Van Allen Probes studies have demonstrated that electrons ranging up to 10 megaelectron volts (MeV) or more can be produced over broad regions of the outer Van Allen zone on timescales as short as a few minutes. The key to such rapid acceleration is the interaction of "seed" populations of ~ 10-200 keV electrons (and subsequently higher energies) with electromagnetic waves in the lower band (whistler-mode) chorus frequency range. Van Allen Probes data show that "source" electrons (in a typical energy range of one to a few tens of keV energy) produced by magnetospheric substorms play a crucial role in feeding free energy into the chorus waves in the outer zone. These chorus waves then, in turn, rapidly heat and accelerate the tens to hundreds of keV seed electrons injected by substorms to much higher energies. Hence, we often see that geomagnetic activity driven by strong solar storms (coronal mass ejections, or CMEs) commonly leads to ultra-relativistic electron production through the intermediary step of waves produced during intense magnetospheric substorms. More generally, wave-particle interactions are of fundamental importance over a broad range of energies and in virtually all regions of the magnetosphere. We provide a summary of many of the wave modes and particle interactions that have been studied in recent times.


Altered cartilage phenotype expressed during intramembranous bone formation.
The sequential phenotypic expression occurring during intramembranous bone formation was investigated using the tooth extraction socket created in rat alveolar bone in vivo. The differential expression of bone extracellular matrix genes, such as collagen I and osteocalcin, was confirmed by RNA transfer blot analysis and in situ hybridization during the active healing period of the bony socket. To clarify the possible involvement of the chondrogenic phenotype during the process of intramembranous bone formation, the expression of cartilage collagen II and IX was further examined in this model. It was found that both alpha 1(II) and alpha 1(IX) mRNAs were present, but the alpha 1(IX) mRNA was a transcript from the downstream start site/promoter, which is a different site in the alpha 1(IX) gene from that used in hyaline cartilage. In situ hybridization indicated that the alpha 1(IX) message was expressed by cells associated with bone matrix in the early formation stage. This finding led to the investigation of type IX collagen expression by osteogenic cells isolated from newborn rat calvariae, in which only the truncated form of alpha 1(IX) mRNA was indicated by RNA transfer analysis. The expression of collagen II and a truncated form of collagen IX may represent an early phenotypic feature of osteoblast differentiation.


Four new stilbenoids from the lianas of Gnetum montanum f. megalocarpum.
From the lianas of Gnetum montanum Markgr. f. megalocarpum Markgr., four new stilbenoids, gnetumontanins A - D ( 1 - 4) were obtained together with 16 known compounds. Gnetumontanin A ( 1) is the first oligostilbene dimerized from two oxyresveratrol units, gnetumontanin B ( 2) is a new stilbene trimer oligomerized from two oxyresveratrol and one resveratrol units, gnetumontanin C ( 3) is a new stilbenoid with a novel skeleton having a delta-lactone moiety and gnetumontanin D ( 4) is a glucoside of 3. Their structures were determined by means of spectroscopic evidence, especially 2D NMR techniques. Gnetumontanin B showed potent inhibition of TNF-alpha with an inhibitory ratio of 58.1 % (P < 0.05) at a concentration of 10 ( - 5) mol L (-1) and the IC (50) was 1.49 x 10 ( - 6) mol L (-1).


On the measurement of fibre density in human muscles.
A computer simulation model and an analytical model simulating the measurement of fibre density during single fibre electromyography is described. The relation between the measured fibre density (including the triggering fibre) and the true theoretical fibre density (including in the measurement also positions with zero fibre counts) is derived. A good agreement was found between the two models, and between laboratory values for fibre density measurements and count histograms. The assumption of a uniform distribution of the fibres in the motor unit territory vs. a Gaussian distribution of the fibres is discussed.


Quantitative fMRI and oxidative neuroenergetics.
The discovery of functional magnetic resonance imaging (fMRI) has greatly impacted neuroscience. The blood oxygenation level-dependent (BOLD) signal, using deoxyhemoglobin as an endogenous paramagnetic contrast agent, exposes regions of interest in task-based and resting-state paradigms. However the BOLD contrast is at best a partial measure of neuronal activity, because the functional maps obtained by differencing or correlations ignore the total neuronal activity in the baseline state. Here we describe how studies of brain energy metabolism at Yale, especially with (13)C magnetic resonance spectroscopy and related techniques, contributed to development of quantitative functional brain imaging with fMRI by providing a reliable measurement of baseline energy. This narrative takes us on a journey, from molecules to mind, with illuminating insights about neuronal-glial activities in relation to energy demand of synaptic activity. These results, along with key contributions from laboratories worldwide, comprise the energetic basis for quantitative interpretation of fMRI data.


[A clinical study on two forces orthodontic technique].
Two Forces Technique was introduced in order to extend its use in daily clinical practice. The advantages of this technique were also mentioned. Various kinds of malocclusion were treated by using Broussard brackets and auxiliary springs according to Two Forces Technique procedure. Satisfied treatment results were achieved based on the comparison of cephalometrics before and after orthodontic treatment. Auxiliary springs and light force were used in this technique, which moved teeth in three dimension precisely. It can be used in correction of various kinds of malocclusion and is easy to manipulate in clinics.


Surface Technologies in Spinal Fusion.
Patients with symptomatic instability of the spine may be treated surgically with interbody fusion. Cost and complexity in this procedure arises owing to the implanted materials involved with facilitating fusion such as titanium or polyetheretherketone. Surface modifications have been developed to augment these base materials such as plasma-spraying polyetheretherketone with titanium or coating implants with hydroxyapatite. Although some evidence has been gathered on these novel materials, additional study is needed to establish the true efficacy of surface modifications for interbody fusion devices in improving long-term patient outcomes.


Extensive repair of acute type A aortic dissection through a partial upper sternotomy and using complete stent-graft replacement of the arch.
Partial upper sternotomy (mini-ER) can be used in some adult cardiac surgeries but is seldom performed in the treatment of acute type A aortic dissection (AAAD). This study aimed to assess the feasibility and short-term outcomes of complete stent-graft replacement of the arch with triple-branched stent graft for AAAD through a mini-ER. From 2015 to 2018, 254 patients with AAAD underwent complete stent-graft replacement of the arch with a triple-branched stent graft. Replacement was performed with conventional full sternotomy (con-ER) in 142 patients and with mini-ER in the other 112 patients. Using propensity score matching, the clinical data were compared between 100 patients in the mini-ER group and 100 patients in the con-ER group. After propensity score matching, there were no significant between-group differences in aortic cross-clamp time, cardiopulmonary bypass time, or total operative time. The amount of mediastinal drainage and number of red blood cell units were significantly lower in the mini-ER group compared with the con-ER group (P < .001). The intubation time was significantly shorter in the mini-ER group (P < .001). The treatment costs were also lower in the mini-ER group (P < .001). There were no significant between-group differences in 30-day mortality (9% vs 8%; P > .99) or postoperative complications. This study shows that extensive repair of AAAD through a mini-ER is feasible. It was superior to con-ER in terms of blood loss, postoperative ventilation time, and treatment costs.


Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies.
A characterization of cell lines that we derived from morulae (three lines), blastocysts (two lines), and the inner cell mass (ICM) is given. The karyotype of all the lines was normal; the genotype of four lines was XX, and four lines were genotypically XY. The pluripotencies and commitment status of the derived lines were estimated. First, there were not less than two-thirds of cells in the populations of the lines derived from morulae and the ICM with both Xs active; 70-100% of cells of the blastocyst-derived lines had one of the Xs in an inactive state. The activity of glucose-6-phosphate dehydrogenase (G6PD) in the lines (genotype XX) derived from morulae and ICM was found to be twofold higher than in lines with genotype XY, and G6PD activity was the same in the blastocyst-derived XX lines and XY lines. Second, when injected intraperitoneally into athymic mice, morulae- and ICM-derived cells gave rise to simple and complex embryoid bodies (EB) resembling to typical "cystic" mouse EBs. Third, when injected subcutaneously to athymic mice, the ICM- or morula-derived cells gave rise to typical teratomas containing derivatives of the three germ layers and components of organogenesis. Comparisons of cell lines of different derivations demonstrated that the pluripotencies of the ES cells derived from morulae or the ICM are higher than those of blastocyst derivation.