Disparity in Breast Cancer Late Stage at Diagnosis in Missouri: Does Rural Versus Urban Residence Matter?
Despite the fact that black women have a lower incidence of breast cancer compared to white women, black women experience higher death rates than any other group. We examined the stage of breast cancer presentation by race and geographic region using population-based breast cancer incidence in all 115 counties in the state of Missouri. We used 2003-2008 breast cancer incidence data from Missouri Cancer Registry and Research Center. County of residence was categorized as urban or rural using the rural-urban continuum code. We computed the conditional proportion of stage at diagnosis by race and metropolitan status and also used Pearson's chi-squared test with Yates' continuity correction to determine statistical significance of association. Results of the study indicate that a greater proportion of black women (38.8 %) compared to white women (30.2 %) were diagnosed with more advanced breast metastasis. Our results further suggest that stage at diagnosis depended on county of residence or metropolitan status (p = .04). Women living in non-metropolitan counties were slightly more likely to have late-stage breast cancer than their metropolitan counterparts (32.0 vs 30.7 %). Overall, black women had 1.5-fold increased odds of late-stage breast cancer diagnosis compared to their white counterparts (OR = 1.50; 95 % CI, 1.39, 1.63; p < 0.0001). While the odds of late diagnosis among women living in non-metropolitan or rural counties was over 11 % higher compared with their metropolitan or urban counterpart. The current study corroborates previous findings that the risk of late-stage breast cancer diagnosis was higher among women residing in non-metropolitan rural counties.


Nitric oxide production in mouse and rat macrophages: a rapid and efficient assay for screening of drugs immunostimulatory effects in human cells.
Activation of inducible nitric oxide (NO) synthase (iNOS) and resulting high-output NO release is known to depend on the action of cytokines. We investigated in vitro production of NO by resident peritoneal macrophages from mice and rats, and secretion of cytokines by these cells as well as by human peripheral blood mononuclear cells (PBMC). The cells were cultured in the presence of a selected group of acyclic nucleoside phosphonates that have previously been shown to possess immunobiological potential. Several of the compounds enhanced production of NO in animal macrophages. This activity was associated with stimulatory effects on secretion of cytokines such as TNF-alpha in all mouse and rat macrophages and human PBMC, and IL-10 in mouse and human cells. Statistically highly significant correlation between the range of NO biosynthesis in rodent cells and extent of cytokine stimulation in human PBMC has been observed. It is suggested that the NO assay may be regarded as an efficient, economical and relatively reliable tool in primary screening for intrinsic immunostimulatory activity of compounds in human cell system, at least from the point of view of cytokine secretion.


Assessing posttraumatic stress related impairment and well-being: The Posttraumatic Stress Related Functioning Inventory (PRFI).
Posttraumatic stress symptoms are associated with poorer social and occupational functioning and quality of life. However, general assessments of functioning do not determine the extent to which these difficulties are directly related to PTSD symptoms. This study examines the psychometric properties of a self-report measure, the 27-item Posttraumatic Stress Related Functioning Inventory (PRFI), which was developed to provide a self-report tool for clinicians and researchers to better understand the perceived impact of PTSD symptoms on functioning. The psychometric properties of the PRFI were examined utilizing data collected within a larger study examining quality of life and functioning in 251 veterans who had served in OEF/OIF/OND and endorsed the presence of subsyndromal or greater levels of PTSD symptoms at screening. One-year test-retest reliability of the measure was examined in a subset of the baseline sample who received a second administration of the PRFI (n = 109). Higher levels of PTSD symptoms were associated with poorer functioning in all domains. The PRFI demonstrated convergent validity with a measure of PTSD symptoms and was less correlated with measures of alcohol and drug use, good internal consistency and test-retest reliability from baseline to one-year follow-up. The PRFI provides self-report information regarding several domains of functioning. This initial examination of psychometric properties of the scale indicated that it may be useful for efficiently eliciting information about the ways in which PTSD symptoms in veterans impact everyday functioning.


IL-17 inhibits adipogenesis in part via C/EBPα, PPARγ and Krüppel-like factors.
IL-17 is an inflammatory cytokine associated with anti-microbial host defense and pathogenesis of autoimmune diseases. Obesity is considered to be an inflammatory condition, but how cytokines and fat metabolism are interconnected remains poorly understood. Mesenchymal stem cells can differentiate into adipocytes, which serve as depots for stored fat. Despite the pro-inflammatory properties of IL-17, both IL-17- and IL-17RA-deficient mice are overweight. Consistently, IL-17 suppresses maturation of cells with adipogenic potential. However, the mechanism underlying IL-17-mediated inhibition is not defined. In this study, we addressed this question by evaluating the impact of IL-17 on a variety of transcription factors (TFs) that control adipogenesis, using 3T3-L1 cells to model adipocyte differentiation. Surprisingly, IL-17 does not suppress adipogenesis via C/EBPβ and C/EBPδ, TFs often considered to be central regulators of adipogenesis. Rather, IL-17 suppresses expression of several pro-adipogenic TFs, including PPARγ and C/EBPα. Moreover, we found that IL-17 regulates expression of several members of the Krüppel-like family (KLF). Specifically, IL-17 suppresses KLF15, a pro-adipogenic TF, and enhances expression of KLF2 and KLF3, which are anti-adipogenic. Thus, IL-17 suppresses adipogenesis at least in part through the combined effects of TFs that regulate adipocyte differentiation.


The role of circulating renin in drinking in response to isoprenaline.
1. In nephrectomized rats, S.C. (0.12 mg. kg body wt.(-1)) or intracerebroventricular (I.C.V.: 0.03 mg. kg(-1)), isoprenaline failed to elicit drinking. However, when preceded (5-20 min) by a non-dipsogenic dose of I.V. pig renin, S.C. isoprenaline induced a marked, and I.C.V. isoprenaline a smaller drinking response. 2 hr after I.V. renin, S.C. isoprenaline no longer caused drinking.2. Pig renin did not enhance drinking in response to 0.12 mg. kg(-1) isoprenaline S.C. in intact or sham-operated rats.3. Isoprenaline (0.12 mg. kg body wt.(-1), S.C.) caused a larger fall of blood pressure in unanaesthetized nephrectomized than in intact unanaesthetized rats, but it was not the resulting hypotension that interfered with the nephrectomized rats' ability to drink, since intact rats with similar falls in blood pressure drank avidly in response to large doses of isoprenaline.4. Since the rate of inactivation of pig renin in nephrectomized rats was not modified by isoprenaline, drinking in nephrectomized animals in response to renin+isoprenaline was not attributable to increased plasma renin levels.5. Since isoprenaline induces drinking in the presence of circulating renin, but in the absence of renin release from kidneys, renin plays a permissive role in isoprenaline-induced drinking. Angiotensin and isoprenaline may interact at the level of intracranial receptors.


Gastric Aspirate Yield For Children With Suspected Pulmonary Tuberculosis.
The optimal number of gastric aspirates to diagnose tuberculosis is unclear. Thirty-two of 280 (11%) children in whom gastric aspirates were obtained grew Mycobacterium tuberculosis. First, second, and third specimens yielded initial culture positivity in 24 of 32, 6 of 32, and 2 of 24 cases, respectively. Intermittent positivity and paucibacillary disease necessitate obtaining multiple specimens.


Engineered polyketide biosynthesis and biocatalysis in Escherichia coli.
Polyketides are important bioactive natural products biosynthesized by bacteria, fungi, and plants. The enzymes that synthesize polyketides are collectively referred to as polyketide synthases (PKSs). Because many of the natural hosts that produce polyketides are difficult to culture or manipulate, establishing a universal heterologous host that is genetically tractable has become an important goal toward the engineered biosynthesis of polyketides and analogues. Here, we summarize the recent progresses in engineering Escherichia coli as a heterologous host for reconstituting PKSs of different types. Our increased understanding of PKS enzymology and structural biology, combined with new tools in protein engineering, metabolic engineering, and synthetic biology, has firmly established E. coli as a powerful host for producing polyketides.


Proof-of-principle experiment for laser-driven cold neutron source.
The scientific and technical advances continue to support novel discoveries by allowing scientists to acquire new insights into the structure and properties of matter using new tools and sources. Notably, neutrons are among the most valuable sources in providing such a capability. At the Institute of Laser Engineering, Osaka, the first steps are taken towards the development of a table-top laser-driven neutron source, capable of producing a wide range of energies with high brightness and temporal resolution. By employing a pure hydrogen moderator, maintained at cryogenic temperature, a cold neutron ([Formula: see text]) flux of [Formula: see text]/pulse was measured at the proximity of the moderator exit surface. The beam duration of hundreds of ns to tens of [Formula: see text] is evaluated for neutron energies ranging from 100s keV down to meV via Monte-Carlo techniques. Presently, with the upcoming J-EPoCH high repetition rate laser at Osaka University, a cold neutron flux in orders of [Formula: see text] is expected to be delivered at the moderator in a compact beamline.


[New challenges in health education. Medical genetics].
The article examines the reasons for the accelerated development of medical genetics in the last 30 years. It dwells on why hereditary diseases have become so prominent in the vital statistics of many countries, and reviews the biological and social aspects of these diseases. It is further noted that, despite the new importance of these diseases, the medical schools in which medical genetics is taught are relatively few, and physicians are turned out without even a rudimentary grounding with which to face problems in this field. The author concludes that there is urgent need to plan and develop an extensive program of education in medical genetics on both the under and postgraduate levels, and in the community itself.


Novel method for bulla detection with video-assisted thoracoscopic surgery in patients with spontaneous pneumothorax.
Detection of bullae is usually performed during lung inflation with an inspiratory hold in collaboration with anesthetists (conventional method). One cause leading to recurrent pneumothorax is failure to detect the position and extent of bullae under the conventional method. We herein present a novel method for detecting bullae under negative intrathoracic pressure, enabling exploration in the narrow cupola space without lung inflation.


Rapid reversible changes to multiple levels of the human somatosensory system following the cessation of repetitive contractions: a somatosensory evoked potential study.
Numerous somatosensory evoked potential (SEP) studies have provided clear evidence that during repetitive voluntary movement, the transmission of somatosensory afferent information is attenuated. The objective of this work was to determine if this gating phenomenon could persist beyond the period of repetitive movement. We recorded spinal, brainstem, and cortical SEPs to median nerve stimulation before and immediately after a modified 20 min repetitive typing task that did not involve the thenar muscles. There were significant decreases in pre-central cortical and subcortical SEP amplitudes for several minutes following task cessation. These results demonstrate the persistence of the gating phenomenon beyond the cessation of the actual repetitive movement. They also indicate that plastic changes do occur in cortical and subcortical components of the somatosensory system, following voluntary repetitive contractions. The persistence of changes in somatosensory processing beyond the period of repetitive activity may be relevant to the initiation of overuse injuries.


Towards the description of charge transfer states in solubilised LHCII using subsystem DFT.
Light harvesting complex II (LHCII) in plants and green algae have been shown to adapt their absorption properties, depending on the concentration of sunlight, switching between a light harvesting and a non-harvesting or quenched state. In a recent work, combining classical molecular dynamics (MD) simulations with quantum chemical calculations (Liguori et al. in Sci Rep 5:15661, 2015) on LHCII, it was shown that the Chl611-Chl612 cluster of the terminal emitter domain can play an important role in modifying the spectral properties of the complex. In that work the importance of charge transfer (CT) effects was highlighted, in re-shaping the absorption intensity of the chlorophyll dimer. Here in this work, we investigate the combined effect of the local excited (LE) and CT states in shaping the energy landscape of the chlorophyll dimer. Using subsystem Density Functional Theory over the classical [Formula: see text]s MD trajectory we look explicitly into the excitation energies of the LE and the CT states of the dimer and their corresponding couplings. Upon doing so, we observe a drop in the excitation energies of the CT states, accompanied by an increase in the couplings between the LE/LE and the LE/CT states facilitated by a shorter interchromophoric distance upon equilibration. Both these changes in conjunction, effectively produces a red-shift of the low-lying mixed exciton/CT states of the supramolecular chromophore pair.


Diabetes Outcomes More than a Decade Following Sustained Weight Loss After Laparoscopic Adjustable Gastric Band Surgery.
Long-term outcome data are needed to define the role of bariatric surgery in type 2 diabetes (T2D). To address this, we collated diabetes outcomes more than a decade after laparoscopic adjustable gastric band (LAGB) surgery. Clinical and biochemical measures from 113 obese T2D patients who underwent LAGB surgery in 2003 and 2004 were analyzed. Diabetes remission was defined as HbA1c < 6.2% (44 mmol/mol) and fasting glucose < 7.0 mmol/L. Seventy-nine patients had weight data at 10 years and attained a median [Q1, Q3] weight loss of 16 [10, 21] percent. Sixty patients attended a follow-up assessment. Their baseline HbA1c of 7.8 [7.1, 9.3] percentage units (62 [54, 78] mmol/mol) had decreased to 6.6 [6.1, 8.4] (49 [43, 68] mmol/mol) despite no significant change in glucose-lowering therapy. Eleven patients (18%) were in diabetes remission and another 18 had HbA1c ≤ 6.5%. Significant improvements in physical measures of quality of life, blood pressure, and lipid profile were also observed but there was no change in the proportion of patients with albuminuria and a significant decline in estimated glomerular filtration rate. Twelve patients in the follow-up cohort (20%) required anti-reflux medication after surgery and 26 (43%) underwent gastric band revision surgery. Weight loss for over 10 years after LAGB surgery delivers clinically meaningful improvements in HbA1c, blood pressure, lipids, and quality of life at the cost of a high rate of revision surgery and increased use of anti-reflux medication. These findings support the use of bariatric surgery as a long-term treatment for weight loss and wellbeing in patients with T2D. Registered with the Australian Clinical trials registry as ACTRN12615000089538.


Hyperechogenic kidneys and polyhydramnios associated with HNF1B gene mutation.
HNF1B mutation is the leading cause of isolated hyperechogenic fetal kidneys with normal or moderately large size. Although most cases have normal amniotic fluid volume, some cases present with early oligohydramnios and renal failure associated with high perinatal mortality. Here we report on seven fetuses from six unrelated families, carrying an HNF1B mutation, and presenting with polyhydramnios during the second or third trimester of pregnancy. Polyhydramnios was transitory in two cases. None of the mothers was presenting gestational diabetes. Bilateral hyperechogenic kidneys with size between -2.5 and +2 SD was the most common renal phenotype at prenatal US. Two patients were born prematurely at 28 and 32 weeks of gestation, respectively. Both presented high urine output the first days of life with urinary salt and potassium loss requiring hydro-electrolytic compensation. All mutations were large deletions removing the whole HNF1B gene. In the absence of maternal diabetes, HNF1B mutation can be associated with polyhydramnios, probably due to fetal polyuria. Thus, HNF1B mutation represents a differential diagnosis of polyhydramnios associated with hyperechogenic (and sometimes enlarged) kidneys.


Evaluation of the potential for virus dispersal during hand drying: a comparison of three methods.
To use a MS2 bacteriophage model to compare three hand-drying methods, paper towels (PT), a warm air dryer (WAD) and a jet air dryer (JAD), for their potential to disperse viruses and contaminate the immediate environment during use. Participants washed their gloved hands with a suspension of MS2 bacteriophage and hands were dried with one of the three hand-drying devices. The quantity of MS2 present in the areas around each device was determined using a plaque assay. Samples were collected from plates containing the indicator strain, placed at varying heights and distances and also from the air. Over a height range of 0·15-1·65 m, the JAD dispersed an average of >60 and >1300-fold more plaque-forming units (PFU) compared to the WAD and PT (P < 0·0001), respectively. The JAD dispersed an average of >20 and >190-fold more PFU in total compared to WAD and PT at all distances tested up to 3 m (P < 0·01) respectively. Air samples collected around each device 15 min after use indicated that the JAD dispersed an average of >50 and >100-fold more PFU compared to the WAD and PT (P < 0·001), respectively. Use of the JAD lead to significantly greater and further dispersal of MS2 bacteriophage from artificially contaminated hands when compared to the WAD and PT. The choice of hand-drying device should be considered carefully in areas where infection prevention concerns are paramount, such as healthcare settings and the food industry.


Amyloid peptides with antimicrobial and/or microbial agglutination activity.
Microbe (including bacteria, fungi, and virus) infection in brains is associated with amyloid fibril deposit and neurodegeneration. Increasing findings suggest that amyloid proteins, like Abeta (Aβ), are important innate immune effectors in preventing infections. In some previous studies, amyloid peptides have been linked to antimicrobial peptides due to their common mechanisms in membrane-disruption ability, while the other mechanisms of bactericidal protein aggregation and protein function knockdown are less discussed. Besides, another important function of amyloid peptides in pathogen agglutination is rarely illustrated. In this review, we summarized and divided the different roles and mechanisms of amyloid peptides against microbes in antimicrobial activity and microbe agglutination activity. Besides, the range of amyloids' antimicrobial spectrum, the effectiveness of amyloid peptide states (monomers, oligomers, and fibrils), and cytotoxicity are discussed. The good properties of amyloid peptides against microbes might provide implications for the development of novel antimicrobial drug. KEY POINTS: • Antimicrobial and/or microbial agglutination is a characteristic of amyloid peptides. • Various mechanisms of amyloid peptides against microbes are discovered recently. • Amyloid peptides might be developed into novel antimicrobial drugs.


Social factors associated with the knowledge about HIV of the immigrants from China, Latin America, the Maghreb and Senegal in the Basque Country (Spain).
The objective of this study was to identify the social factors that explain the differences in knowledge with regards to HIV/AIDS among immigrants in the Basque Country (Spain). We conducted a cross-sectional study based on information obtained in the Basque Health Survey for 754 immigrants from: 86 China, 368 Latin America, 237 the Maghreb and 74 Senegal. Odds ratios (95% CI) were calculated from logistic regression models to measure the degree of association between inadequate knowledge regarding transmission, prevention and places where HIV testing is offered, and the independent variables. We found that this inadequate knowledge is associated with place of birth, sex, a lower level of education, immigration status, difficulties in understanding Spanish, and not receiving advice about AIDS in primary care. These findings indicate that initiatives must be developed to promote equity in the provision of healthcare through clinical guidelines, including details of the specific needs of different groups of immigrants and considering gender issues.


Potential distributions generated by point stimulation in a myocardial volume: simulation studies in a model of anisotropic ventricular muscle.
We present simulations of extracellular potential patterns elicited by delivering ectopic stimuli to a parallelepipedal slab of ventricular tissue represented as an anisotropic bidomain incorporating epi-endocardial fiber rotation. Simulations were based on an eikonal model that determines wavefront shapes throughout the slab at every time instant during the depolarization phase, coupled with an approximate model of the action potential profile. The endocardial face of the slab was in contact with blood and the composite volume was surrounded by an insulating medium. The effect of a simplified Purkinje network was also studied. (1) For all pacing depths, except endocardial pacing, a central negative area and two potential maxima were observed at QRS onset in all intramural planes parallel to the epicardium. In all planes, the axis joining the two maxima was approximately aligned with the direction of fibers in the plane of pacing. Endocardial pacing generated a different pattern, but only when blood was present; (2) During later stages of excitation, outflowing currents (from the wavefront toward the resting tissue) were always emitted, at all intramural depths, only from those portions of the wavefront that spread along fibers. At any given instant, the position of the two potential maxima in a series of planes parallel to the epicardium and intersecting the wavefront rotated as a function of depth, following the rotating direction of intramural fibers. Purkinje involvement modified the above patterns. Epicardial and endocardial potential maps provided information on pacing site and depth and on subsequent intramural propagation by reflecting the clockwise or counter-clockwise rotation of the deep positivity. Results may be applicable to epicardial and endocardial potential maps recorded at surgery or from endocavitary probes.


Microwave synthesis and in vitro stability of diclofenac-β-cyclodextrin conjugate for colon delivery.
The aim of this work was to synthesize an ester prodrug of diclofenac and β-cyclodextrin suitable for colonic delivery. The synthesis of an ester linkage between diclofenac and β-cyclodextrin was conducted by the nucleophilic substitution of mono-6-tosyl-β-cyclodextrin under microwaves irradiation. After purification, the conjugate was characterized by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry; infrared (IR) spectroscopy; proton nuclear magnetic resonance ((1)H NMR) spectroscopy; and two-dimensional rotating frame nuclear overhauser effect (ROESY) spectroscopy. The purity was qualified by high pressure liquid chromatography (HPLC). To assess its potential for colonic delivery, the conjugate was evaluated for stability in simulated gastric and small intestinal fluids, and in fecal material from humans processed within a slurry under anaerobic conditions. The conjugate was successfully synthesized with a yield of 20% following purification. The mass spectra showed the parent peak m/z 1434 corresponding to [conjugate+Na] adduct. IR and NMR results confirmed that the carboxyl group of diclofenac is covalently bound to one of the hydroxyl groups of cyclodextrin by an ester linkage. Moreover, ROESY data indicated that the formation of the conjugate is not accompanied by the inclusion of diclofenac within the cyclodextrin. The conjugate was otherwise stable in simulated gastric and small intestinal conditions, but was also readily hydrolyzed liberating diclofenac in less than 2h within the human fecal slurry. This confirmed the potential for this new prodrug as a carrier for colonic delivery.


In vitro fertilization in spontaneous cycles--our experience.
To study the efficacy of a simple protocol of natural cycle in vitro fertilization. A retrospective study of 59 natural treatment cycles in 37 infertile couples with previous unsuccessful attempts of conventional in vitro fertilization. In 24% of cycles, the aspiration was cancelled because of inadequate visualization of follicles or because of preterm ovulation. Aspiration was performed in 45 cycles with oocyte retrieval of 82% per aspiration. Embryo transfer was performed in 30 cycles, pregnancy rate per pick-up was 15%. In vitro fertilization in a natural cycle is a simple, relatively cheap and comfortable procedure with reasonable results and can be offered to patients scheduled not only for in vitro fertilization because of tubal factor but also to patients with endometriosis or unexplained infertility.


Health-related quality of life of Chinese patients with prostate cancer in comparison to general population and other cancer populations.
The purpose of this study was to compare the health-related quality of life (HRQOL) of Chinese patients with prostate cancer against the general population and patients with colorectal cancer, breast cancer, nasopharyngeal cancer, and leukemia. Chinese male patients (n = 291) with a confirmed diagnosis of prostate cancer were recruited from a urological specialist outpatient clinic in Hong Kong. HRQOL was measured by a condition-specific Functional Assessment of Cancer Therapy-Prostate (FACT-P) and a generic Chinese (HK) SF-12 Health Survey Version 2 (SF-12v2) questionnaire. Mean HRQOL scores of condition-specific and generic questionnaires were compared to available scores derived from other cancers and age-matched male general population, respectively. Chinese patients with prostate cancer had lower general health and vitality domains and lower mental component summary scores than the age-matched Hong Kong normative population. Patients with prostate cancer reported better condition-specific HRQOL (physical well-being, emotional well-being and function well-being) when compared to general cancer population, patients with breast cancer, colorectal cancer, nasopharyngeal cancer, and leukemia in Hong Kong. Patients with prostate cancer substantially perceived their HRQOL to be better, compared to patients with other cancers, with overall health, energy, and mental health below of Hong Kong general population. Interventions should target at these domains in order to improve the HRQOL of patients with prostate cancer. It is reassuring to find that prostate cancer had less negative impact on HRQOL than other cancer types did.


The influences of temperature and humidity upon the isolated surfactant film of the dog.
A model of the gas-liquid barrier (surfactant film) of the lung was used to investigate the influence of temperature and of humidification of the gas upon the behaviour of films during rhythmic compression and expansion of their surface. Film behaviour was studied at room temperature or 37 degrees C, and at ambient humidity or high relative humidity. Changes of minimal surface tension (gamma min) and maximal surface tension (gamma max) were followed up to 1000 cycles. At 37 degrees C we measured higher values for gamma min and lower values for gamma max. At room temperature complete humidification does not influence surface tension, but at 37 degrees C gamma min increases. Thus both high temperature and high relative humidity result in sharp rise of gamma min, whereas high temperature alone is responsible for the temporary drop of gamma max. Considering these effects, investigations to study influences of foreign gases and of air pollution upon the surfactant film should be performed under conditions which approach those of the lung as close as possible. The possible influence of CO2 is discussed.


Gangliosides in T cell development and function of mice.
The molecular diversity of glycosphingolipids (GSLs) that arouse during the course of evolution clearly plays an essential role in maintenance of biological homeostasis. Why is such a wide variety of GSLs necessary, and what gave rise to the expression mechanisms that are selective and specific to individual cells, tissues, or organs? What is the biological significance of these mechanisms? The same questions apply to GSLs involved in T cell development and activation. Primary CD4+ T cells and CD8+ T cells preferentially express differing ganglioside series: a-series and o-series, respectively. Conversely, a-series and o-series ganglioside deficiency results respectively in CD4+ and CD8+ T cell dysfunction. Dynamic changes in ganglioside expression occur during T cell development in thymus. Ganglioside GM3 synthase deficiency, which results in lack of a-series gangliosides, ameliorated CD4+ T cell-mediated airway hypersensitivity in a mouse model of allergic asthma. In this review, we summarize findings from these and many studies to illustrate the key roles of gangliosides in T cell differentiation and function.


Stereospecificity of the intracellular binding of norethisterone and its A-ring reduced metabolites.
The interaction of norethisterone (NET) and four A-ring reduced metabolites of NET with cytosol receptors for progesterone (PR), androgen (AR), and estrogen (ER) was investigated. Cytosol preparations from: uteri of adult estrogen-primed castrated rats, ventral prostates of adult castrated rats and uteri of immature rats were used as the source of PR, AR, and ER respectively. 3H-Labeled ORG-2058, R-1881, and 17 beta-estradiol were used as the radioligands. The results of competitive studies disclosed that: the most efficient competitor for PR binding sites was NET (Ki = 1.1 X 10(-7) M) followed by 5 alpha-dihydro NET (5 alpha-NET), whereas the 3 alpha,5 alpha; 3 beta,5 alpha and 3 alpha,5 beta-tetrahydro NET derivatives were ineffective the most efficient competitor for AR binding sites was 5 alpha-NET (Ki = 1 X 10(-8), immediately followed by NET, while the three tetrahydro NET derivatives were not competitors and remarkable competition for ER binding sites was only exhibited by the 3 beta,5 alpha-tetrahydro NET derivative (Ki = 4.6 X 10(-8) M) and to a lesser extent by its 3 alpha,5 alpha-epimeric alcohol, while NET and 5 alpha-NET were completely ineffective. These findings demonstrate the stereospecificity of the intracellular binding of NET and its reduced metabolites with cytosol steroid putative receptors, and provide biochemical support to the understanding of the variety of hormone-like effects observed after the in vivo administration of NET.


Assessment of Immune Responses in an Animal Model of Wheat Food Allergy via Epicutaneous Sensitization.
Wheat allergy is a pathological event involving immunocompetent cells against ingested wheat allergen and is clearly associated with transdermal sensitization. However, the molecular mechanisms involved in the disease etiology are not completely understood. A complex cellular and tissue network linking to food allergy makes it difficult to understand the molecular mechanism of allergenicity. Animal models are valuable tools to deduce basic principles of human disease without invasive intervention trials. A mouse model of wheat allergy has provided insights into effects of skin exposure to wheat protein; it is a plausible route of human sensitization for wheat anaphylaxis. Further investigation of this model will capture the essential occurrence and flow of events, bringing useful clues to develop effective treatment and control strategies against wheat allergy. Here, we describe a method for analyzing the expression of cell surface molecules in single cells isolated from lymphoid tissue with flow cytometry. Sensitization by wheat extracts significantly increases antigen-specific T cells in the spleen. Collecting information regarding the contribution of immune cells to allergic sensitization in the development of wheat allergy would be useful in preventing and treating food allergies.


Effect of aerobic exercise on lung regeneration and inflammation in mice.
Aerobic exercise is well recognized to be beneficial to physical and mental health. Many studies have shown that aerobic exercise can improve the human immune system, but whether it could affect lung regeneration and inflammation remained unclear. Bronchioloalveolar stem cells (BASCs) play a key role in lung regeneration and repair, but it is unclear whether aerobic exercise affects BASCs. Here, we randomly divided 8 weeks old male mice into three groups: the control group without any aerobic exercise; the rest group which received 2 weeks of aerobic exercise (running wheel training) plus 5 days' rest, and the exercise group which received 2 weeks of aerobic exercise without any rest. Our data indicated that mice in the exercise group had significantly increased BASCs compared to the control group, such difference did not exist in the rest group. Furthermore, the immune profiling suggested that lung inflammation was slightly up-regulated in the exercise group, particularly the inflammatory monocytes and IL-17A+ T cells. In conclusion, we provide direct evidence showing that aerobic exercise can facilitate lung regeneration with mild inflammatory effect, this finding is of great importance in the current COVID-19 pandemic.


Development and participant assessment of a practical quality improvement educational initiative for surgical residents.
As patient-safety and quality efforts spread throughout health care, the need for physician involvement is critical, yet structured training programs during surgical residency are still uncommon. Our objective was to develop an extended quality-improvement curriculum for surgical residents that included formal didactics and structured practical experience. Surgical trainees completed an 8-hour didactic program in quality-improvement methodology at the start of PGY3. Small teams developed practical quality-improvement projects based on needs identified during clinical experience. With the assistance of the hospital's process-improvement team and surgical faculty, residents worked through their selected projects during the following year. Residents were anonymously surveyed after their participation to assess the experience. During the first 3 years of the program, 17 residents participated, with 100% survey completion. Seven quality-improvement projects were developed, with 57% completing all DMAIC (Define, Measure, Analyze, Improve, Control) phases. Initial projects involved issues of clinical efficiency and later projects increasingly focused on clinical care questions. Residents found the experience educationally important (65%) and believed they were well equipped to lead similar initiatives in the future (70%). Based on feedback, the timeline was expanded from 12 to 24 months and changed to start in PGY2. Developing an extended curriculum using both didactic sessions and applied projects to teach residents the theory and implementation of quality improvement is possible and effective. It addresses the ACGME competencies of practice-based improvement and learning and systems-based practice. Our iterative experience during the past 3 years can serve as a guide for other programs.


Medusa: a simple tool for interaction graph analysis.
Medusa is a Java application for visualizing and manipulating graphs of interaction, such as data from the STRING database. It features an intuitive user interface developed with the help of biologists. Medusa is optimized for accessing protein interaction data from STRING, but can be used for any type of graph from any scientific field.


Phospholipase A2 promotes raft budding and fission from giant liposomes.
Cellular processes involving membrane vesiculation are related to cellular transport and membrane components trafficking. Endocytosis, formation of caveolae and caveosomes, as well as Golgi membranes traffic have been linked to the existence and dynamics of particular types of lipid/protein membrane domains, enriched in sphingolipids and cholesterol, called rafts [Nature 387 (1997) 569; Trends Cell Biol. 12 (2002) 296; Biochemistry 27 (1988) 6197]. In addition, the participation of phospholipases in the vesiculation of Golgi and other membranes has been already established [Traffic 1 (2000) 504] essentially in their role in the production of second messenger molecules. In this work we illustrate with raft-containing giant lipid vesicles a mechanism for raft-vesicle expulsion from the membrane due to the activity of a single enzyme-phospholipase A(2) (PLA(2)). This leads to the hypothesis that the PLA(2), apart from its role in second messenger generation, might play a direct and general role in the vesiculation processes underlying the intermembrane transport of rafts through purely physicochemical mechanisms. These mechanisms would be: enzyme adsorption leading to membrane curvature generation (budding), and enzyme activity modulation of the line tension at the raft boundaries, which induces vesicle fission.


Flow Cytometry-Based Quantification of HIV-Induced T Cell Chemotactic Response.
The human immunodeficiency virus (HIV) infects blood CD4 T cells through binding to CD4 and the chemokine co-receptor, CXCR4 or CCR5. This viral binding to CXCR4 or CCR5 also triggers the activation of a variety of signaling molecules such as LIMK/cofilin and WAVE2/Arp2/3 to promote actin dynamics, which are necessary for viral nuclear migration and the latent infection of blood resting CD4 T cells. In this chapter, we describe the methods for quantification of HIV-induced actin polymerization and cofilin phosphorylation in human T cells using flow cytometry.


The relationships between stress, stress-coping behaviors, and suicidal risk among Thais who had become unemployed due to the COVID-19 pandemic: A cross-sectional study.
The COVID-19 pandemic has resulted in severe mental health problems worldwide. Thus, in addition to the high number of people who have died from infection with complications, some have committed suicide. This study aimed to determine the relationships between stress, stress-coping behaviors, and suicidal risk among those who had become unemployed in Thailand due to the COVID-19 pandemic. This study had a cross-sectional correlational design and included 447 unemployed Thais at least 18 years of age who had become unemployed due to the COVID-19 pandemic. The participants were selected through multistage sampling. A self-administered questionnaire was used for data collection. The data were then analyzed using frequency, percentage, and Spearman's correlation coefficient. Most participants had moderate-level stress (73.16%) and stress-coping behaviors (71.81%). Almost all the participants had no suicidal risk (76.73%). The stress level and overall stress-coping behavior were positively correlated with suicidal risk (r = 0.305, p <0.01 and r = 0.352, p <0.01, respectively). Stress and stress-coping behaviors were associated with suicidal risk among Thais who had become unemployed due to the COVID-19 pandemic. Hence, nurses must screen patients with psychological problems, especially those who have become unemployed due to the COVID-19 pandemic, for suicide risk. Developing interventions to reduce such patients' stress and promote appropriate stress-coping behaviors is essential.


Targeted Synthesis of NIR Luminescent Rhenium Diimine cis,trans-[Re( NN )(CO)2 (L)2 ]n+ Complexes Containing N-Donor Axial Ligands: Photophysical, Electrochemical, and Theoretical Studies.
The combined action of ultraviolet irradiation and microwave heating onto acetonitrile solution of [Re( NN )(CO)3 (NCMe)]OTf ( NN =phenantroline and neocuproine) afforded cis,trans-Re( NN )(CO)2 (NCMe)2 ]+ acetonitrile derivatives. Substitution of relatively labile NCMe with a series of aromatic N-donor ligands (pyridine, pyrazine, 4,4'-bipyridine, N-methyl-4,4'-bipyridine) gave a novel family of the diimine cis,trans-[Re( NN )(CO)2 (L)2 ]+ complexes. Photophysical studies of the obtained compounds in solution revealed unusually high absorption across the visible region and NIR phosphorescence with emission band maxima ranging from 711 to 805 nm. The nature of emissive excited states was studied using DFT calculations to show dominant contribution of 3 MLCT (dπ(Re)→π*( NN )) character. Electrochemical (CV and DPV) studies of the monocationic diimine complexes revealed one reduction and one oxidation wave assigned to reduction of the diimine moiety and oxidation of the rhenium center, respectively.


Rationally designed nanovehicles to overcome cancer chemoresistance.
Drug resistance is a primary hindrance towards curative cancer chemotherapy. Nanotechnology holds great promise in establishing efficacious and innovative strategies to overcome chemoresistance, and markedly facilitate complementary treatments and cancer diagnostics. Various nanomedical devices are being introduced and evaluated, demonstrating encouraging results. While stealth liposomes serve as a benchmark, astonishing progress is witnessed in polymeric nanovehicles, sometimes combined with low molecular weight surfactants, some of which inhibit drug resistance in addition to solubilizing drugs. Cutting edge multifunctional or quadrugnostic nanoparticles currently developed offer simultaneous targeted delivery of chemotherapeutics and chemosensitizers or drug-resistance gene silencing cargo, along with diagnostic imaging agents, like metallic NPs. Viral and cellular components offer exciting new routes for cancer targeting and treatment. Targeting intracellular compartments is another challenging frontier spawning pioneering approaches and results. To further enhance rational design of nanomedicine for overcoming drug resistance, we review the latest thoughts and accomplishments in recent literature.


Efficient generation of neutral and charged biexcitons in encapsulated WSe2 monolayers.
Higher-order correlated excitonic states arise from the mutual interactions of excitons, which generally requires a significant exciton density and therefore high excitation levels. Here, we report the emergence of two biexcitons species, one neutral and one charged, in monolayer tungsten diselenide under moderate continuous-wave excitation. The efficient formation of biexcitons is facilitated by the long lifetime of the dark exciton state associated with a spin-forbidden transition, as well as improved sample quality from encapsulation between hexagonal boron nitride layers. From studies of the polarization and magnetic field dependence of the neutral biexciton, we conclude that this species is composed of a bright and a dark excitons residing in opposite valleys in momentum space. Our observations demonstrate that the distinctive features associated with biexciton states can be accessed at low light intensities and excitation densities.


Effect of 5-hydroxytryptamine blockade with ketanserin on myocardial uptake of epinephrine and norepinephrine in patients with congestive heart failure.
Serotonin (5-hydroxytryptamine) has multiple cardiovascular actions. The presence of serotonin in the heart suggests it may be an endogenous source of inotropic support during physiologic or pathologic stress. Serotonin may increase cardiac contractility by augmenting release of norepinephrine at sympathetic nerve endings. Norepinephrine release is markedly elevated in patients with heart failure. To explore the role of serotonin in enhancing norepinephrine release in patients with heart failure, ketanserin, a specific serotonin antagonist, was used as a physiologic tool to examine the effect on transmyocardial norepinephrine flux. Ketanserin (10 mg bolus, 4 mg/hr infusion for +/- 40 min) was administered intravenously to nine patients with congestive heart failure (NYHA III or IV) secondary to congestive cardiomyopathy (N = 7), or ischemic heart disease (N = 2). Plasma catecholamines (norepinephrine, epinephrine, dopamine) were measured in the aorta (Ao) and the coronary sinus (CS) of patients at rest and during supine leg exercise before and after administration of ketanserin. Baseline norepinephrine levels were markedly elevated at rest and during exercise in all patients. Norepinephrine levels were significantly higher in the CS than in the Ao (rest, CS 1185 +/- 235, Ao 878 +/- 381 pg/mL, P less than .05; exercise, CS 2239 +/- 697, Ao 1453 +/- 697 pg/mL, P less than .05). Baseline epinephrine levels were within normal limits. In contrast to norepinephrine levels, epinephrine levels were consistently higher in the Ao than in the CS, indicating unimpaired extraction or uptake across the heart. The relationship between norepinephrine and epinephrine concentration in the Ao and CS suggested a net overflow of norepinephrine in the CS.(ABSTRACT TRUNCATED AT 250 WORDS)


Deciphering gene-environment interactions through mouse models of allergic asthma.
Identifying the genetic origins of human complex traits is a time-consuming and labor-intensive process that has as yet only yielded a relatively small number of confirmed susceptibility genes and an even smaller number of confirmed susceptibility alleles. One potential explanation for these difficulties might be the presence of unrecognized environmental factors that moderate the contribution of genetic loci to disease and vary between populations. These factors need not necessarily be limited to environmental parameters of intuitive importance (eg, cigarette smoke or allergen exposure) but also can include more cryptic sources of variation associated with the specific study environment (eg, study apparatus or ambient temperature). Analysis of these interactions in human subjects, although a gold standard, is time-consuming and constrained by ethical and technical issues. Investigations in mouse models, on the other hand, represent a simple and flexible system in which to explore gene-environment interaction effects. In this review we discuss the utility of mouse models in the detection of gene-environment interaction effects and consider the limitations on their application.


Neonatal hypertonia: I. Classification and structural-functional correlates.
Neonatal hypertonic states can be encountered as expressions of abnormal tone and posture. It would be useful for the neonatal neurointensivist to more precisely describe the various presentations of neonatal hypertonia, taking into consideration a classification scheme adopted for hypertonia in children at older ages. An understanding of the ontogeny of muscle tone and posture during fetal and postnatal preterm time periods with maturation to full-term ages will help conceptualize the developmental structural-functional correlates that subserve the evolving expression of this abnormal clinical sign. In the future, a more accurate description of neonatal hypertonic states should be part of the complete clinical examination to help integrate etiology, timing of injury, and neurologic localization before choosing the appropriate therapeutic intervention.


Geographic Location Impacts Patient Portal Use via Desktop and Mobile Devices.
Disparities in patient portal use are impacted by individuals' access to technology and the internet as well as their skills and health behaviors. An individual's geographic location may impact these factors as well as contribute to their decision to use a portal, their choice of device to access the portal, and their use of portal functions. This study evaluated patient portal use by geographic location according to three comparators: proximity to the medical center offering the portal, urban/rural classification, and degree of digital distress. Patients residing farther from the medical center, in rural areas, or in areas of higher digital distress were less likely to be active portal users. Patients in areas of higher digital distress were more likely to use the mobile portal application instead of the desktop portal website alone. Users of the mobile portal application used portal functions more frequently, and being a mobile user had a greater impact on the use of some portal functions by patients residing in areas of higher digital distress. Mobile patient portal applications have the potential to increase portal use, but work is needed to ensure equitable internet access, to promote mobile patient portal applications, and to cultivate individuals' skills to use portals.


Evaluation of activity, chronicity and tubulointerstitial indices for childhood lupus nephritis.
Few data exist on use of the National Institutes of Health (NIH) activity index (AI) and chronicity index (CI) in childhood lupus nephritis (LN). A tubulointerstitial activity index (TIAI) has been derived but not validated. We evaluated clinicopathologic correlations of the AI, CI and TIAI in children with LN who had undergone initial renal biopsy (n=25, age 12.4+/-2.7 years, biopsy 1) and 1 year after treatment (n=15, biopsy 2). The TIAI correlated with the AI at biopsy 1 (r=0.76, P=0.001) and biopsy 2 (r=0.52, P=0.05), but not with CI scores. Mean AI and CI scores changed substantially from biopsy 1 to biopsy 2 (P<0.05), but TIAI scores did not. Higher AI and TIAI scores correlated with proteinuria at both biopsies (r=0.51-0.76, P<0.05); CI scores correlated with estimated creatinine clearance (r=0.46-0.58, P<0.05). Improved AI score from biopsy 1 to biopsy 2 was associated with decrease in proteinuria. These results suggest that the AI and CI are useful in childhood LN. The TIAI may be a valid measure to evaluate the tubulointerstitium, but research is needed to define its responsiveness to change with therapy.


The association of emotion regulation with distress tolerance depends on a neural correlate of cognitive control.
Distress tolerance is associated with transdiagnostic mental health problems. Theory and research implicate emotion regulation and cognitive control as factors in distress tolerance but their unique contributions and interdependency have been unclear. This study tested how emotion regulation and the N2, a neural index of cognitive control, uniquely and interactively predicted distress tolerance. Undergraduate psychology students (N = 57) completed self-report measures and a Go-NoGo task, from which the N2 was extracted using PCA. The Go-NoGo task was counter-balanced to avoid confounding stimulus characteristics and frequency of stimulus presentation. Emotion regulation predicted distress tolerance, but the N2 did not. The association of emotion regulation with distress tolerance was moderated by the N2, such that the association was larger at higher N2 amplitudes. The use of a non-clinical student sample limits the generalizability of the results. The data are cross-sectional and correlational, preventing conclusions about causality. The findings indicate that emotion regulation is associated with better distress tolerance at higher levels of N2 amplitude, a neural correlate of cognitive control. Emotion regulation may be more effective at enabling distress tolerance in individuals with better cognitive control. This supports past work indicating that distress tolerance interventions may provide benefit by developing emotion regulation skills. Additional research is needed to test if such an approach is more effective in individuals with better cognitive control.


[The first case of acquired hemoglobinopathy H in Russia in a patient developing unclassified myelodysplastic syndrome/myeloproliferative disease].
A 55 year-old man with hemolytic anemia is described. Careful clinical and laboratory studies showed that this condition was a manifestation of non-hereditary hemoglobinopathy N. The clinical symptoms suggested acquired hemoglobinopathy N that devloped parallel to myelodysplastic syndrome/myeloproliferative disease.


Mechanical properties of a medical β-type titanium alloy with specific microstructural evolution through high-pressure torsion.
The effect of high-pressure torsion (HPT) processing on the microstructure and mechanical biocompatibility includes Young's modulus, tensile strength, ductility, fatigue life, fretting fatigue, wear properties and other functionalities such as super elasticity and shape memory effect, etc. at levels suitable for structural biomaterials used in implants that replace hard tissue in the broad sense (Sumitomo et al., 2008 [4]). In particular, in this study, the mechanical biocompatibility implies a combination of great hardness and high strength with an adequate ductility while keeping low Young's modulus of a novel Ti-29Nb-13Ta-4.6Zr (TNTZ) for biomedical applications at rotation numbers (N) ranging from 1 to 60 under a pressure of 1.25 GPa at room temperature was systematically investigated in order to increase its mechanical strength with maintaining low Young's modulus and an adequate ductility. TNTZ subjected to HPT processing (TNTZHPT) at low N exhibits a heterogeneous microstructure in micro-scale and nano-scale consisting of a matrix and a non-etched band, which has nanosized equiaxed and elongated single β grains, along its cross section. The grains exhibit high dislocation densities, consequently non-equilibrium grain boundaries, and non-uniform subgrains distorted by severe deformation. At high N which is N>20, TNTZHPT has a more homogeneous microstructure in nano-scale with increasing equivalent strain, εeq. Therefore, TNTZHPT at high N exhibits a more homogenous hardness distribution. The tensile strength and 0.2% proof stress of TNTZHPT increase significantly with N over the range of 0≤N≤5, and then become saturated at around 1100 MPa and 800 MPa at N≥10. However, the ductility of TNTZHPT shows a reverse trend and a low-level elongation, at around 7%. And, Young's modulus of TNTZHPT decreases slightly to 60 GPa with increasing N and then becomes saturated at N≥10. These obtained results confirm that the mechanical strength of TNTZ can be improved while maintaining a low Young's modulus in single β grain structures through severe plastic deformation.


Exponential model for a regulatory enzyme. Computer program for the determination of the model constants from initial velocity data.
The paper describes a program (DESCENT) which evaluates the constants of the exponential model for a regulatory enzyme with up to four substrates or up to three substrates and one effector. The program operates by repetitive adjustment of the model constants so as to secure a better fit between the observed and calculated initial velocities of reaction. At each adjustment, all the constants are incremented simultaneously by amounts determined by a steepest descent criterion. The program is tested by artificial data with and without added error and it is shown that good estimates of the constants can be recovered.


Efficacy and tolerability of rilmenidine compared with isradipine in hypertensive patients with features of metabolic syndrome.
A high prevalence of associated metabolic cardiovascular risk factors is often observed among hypertensive subjects. The aim of the present study was to assess the effects of 1-2 mg/day of rilmenidine, a centrally acting antihypertensive agent with selectivity for I(1) imidazoline receptors, vs. 2.5-5 mg/twice daily of isradipine, a dihydropyridine calcium channel blocker, in hypertensive patients with features of the metabolic syndrome. In this 6-month multicentre, comparative, double-blind, parallel group study, the primary objective was to assess the effects of the treatments on blood pressure (BP); the secondary endpoints were to assess glucose and lipid metabolism, in addition to clinical and biological tolerability. In non-responder patients, dose adjustment was possible from the first month and adding a diuretic from the third month. Of an intention-to-treat population of 93 patients, 84 per protocol patients completed the study: 42 in the rilmenidine group and 42 in the isradipine group. BP decreased significantly (p < 0.001) and similarly in both groups (systolic blood pressure, SBP: -16.0 +/- 17.2 mmHg and -15.0 +/- 13.0 mmHg, and diastolic blood pressure, DBP: -9.0 +/- 9.4 mmHg and -9.0 +/- 8.7 mmHg with rilmenidine and isradipine, respectively). Normalisation (DBP < 90 mmHg and SBP < 140 mmHg) and response (normalisation or decrease in SBP >or= 20 mmHg or decrease in DBP >or= 10 mmHg) rates were respectively 57% and 72% with rilmenidine and 64% and 79% with isradipine (NS between groups). The effects of the treatments on both glucose and lipid metabolism were comparable: no significant difference from baseline was observed on the main parameters including insulin sensitivity indexes. The two treatments appeared to be well tolerated throughout the study, with no serious adverse reaction reported in the rilmenidine group and one serious adverse event in the isradipine group (a perimalleolar oedema), leading to withdrawal from the study for the affected patient. This study suggests that in hypertensive patients with metabolic disorders, rilmenidine is an effective antihypertensive treatment, comparable to isradipine, with metabolic neutrality and a good tolerance profile.


The vitamin B1 status among young Egyptians from the oasis in relation to glucose-6 phosphate dehydrogenase deficiency.
Erythrocyte transketolase activity was assayed and %TPP effect was calculated to define the vitamin B1 status among 63 young boys and girls from the Oasis with normal or G6PD-deficiency. Based on the mean %TPP values; 15.6, 75 and 60% of the studied normal, G6PD-deficient males and females; respectively were deficient in B1.


Molecular cloning and sequence analysis of a seed-expressed acyl carrier protein (ACP) gene from Brassica campestris (Agrani).
We describe here the nucleotide sequence of the Brassica campestris ACPSF1 gene which encodes a seed-expressed acyl carrier protein (ACP). The 3600 bp sequence consists of 1740 bp upstream of the translation start codon, 828 bp spanning the coding region which is interrupted by three introns and 1032 bp downstream of the stop codon. Using a ACPSF1 gene-specific probe, transcripts could be detected in developing seeds, but not in leaves. The gene is now the only known member that represents group I seed-expressed ACP multigene family of Brassica species. The 5' flanking sequence of the ACPSF1 gene was examined for putative transcriptional regulatory elements. A sequence alignment of the 5' flanking regions of the available seed-expressed ACP genes of Brassica species showed some conserved regions which might have some common regulatory significance.


Nicotinamide, a vitamin B3 ameliorates depressive behaviors independent of SIRT1 activity in mice.
Sirtuin 1 (SIRT1), is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase and a candidate gene for depression. Nicotinamide (NAM), a form of vitamin B3, is reported as a potential inhibitor of SIRT1. Our previous study found that the 24-h-restraint stress could induce long-term depressive-like phenotypes in mice. These mice displayed increased SIRT1 activity. Here, we studied whether NAM was capable of attenuating depressive behaviors through inhibiting SIRT1 activity. Surprisingly, the application of NAM significantly reversed the depressive behaviors but increased SIRT1 activity further. In contrast, the level of adenosine triphosphate (ATP) was reduced in the restraint model for depression, and recovered by the administration of NAM. Furthermore, the Sirt1flox/flox; Nestin-Cre mice exhibited antidepressant behaviors and increased ATP levels. These data suggest that ATP plays an important role in depression pathogenesis, and NAM could be a potential treatment method for depression by regulating ATP independent of SIRT1 activity.


[Association between timing of introducing complementary foods and anemia of infants aged 6-11 months in four provinces of China].
To analyze the anemia status of infants aged 6-11 months in Beijing, Shanxi, Jiangxi and Zhejiang of China, and to explore the association between timing of introducing complementary foods and hemoglobin level, anemia of infants aged 6-11 months. Data was from National Nutrition and Health Systematic Survey for 0-18 Years Old Children in China. A total of 1404 infants aged 6-11 months from Beijing, Shanxi, Jiangxi and Zhejiang were enrolled in this study. Demographic characteristics, socioeconomic status, birth status and complementary feeding information were collected through questionnaire survey. HemoCue Hb201+ hemoglobin analyzer was used to measure hemoglobin value. The exposure variables in this study were timing of introducing complementary foods(≤5 months, 6 months and ≥7 months), and the outcome variables were hemoglobin level and anemia rate. The association between timing of introducing complementary foods and hemoglobin level was analyzed by using multivariate linear regression model, and the association between timing of introducing complementary foods and anemia rate was analyzed by using multivariate Logistic regression model. The hemoglobin levels of infants aged 6-11 months were(114.8±11.0)g/L, (115.5±10.5)g/L in urban areas and(114.1±11.5) g/L in rural areas. The anemia rate was 28.2%, 24.0% in urban areas and 32.9% in rural areas. The hemoglobin levels of infants introducing complementary foods at ≤5 months, 6 months and ≥7 months were(114.0±11.1), (115.2±10.9) and(114.5±10.7) g/L, respectively. After adjusting for potential confounding factors, there was no significant difference in hemoglobin level between the ≤5 months group and 6 months group(F=2.37, P=0.124), and no significant difference between the ≥ 7 months group and the 6 months group(F=0.09, P=0.770). The anemia rate of infants introducing complementary foods at ≤5 months, 6 months and ≥7 months were 32.3%, 27.9% and 22.7%, respectively. After adjusting for potential confounding factors, there was no significant difference in anemia rate between the ≤5 months group and 6 months group(OR=1.26(95%CI 0.86-1.83)), and no significant difference between the ≥7 months group and the 6 months group(OR=0.65(95%CI 0.35-1.20)). Anemia remains a serious problem for infants aged 6-11 months in Beijing, Shanxi, Jiangxi and Zhejiang. Timing of introducing complementary foods may not be related with hemoglobin level and anemia rate of infants aged 6-11 months.


Influence of diet on chromatin organization in insect mid-gut cells, and its implications for the understanding of aging in this model system.
Female Sarcophaga bullata were fed on three different dietary combinations: liver/water; sugar/water; and sugar/liver/water. These diets resulted in different survival patterns for the insect, with the longest lifespans being expressed on the last treatment. The Feulgen-DNA values for mid-gut cell nuclei were determined using a scanning and integrating microdensitometer. The cell nuclei of the mid-gut reacted to the presence of nutrients by an increase in the extinction values for Feulgen-DNA when compared to the unfed state. There were also significant differences between the various treatments in the extent of the activation shown by the mid-gut cells. The dietary regimes resulting in the longest lifespan showed a complete and uniform activation of the mid-gut epithelium, whereas other treatments did not. These observations suggest that changes in the chromatin organization occur with diet, and that maximum Feulgen-DNA extinctions occur (i.e. chromatin uncoiled and supporting transcription) on the sugar/liver/water diet. Nuclei showing maximum extinctions do not show an age-related change between 3 and 12 days of life. However, if the nuclear activation is partial, or incomplete, then age-related reversals in chromatin condensation take place.


Cloning and sequence of guinea pig interleukin 2 (IL-2).
Interleukin 2 (IL-2) is a T-cell proliferation factor released from TH0- and TH1-type helper T-cells and is an essential cytokine for certain immune responses. We reported here cloning and sequence of IL-2 cDNA in guinea pigs, which have been used for a long time in various immunological experiments and in vivo screening tests for skin sensitization potential of chemicals. Consequently, a cDNA clone was obtained encoding guinea pig IL-2 of 520 bp in length, which contained a complete open reading frame. Alignment of the amino acid sequence with human IL-2 indicates that guinea pig IL-2 is composed of 20 amino acids (aa) of a signal peptide and 132 aa of a mature peptide with a predicted molecular weight of 15133. Guinea pig IL-2 has an amino acid homology of 62% with human IL-2, 52% with murine IL-2, and 55% with rat IL-2. In addition, guinea pig IL-2 has a possible N-linked glycosylation site as seen in bovine and porcine IL-2.


Mercury inhibits the L170C mutant of aquaporin Z by making waters clog the water channel.
We conduct in silico experiments of the L170C mutant of the Escherichia coli aquaporin Z (AQPZ) with and without mercury bonded to residue Cys 170. We find that bonding mercury to Cys 170 does not induce consequential structural changes to the protein. We further find that mercury does not stick in the middle of the water channel to simply occlude water permeation, but resides on the wall of the water pore. However, we observe that the water permeation coefficient of L170C-Hg(+) (with one mercury ion bonded to Cys 170) is approximately half of that of the mercury-free L170C. We examine the interactions between the mercury ion and the waters in its vicinity and find that five to six waters are strongly attracted by the mercury ion, occluding the space of the water channel. Therefore we conclude that mercury, at low concentration, inhibits AQPZ-L170C mutant by making water molecules clog the water channel.


Effect of endometrial thickness and embryo quality on live-birth rate of fresh IVF/ICSI cycles: a retrospective cohort study.
Successful implantation and delivery require both the functional embryo and receptive endometrium in assisted reproductive technology (ART) cycles. However, little is known about embryo-endometrial interaction on live-birth. We aimed to investigate the independent effect and interaction of endometrial thickness (EMT) and embryo quality on live-birth in fresh embryo transfer (ET) cycles. We conducted a retrospective cohort study including 15,012 ART cycles between 2013 and 2016 in three centers in China. Poisson regression with generalized estimating equations was employed to calculate relative risks (RRs) and 95% confidence intervals (CIs). We estimated the interaction of embryo quality and EMT on live-birth rate (LBR). The LBR per cycle was 42.8% overall. LBR increased with increasing EMT and reached a plateau (50.6 to 54.2%) when EMT was 11 mm or thicker. Embryo quality represented by cumulative score was associated with LBR independently of number of embryos transferred and EMT. LBR was not increased with thicker EMT when only Q1 cleavage-stage embryo transferred (aRR 0.95, 95%CI 0.61-1.46). LBR was not increased significantly with thicker EMT with transfer of two good-quality cleavage-stage embryos and any blastocyst combination except Q1 group. There was significant interaction between EMT and embryo quality on LBR for cleavage-stage ETs (P=0.023). This study demonstrated the nonlinear EMT-LBR association and the EMT cut-off value of 11 mm which may be of more clinical significance for predicting live-birth. Embryo quality is an independent prognostic tool for LBR. Our finding of significant embryo-endometrial interaction indicates combination of EMT and embryos quality might improve the prognostic value in clinical practice for live-birth in patients undergoing transfer of 1-2 fresh cleavage-stage embryos.


Spirometry is affected by intelligence and behavior in Duchenne muscular dystrophy.
Children with Duchenne muscular dystrophy (DMD) have progressive respiratory muscle weakness. Spirometry monitors progress, but is effort-dependent. Intelligence quotients (IQ) average one standard deviation below normal, and behavioral disturbance is common. Our aim was to assess if impaired intelligence or behavior influences spirometry in children with DMD, and if computerized visual incentives (CVI) are beneficial. Forty-seven boys with DMD, of mean age 12.6 years (range, 6-19), were recruited. Full-scale, performance, and verbal IQ, and parent-and-teacher-reported oppositional behavior scores, were recorded. Each was divided into moderate, mild, and no impairment groups. A randomized crossover design was applied to performing spirometry with or without CVI first. A Jaeger Masterscope (version 4.60) was used. Linear regression defined the relationship between spirometry and both IQ and behavior scores. The paired Student's t- test compared spirometry performed with and without CVI for the overall group and subgroups. Boys with DMD can adequately perform spirometry. There is an association between %FEV1 and %FVC with full-scale (r = 0.50, P = 0.002; r = 0.49, P = 0.003, respectively), performance (r = 0.68, P < 0.0005; r = 0.68, P < 0.0005, respectively) and verbal (r = 0.39, P = 0.043; r = 0.36, P = 0.037, respectively) IQ, but not with parent (P = 0.77, P = 0.70, respectively) or teacher (P = 0.90, P = 0.90, respectively)-reported oppositional behavior scores. The effect of CVI was significant in those with moderate full-scale (P = 0.03), performance (P = 0.002), and verbal (P = 0.02) intellectual impairment, and moderately severe teacher-reported oppositional behavior (P = 0.02). In conclusion, spirometry results are related to intelligence in DMD. Using CVI improves the FVC obtained in those with moderate intellectual or behavioral impairment.


Mood disturbances in motor neurone disease.
This study explores the severity of depression and anxiety experienced by patients suffering from motor neurone disease and seeks to link this to illness progression, recent life events and personality factors. The 18 patients who participated in the study were assessed for the presence of psychiatric symptoms using the Beck Depressive Inventory and the Hospital Anxiety and Depression Scale. The severity of the illness and the life events during the course of the illness were measured using the Norris scale and the Holmes and Rahe Social Readjustment Rating Scale. A personality assessment was made using the Eysenck Personality Questionnaire (EPQ). Only four out of these 18 patients (23%) in the study suffered depression and of these three (17%) were mild and one (6%) was of moderate severity. A further six patients (33%) were rated as borderline depression. Only two patients suffered from an anxiety state and both had concurrent mild depression. No correlations of depression were found with the life events or illness progression. Only the L sub-scale of the EPQ (15.6+/-4.9) exceeds values expected for the general population. Despite the severity and frequency of life events during the course of the illness, most patients do not develop a depressive illness. The reason for this unexpected result is unclear. Depression is believed to result from underactivity of the serotonergic neurotransmitter system. However, in MND this system is relatively unaffected in contrast to dementia and other neurodegenerative disorders. The patients' high L scores suggest that many may cope with their illness by widespread use of denial as a psychological defence.


Is HIV infection associated with an increased risk for cholera? Findings from a case-control study in Mozambique.
As residents of sub-Saharan Africa are at high risk for HIV and cholera, it is biologically plausible that immune suppression caused by HIV infection predisposes to cholera. Our aim was to assess the potential association between both diseases. We conducted a case-control study in Beira, Mozambique, a high-risk area for HIV and cholera. Between 1 January 2005 and 30 June 2006, experienced counsellors invited 132 suspected cholera cases and 528 age- and sex-matched controls to an HIV counselling and testing centre. Forty (30%) of the invited cases and 127 (24%) of the invited controls came for HIV testing. No significant differences in demographic and socio-economic baseline characteristics were detected between participants and non-participants. Twenty five of 167 (15%) individuals who underwent testing were found HIV-positive. The probability of a positive HIV-test was highest in participants between 40 and 49 years; 6 of 14 (43%) tested HIV-positive. Nine of 40 (23%) cholera cases were found to be HIV-infected compared with 16 of 127 (13%) controls (adjusted odds ratio 2.6; 95% CI 0.9-7.5; P = 0.08). The findings suggest that in a cholera-endemic area, HIV infection is associated with an increased risk for cholera. More research in HIV endemic settings is needed to confirm the findings and to explore the effect of HIV-related immunosuppression on the transmission of cholera.


Utility of graded prognostic assessment in evaluation of patients with brainstem metastases treated with radiosurgery.
Prospective data regarding the safety and efficacy of stereotactic radiosurgery (SRS) for patients with metastatic disease involving the brainstem are lacking. The aim of this study was to assess the efficacy and toxicity of SRS for patients with brainstem metastases treated at our institution. From September 2007 to October 2015, patients treated with SRS for brain metastases were prospectively entered into an institutional database. Forty eight patients with 51 lesions involving the brainstem with clinical follow-up were identified. Local control (LC), elsewhere brain failure (EBF) and overall survival (OS) were assessed from the date of radiosurgery using the Kaplan-Meier method. Univariate and multivariate analyses of factors related to OS were performed using a Cox proportional hazards model. Median clinical follow-up was 4.8 months. Median patient age was 62 (range: 28-87); non-small cell lung and breast cancer were the most common primaries at 54% and 21% respectively. Median brainstem lesion volume was 0.12cm(3) (range: 0.01-3.67cm(3)). Whole brain radiotherapy was previously utilized in 19 patients (40%). The median OS was 7.6 months and the 12 month LC rate was 89%. Only 2 patients (4%) experienced grade 3 motor toxicity secondary to SRS. 11 of the 16 patients (69%) initially presenting with symptoms related to brainstem metastases had symptom improvement or resolution following SRS. On multivariate analysis, graded prognostic assessment (GPA) score>2 was predictive of improved survival (p<0.01) while prior chemotherapy use predicted decreased survival (p=0.049). SRS is associated with high LC rates and low toxicity for brainstem metastases. Improved OS was seen for patients with GPA score>2. GPA appears to be a useful tool for assessing prognosis in patients with brainstem metastases. Small volume lesions were safely treated with or without prior whole brain radiotherapy.


Regulated proteolysis in light signaling.
Photoreceptors regulate many aspects of development throughout the life cycle of a plant. Recent advances have demonstrated the importance of ubiquitin-mediated proteolysis in the control of development by light. Both some of the photoreceptors themselves and, in particular, transcription factors that are involved in transducing the light signal are subject to regulated ubiquitination and subsequent degradation by the 26S proteasome.


Sugar-substituted 2-azetidinones as cholesterol absorption inhibitors.
The asymmetric synthesis of a glucuronide conjugate of the 2-azetidinone cholesterol absorption inhibitor Sch 48461 was accomplished to confirm the structure of a metabolite isolated from in vivo sources. Key features of this article include the asymmetric synthesis of 2-azetidinones by Evan's chiral oxazolidinone methodology and glucuronide formation by a Mitsunobu protocol.


Extraction of a large self-amputated colonic lipoma: A case report.
Despite being the most common benign tumor of nonepithelial origin in the colon, colonic lipomas are nonetheless considered a rare occurrence. The minority of patients presenting with symptomatic colonic lipoma are generally treated with resection. We report a case of a symptomatic patient who, on presentation, was found to have a partially obstructing, self-amputated colonic mass on colonoscopy, requiring endoscopic fragmentation to extrude what was later histologically diagnosed to be a lipoma.


Atrial fibrillation and COVID-19 in older patients: how disability contributes to shape the risk profile. An analysis of the GeroCovid registry.
Atrial fibrillation (AF) is often complicated by disabling conditions in the elderly. COVID-19 has high mortality in older people. This study aimed at evaluating the relationship of pre-infection AF with characteristics and survival of older COVID-19 patients. We retrospectively analyzed inpatients aged ≥ 60 years enrolled in GeroCovid Observational, a multicenter registry endorsed by the Italian and the Norwegian Societies of Gerontology and Geriatrics. Pre-COVID-19 sociodemographic, functional, and medical data were systematically collected, as well as in-hospital mortality. Between March and June 2020, 808 COVID-19 subjects were enrolled (age 79 ± 9 years; men 51.7%). The prevalence of AF was 21.8%. AF patients were older (82 ± 8 vs. 77 ± 9 years, p < 0.001), had a higher CHA2DS2-VASc score (4.1 ± 1.5 vs. 3.2 ± 1.5, p < 0.001) and were more likely to present almost all comorbidities. At multivariable analysis, advanced age, white blood cell count, the presence of heart and peripheral artery diseases were significantly associated with the presence of AF. In-hospital mortality was higher in AF patients (36.9 vs. 27.5%; OR = 1.55, 95% CI = 1.09-2.20; p = 0.015). A decision tree analysis showed that, in AF subjects, preserved functional status at admission was the most important factor associated with survival. In patients without AF, baseline COVID-19 severity was the most relevant variable related to clinical prognosis. AF is frequent in older patients with COVID-19, in whom it associates with clinical complexity and high mortality. Pre-infection disability shapes the prognosis of this extremely vulnerable segment of hospitalized subjects. GeroCovid Observational was registered at www.clinicaltrials.gov (NCT04379440).


Bone elongation using monolateral external fixation: a practical guide.
In the literature, we can find many articles that describe in detail specific complex procedures related to the limb reconstruction. However, the general information on the biological and mechanical bases of callotasis is out of date, and the surgeons must relate to works dating from the early 1980s. These articles also come from a period in which the callotasis technique was being developed and, therefore, incur in discrepancies depending on the year they were written or the school of the author. This paper provides a general and summarised overview of the theoretical and practical aspects interesting to a surgeon that needs clear information on the bone elongations performed with the help of a monolateral external fixator.


Two Years of Improved Neurological Function With Nusinersen in a 48-Year-Old Patient With Spinal Muscular Atrophy Type 3.
Nusinersen antisense oligonucleotide infusions have been shown to be effective in the treatment spinal muscular atrophy. The majority of the evidence has been collected in young type 1 and type 2 patients, and evidence of efficacy in adult patients is limited. A 48-year-old woman with spinal muscular atrophy type 3 who has received the loading dose and 8 maintenance infusions over an 8-month period. Grip and pinch strength, measured by hand-held dynamometry measured at baseline and in 6 to 12 months interval improved over a 24-month period. She also reported multiple other subjective improvements in function. This is the first published case of nusinersen in a middle-aged adult with spinal muscular atrophy. Sustained clinically meaningful improvement may be possible with nusinersen initiation in mid adulthood.


The Power of Plasticity-Metabolic Regulation of Hepatic Stellate Cells.
Hepatic stellate cells (HSCs) are resident non-parenchymal liver pericytes whose plasticity enables them to regulate a remarkable range of physiologic and pathologic responses. To support their functions in health and disease, HSCs engage pathways regulating carbohydrate, mitochondrial, lipid, and retinoid homeostasis. In chronic liver injury, HSCs drive hepatic fibrosis and are implicated in inflammation and cancer. To do so, the cells activate, or transdifferentiate, from a quiescent state into proliferative, motile myofibroblasts that secrete extracellular matrix, which demands rapid adaptation to meet a heightened energy need. Adaptations include reprogramming of central carbon metabolism, enhanced mitochondrial number and activity, endoplasmic reticulum stress, and liberation of free fatty acids through autophagy-dependent hydrolysis of retinyl esters that are stored in cytoplasmic droplets. As an archetype for pericytes in other tissues, recognition of the HSC's metabolic drivers and vulnerabilities offer the potential to target these pathways therapeutically to enhance parenchymal growth and modulate repair.


Mechanism of induction of hepatic microsomal drug metabolizing enzymes by a series of barbiturates.
The inducing effect of certain barbiturates (secobarbitone, thiopentone, pentobarbitone, allobarbitone, phenobarbitone and barbitone) on the levels of the hepatic microsomal drug-metabolizing enzymes has been studied in the rat both in vivo and in vitro. The extent of induction was related to the plasma half-lives of the barbiturates; compounds with low rates of metabolism and long half-lives were the most potent inducing agents. The latter (phenobarbitone, pentobarbitone and allobarbitone) were shown by spectral technique to interact with cytochrome P-450 suggesting that their mechanism of enzyme induction was 'substrate induction' in type. Barbiturates containing an allyl group (secobarbitone and allobarbitone) had a weaker inducing effect than expected, possibly due to their destruction of cytochrome P-450. Despite its short plasma half-life of 0-5 h thiopentone was a relatively potent inducer probably due to its metabolism to pentobarbitone, which has a much longer plasma half-life (1-3 h). Barbitone is an effective inducer of the drug-metabolizing enzymes, yet does not interact spectrally with cytochrome P-450; this is in accord with the observations that although there are increases in NADPH-cytochrome c reductase and cytochrome b5, following administration of barbitone there is no increase in cytochrome P-450. Barbiturate pretreatment does not affect the activities of glucose-6-phosphatase, glucose-6-phosphate dehydrogenase or 6-phosphogluconate dehydrogenase.


Comparative Toxic Effect of Bulk Copper Oxide (CuO) and CuO Nanoparticles on Human Red Blood Cells.
Destruction of red blood cell is associated with anemia and other pathological status; hence, the hemolytic effects of all chemicals and particles which come into contact with blood components must be considered. Nanomaterials and nanoparticles are potential substitutes for common material and particles, and assessment of their effect on blood components is a necessary part of their safety evaluation. High surface-to-volume ratio of nanoparticles may cause their toxic effects differ from those observed for bulk material. The aim of this study was to compare the hemolytic effects of CuO nanoparticles and bulk CuO. Red blood cells were isolated from blood of healthy subjects and hemolytic effects assayed following treatment of cells with 0.005-0.25 mM of CuO (bulk and nanoparticles) for 6 h. For assessment of other parameters, cells were incubated with 0.01, 0.05, and 0.25 mM of CuO nanoparticles and bulk CuO for 1, 2, and 3 h. Our results demonstrate that CuO nanoparticles, in particular, caused toxic hemolytic effects in concentration-dependent manner, and this effect maybe through formation of ROS, glutathione depletion, and lipid peroxidation. In conclusion, CuO nanoparticles are shown to effectively destruct human red blood cells in comparison to bulk CuO.


Cholinergic projections from the basal forebrain to the basolateral amygdaloid complex: a combined retrograde fluorescent and immunohistochemical study.
We have examined the location of cholinergic and non-cholinergic neurons that project to the rat basolateral amygdaloid nucleus by using choline acetyltransferase (ChAT) immunohistochemistry in combination with retrograde fluorescent tracing on the same tissue section. Since many tracer-and ChAT-positive neurons were identified in basal forebrain areas, including the ventral pallidum, we also stained many of the sections for glutamate decarboxylase, a suitable marker for the delineation of pallidal areas. Cholinergic neurons projecting to the basolateral amygdaloid nucleus were observed in a continuous territory stretching from the dorsal part of ventral pallidum, through sublenticular substantia innominata to ventral parts of globus pallidus and peripallidal areas. Non-cholinergic neurons projecting to the basolateral amygdaloid nucleus were found intermixed within the same structures and constitute approximately 25% of the amygdalopetal projection neurons in these ventral forebrain structures. Since amygdalopetal cholinergic neurons were demonstrated in areas generally recognized as giving rise to cholinergic projections to cerebral cortex, several retrograde double-labeling experiments with two different fluorescent tracers were performed for the purpose of detecting the possible existence of collateral projections. The results obtained showed that the cholinergic basal forebrain neurons in general project to only one forebrain region, and, furthermore, that the cholinergic system consists of partially overlapping subsets of neurons that project to various neocortical and allocortical areas and to the amygdaloid body.


Embryonic ethanol exposure impairs detour learning in chicks.
Six groups of 30 fertile eggs each were injected with 200 microliters of either sterile water or a 37.5% (v/v) ethanol solution immediately before incubation or on days 7 or 14 of incubation. Regardless of day of injection, the ethanol groups had a lower proportion of chicks who completed pipping and hatching. Of the chicks surviving to pip and hatch, the group injected with ethanol immediately before incubation was delayed significantly in pipping compared to the other ethanol-injected groups and to the group injected with water immediately before incubation (p less than 0.05 in all cases). Also, compared to the chicks injected with water, the chicks in all ethanol groups required more trials to attain criterion on a detour learning task when tested 7-10 days after hatching (p less than 0.05).


A dimeric proteomimetic prevents SARS-CoV-2 infection by dimerizing the spike protein.
Protein tertiary structure mimetics are valuable tools to target large protein-protein interaction interfaces. Here, we demonstrate a strategy for designing dimeric helix-hairpin motifs from a previously reported three-helix-bundle miniprotein that targets the receptor-binding domain (RBD) of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Through truncation of the third helix and optimization of the interhelical loop residues of the miniprotein, we developed a thermostable dimeric helix-hairpin. The dimeric four-helix bundle competes with the human angiotensin-converting enzyme 2 (ACE2) in binding to RBD with 2:2 stoichiometry. Cryogenic-electron microscopy revealed the formation of dimeric spike ectodomain trimer by the four-helix bundle, where all the three RBDs from either spike protein are attached head-to-head in an open conformation, revealing a novel mechanism for virus neutralization. The proteomimetic protects hamsters from high dose viral challenge with replicative SARS-CoV-2 viruses, demonstrating the promise of this class of peptides that inhibit protein-protein interaction through target dimerization.


The NEEDNT Food List: non-essential, energy-dense, nutritionally-deficient foods.
To provide a list of non-essential, energy-dense, nutritionally-deficient foods in New Zealand (NEEDNT foods) which are usually high in calories and either bereft of nutritional benefits or easily replaced with lower calorie, more nutritious alternatives. The List was compiled using the National Heart Foundation and Diabetes New Zealand "Foods to Avoid", "Stop Eating" and "Optional Foods" lists and the Canterbury District Health Board "Supermarket Shopping Guide". Foods and beverages were included if they contained alcohol, saturated fat, added sugar, were prepared using a high fat cooking method or contained a large amount of energy relative to their essential nutrient value. As it has no energy value, salt was not a criterion for inclusion on the List. Over 50 potential foods or groups of foods were identified that contained alcohol, saturated fat, added sugar, were prepared using a high fat cooking method or contained a large amount of energy relative to their essential nutrient value. Fifty foods/groups of foods were included on the final list (Table 1). The NEEDNT Food List will be a useful tool for medical practitioners and other health professionals working with people wanting to lose weight [corrected].


Which diameter and angle rule provides optimal flow patterns in a coronary bifurcation?
The branching angle and diameter ratio in epicardial coronary artery bifurcations are two important determinants of atherogenesis. Murray's cubed diameter law and bifurcation angle have been assumed to yield optimal flows through a bifurcation. In contrast, we have recently shown a 7/3 diameter law (HK diameter model), based on minimum energy hypothesis in an entire tree structure. Here, we derive a bifurcation angle rule corresponding to the HK diameter model and critically evaluate the streamline flow through HK and Murray-type bifurcations. The bifurcations from coronary casts were found to obey the HK diameter model and angle rule much more than Murray's model. A finite element model was used to investigate flow patterns for coronary artery bifurcations of various types. The inlet velocity and pressure boundary conditions were measured by ComboWire. Y-bifurcation of Murray type decreased wall shear stress-WSS (10%-40%) and created an increased oscillatory shear index-OSI in atherosclerosis-prone regions as compared with HK-type bifurcations. The HK-type bifurcations were found to have more optimal flow patterns (i.e., higher WSS and lower OSI) than Murray-type bifurcations which have been traditionally believed to be optimized. This study has implications for changes in bifurcation angles and diameters in percutaneous coronary intervention.


Surgical management of lung cancer with solitary cerebral metastasis.
Between 1964 and 1986, 19 patients underwent resection of both a primary lung cancer and the associated brain metastasis. One patient underwent resection of 2 separate primary lung cancers and the associated metastases. The 12 men and 7 women ranged in age from 42 to 67 years (mean, 54.6 years). The cell type was adenocarcinoma in 12 tumors, squamous or adenosquamous cell in 5, large cell undifferentiated or anaplastic in 2, and malignant carcinoid in 1 tumor. The types of resection were as follows: lobectomy for 12 neoplasms, pneumonectomy for 5, bilobectomy for 2, and wedge resection for 1 neoplasm. Radiotherapy to the brain was given in connection with sixteen of the twenty craniotomies. The patient with 2 separate primary neoplasms survived 19 years before dying 5 months after the second craniotomy. The mean survival is 8.0 +/- 2.1 years (+/- the standard error), and the median survival is 1.67 years. Survival at 1 year was 65 +/- 10.7% and at 5 years, 45 +/- 11.1%. On univariate analysis, the following factors were found to correlate significantly with longer survival: a lung tumor in Stage I or II; negative mediastinal nodes; curative rather than palliative resection of the lung tumor; and age younger than 55 years. However, on multivariate analysis, only curative resection was a significant factor (p less than 0.01). We believe these results justify continued application of this combined surgical approach to patients having limited-stage lung cancer with a solitary brain metastasis.


Dietary Rapeseed Oil Supplementation Reduces Hepatic Steatosis in Obese Men-A Randomized Controlled Trial.
Effective treatment for obesity associated non-alcoholic fatty liver disease (NAFLD) is limited. Dietary supplementation of n-3 polyunsaturated fatty acids, specifically alpha linolenic acid (ALA), can resolve intrahepatic lipid content (IHL). This study investigates the effect of daily supplementation of either refined rapeseed (RA), containing high amounts of ALA, or refined olive (OL) oil on IHL and glucose metabolism in NAFLD patients. 27 obese men consumed an isocaloric diet including either 50 g of RA or OL daily for 8 weeks. Hepatic proton magnetic resonance spectroscopy, hyperinsulinemic-euglycemic clamp studies and blood tests are performed before and at the end of the study. At 8 weeks a significant reduction in IHL is observed for RA (13.1 ± 1.6 before versus 11.1 ± 1.6% after intervention) versus OL (13.3 ± 2.5 before versus 15.7 ± 2.7% after intervention). For RA, a 21% reduction (P < 0.02) in serum free fatty acids (FFA) and a 1.68-fold increase (P = 0.03) of serum interleukin-6 (IL-6) is observed after 8 weeks. RA has a beneficial effect on hepatic lipid metabolism as shown by reduced IHL and serum FFA. RA induced IL-6 production seems to be liver protective confirming previous results.


Improving drug discovery with a hybrid deep generative model using reinforcement learning trained on a Bayesian docking approximation.
Generative approaches to molecular design are an area of intense study in recent years as a method to generate new pharmaceuticals with desired properties. Often though, these types of efforts are constrained by limited experimental activity data, resulting in either models that generate molecules with poor performance or models that are overfit and produce close analogs of known molecules. In this paper, we reduce this data dependency for the generation of new chemotypes by incorporating docking scores of known and de novo molecules to expand the applicability domain of the reward function and diversify the compounds generated during reinforcement learning. Our approach employs a deep generative model initially trained using a combination of limited known drug activity and an approximate docking score provided by a second machine learned Bayes regression model, with final evaluation of high scoring compounds by a full docking simulation. This strategy results in molecules with docking scores improved by 10-20% compared to molecules of similar size, while being 130 × faster than a docking only approach on a typical GPU workstation. We also show that the increased docking scores correlate with (1) docking poses with interactions similar to known inhibitors and (2) result in higher MM-GBSA binding energies comparable to the energies of known DDR1 inhibitors, demonstrating that the Bayesian model contains sufficient information for the network to learn to efficiently interact with the binding pocket during reinforcement learning. This outcome shows that the combination of the learned latent molecular representation along with the feature-based docking regression is sufficient for reinforcement learning to infer the relationship between the molecules and the receptor binding site, which suggest that our method can be a powerful tool for the discovery of new chemotypes with potential therapeutic applications.


Determination of complete sequence information of the human ABO blood group orthologous gene in pigs and breed difference in blood type frequencies.
The sequence information of the genomic form of the human ABO blood group orthologous gene (erythrocyte antigen A, EAA) is not complete in pigs. Therefore, we cloned and characterized the nucleotide sequence of EAA intron 7, which is critical to understand genetic difference between A and 0 blood groups in pigs, covering complete genomic sequence information of EAA excluding a ~560bp unsequencible gap. We also analyzed genetic polymorphisms within EAA intron 7 and exon 8. We found difference in A0 blood group frequencies among pig breeds. In addition, we designed a new genomic DNA-based A0 blood group typing method and improved the accuracy and simplicity of the typing.


Effect of Factors Secreted by the Placenta on Phenotype of THP-1 Cells Cultured on a 3D Scaffold.
We studied the effects of secretory products of the placenta obtained from women with normal pregnancy and preeclampsia on the expression of surface markers by THP-1 cells cultured on a 3D Matrigel scaffold. Secretory products of third trimester placentas obtained from women with normal pregnancy reduced the relative number of THP-1 cells expressing CD54 and CD14 molecules and expression of CD14 and CD95 molecules by THP-1 cells in comparison with the effect of secretory products first trimester placentas. In parallel, the intensity of CD49d expression by THP-1 cells increased in the presence of secretory products of third trimester placentas in comparison with the first trimester. No differences in the expression of the studied molecules by THP-1 cells under the effect of placentas from women with physiological pregnancy and patients with preeclampsia were found.