Maternal Dietary Supplementation with Oligofructose-Enriched Inulin in Gestating/Lactating Rats Preserves Maternal Bone and Improves Bone Microarchitecture in Their Offspring.
Nutrition during pregnancy and lactation could exert a key role not only on maternal bone, but also could influence the skeletal development of the offspring. This study was performed in rats to assess the relationship between maternal dietary intake of prebiotic oligofructose-enriched inulin and its role in bone turnover during gestation and lactation, as well as its effect on offspring peak bone mass/architecture during early adulthood. Rat dams were fed either with standard rodent diet (CC group), calcium-fortified diet (Ca group), or prebiotic oligofructose-enriched inulin supplemented diet (Pre group), during the second half of gestation and lactation. Bone mineral density (BMD) and content (BMC), as well as micro-structure of dams and offspring at different stages were analysed. Dams in the Pre group had significantly higher trabecular thickness (Tb.Th), trabecular bone volume fraction (BV/TV) and smaller specific bone surface (BS/BV) of the tibia in comparison with CC dams. The Pre group offspring during early adulthood had an increase of the lumbar vertebra BMD when compared with offspring of CC and Ca groups. The Pre group offspring also showed significant increase versus CC in cancellous and cortical structural parameters of the lumbar vertebra 4 such as Tb.Th, cortical BMD and decreased BS/BV. The results indicate that oligofructose-enriched inulin supplementation can be considered as a plausible nutritional option for protecting against maternal bone loss during gestation and lactation preventing bone fragility and for optimizing peak bone mass and architecture of the offspring in order to increase bone strength.


The association between clusters of chronic conditions and psychological well-being in younger and older people-A cross-sectional, population-based study from the Lolland-Falster Health Study, Denmark.
To investigate the association between clusters of conditions and psychological well-being across age groups. This cross-sectional study used data collected in the Danish population-based Lolland-Falster Health Study. We included adults over the age of 18 years. Self-reported chronic conditions were divided into 10 groups of conditions. The primary outcome was psychological well-being (the WHO-5 Well-Being Index). Factor analysis constructed the clusters of conditions, and regression analysis investigated the association between clusters and psychological well-being. Of 10,781 participants, 31.4% were between 18 and 49 years, 35.7% were between 50 and 64 years and 32.9% were above ≥65 years. 35.2% had conditions represented in 1 and 32.9% in at least 2 of 10 condition groups. Across age groups, living with one or more chronic conditions was associated with poorer psychological well-being. Two chronic condition patterns were identified; one comprised cardiovascular, endocrine, kidney, musculoskeletal and cancer conditions, the second mental, lung, neurological, gastrointestinal and sensory conditions. Both patterns were associated with poorer psychological well-being (Pattern 1: -4.5 (95% CI: -5.3 to -3.7), Pattern 2: -9.1 (95% CI -13.8 to -8.2). For pattern 2, participants ≥65 years had poorer psychological well-being compared to younger (-12.6 (95% CI -14.2 to -11.0) vs -6.6 (95% CI: -7.8 to -5.4) for 18-49 years and -8.7 (95% CI: -10.1 to -7.3) for 50-64 years, interaction: p ≤ 0.001). Living with one or more chronic conditions is associated with poorer psychological well-being. Findings point toward a greater focus on supporting psychological well-being in older adults with both mental and somatic conditions.


Non-thermal melting in semiconductors measured at femtosecond resolution.
Ultrafast time-resolved optical spectroscopy has revealed new classes of physical, chemical and biological reactions, in which directed, deterministic motions of atoms have a key role. This contrasts with the random, diffusive motion of atoms across activation barriers that typically determines kinetic rates on slower timescales. An example of these new processes is the ultrafast melting of semiconductors, which is believed to arise from a strong modification of the inter-atomic forces owing to laser-induced promotion of a large fraction (10% or more) of the valence electrons to the conduction band. The atoms immediately begin to move and rapidly gain sufficient kinetic energy to induce melting--much faster than the several picoseconds required to convert the electronic energy into thermal motions. Here we present measurements of the characteristic melting time of InSb with a recently developed technique of ultrafast time-resolved X-ray diffraction that, in contrast to optical spectroscopy, provides a direct probe of the changing atomic structure. The data establish unambiguously a loss of long-range order up to 900 A inside the crystal, with time constants as short as 350 femtoseconds. This ability to obtain the quantitative structural characterization of non-thermal processes should find widespread application in the study of ultrafast dynamics in other physical, chemical and biological systems.


Anatomical and functional outcomes following a precise, graded, dorsal laceration spinal cord injury in C57BL/6 mice.
To study the pathophysiology of spinal cord injury (SCI), we used the LISA-Vibraknife to generate a precise and reproducible dorsal laceration SCI in the mouse. The surgical procedure involved a T9 laminectomy, dural resection, and a spinal cord laceration to a precisely controlled depth. Four dorsal hemisection injuries with lesion depths of 0.5, 0.8, 1.1, and 1.4 mm, as well as normal, sham (laminectomy and dural removal only), and transection controls were examined. Assessments including the Basso Mouse Scale (BMS), footprint analysis, beam walk, toe spread reflex, Hargreaves' test, and transcranial magnetic motor-evoked potential (tcMMEP) analysis were performed to assess motor, sensorimotor, and sensory function. These outcome measures demonstrated significant increases in functional deficits as the depth of the lesion increased, and significant behavioral recovery was observed in the groups over time. Quantitative histological examination showed significant differences between the injury groups and insignificant lesion depth variance within each of the groups. Statistically significant differences were additionally found in the amount of ventral spared tissue at the lesion site between the injury groups. This novel, graded, reproducible laceration SCI model can be used in future studies to look more closely at underlying mechanisms that lead to functional deficits following SCI, as well as to determine the efficacy of therapeutic intervention strategies in the injury and recovery processes following SCI.


Inflammatory potential of the diet and mortality in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain).
Low-grade chronic inflammation is associated with several chronic conditions, and diet is known to play a role in chronic inflammation. We aimed to evaluate the association between the inflammatory potential of the diet and mortality in the Spanish population from the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The study included 41 199 participants (62% female) aged 29-69 years from five Spanish regions. During 18 years of follow-up 3316 deaths were identified. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 30 dietetic components and their corresponding inflammatory scores (weights). The association between the ISD and mortality was analyzed by multivariate Cox regression models. There was a significant association between ISD and mortality: subjects classified in the fifth quintile of the ISD (more proinflammatory diets) had a hazard ratio of 1.42 (95%-confidence interval 1.25-1.60) as compared with those in the first quintile; the corresponding figures were 1.89 (1.48-2.40) for cardiovascular diseases mortality and 1.44 (1.22-1.69) for death by cancer. Consuming more proinflammatory diets, expressed by means of the ISD, is associated with higher mortality; this effect seems to be stronger for deaths by cardiovascular diseases.


Clinical in situ study investigating abrasive effects of two commercially available toothpastes.
The aim of this study was to determine if the abrasive effect on dentine of two commercially available toothpastes, known to vary in their in vitro abrasive levels, can be differentiated in an in situ model after 10 days, assessed by contact profilometry. This was a single centre, single blind, randomized, split mouth, two treatment, in situ study, in 34 healthy subjects, evaluating the abrasive effects of two marketed desensitizing toothpastes, (Colgate Sensitive Multi Protection toothpaste - C; Sensodyne Total Protection - S). Subjects wore bi-lateral, lower buccal appliances, each fitted with four dentine sections which were power brushed three times a day with the treatment regimen. Each subject received two toothpaste treatments for 10 days during the treatment period. Samples were measured at baseline and day 10 by contact and non-contact profilometry and day 5 by contact profilometry. Thirty-four subjects were included in the efficacy analysis. Results from contact profilometry showed statistically significant (P < 0.0001) dentine loss compared to baseline at day 5 and 10 for both pastes. At each time point, C showed statistically significantly greater dentine loss than S, P < 0.0001. After 10 days treatment, the difference in dentine loss between the pastes was 1.4 microm. The non-contact profilometry data showed similar trends. After 10 days of treatment, C showed statistically significantly greater dentine loss than S, with treatment difference of 0.9 microm, P = 0.0057. The methodology used has successfully differentiated between the abrasivity of the two pastes in respect of dentine surface loss over time in an in situ environment.


Coherent field propagation between tilted planes.
Propagating electromagnetic light fields between nonparallel planes is of special importance, e.g., within the design of novel computer-generated holograms or the simulation of optical systems. In contrast to the extensively discussed evaluation between parallel planes, the diffraction-based propagation of light onto a tilted plane is more burdensome, since discrete fast Fourier transforms cannot be applied directly. In this work, we propose a quasi-fast algorithm (O(N3 log N)) that deals with this problem. Based on a proper decomposition into three rotations, the vectorial field distribution is calculated on a tilted plane using the spectrum of plane waves. The algorithm works on equidistant grids, so neither nonuniform Fourier transforms nor an explicit complex interpolation is necessary. The proposed algorithm is discussed in detail and applied to several examples of practical interest.


[D-dimer and plasminogen activator of the urokinase type: personal experiences with breast cancer].
Plasma values of d-dimer, a stable end product of plasmin-induced fibrinolysis, were ascertained in 128 female patients with mammary carcinoma. These patients demonstrated significantly increased d-dimers in comparison with the control group with benign mammary disease (p < 0.01). The sensitivity and specificity of d-dimer were slightly higher than those of the established tumour marker CA 15-3 and CEA. There was no correlation between d-dimers in the plasma and increased expression of urokinase plasminogen activator (UPA) in the tissue. Increased d-dimers in the plasma of female patients with mammary carcinoma reflect multi-factoral interactions between carcinoma growth and the haemostatic-fibrinolytic system, and may be used as tumour markers.


Resistomycin Suppresses Prostate Cancer Cell Growth by Instigating Oxidative Stress, Mitochondrial Apoptosis, and Cell Cycle Arrest.
Globally, prostate cancer is among the most threatening and leading causes of death in men. This study, therefore, aimed to search for an ideal antitumor strategy with high efficacy, low drug resistance, and no or few adverse effects. Resistomycin is a natural antibiotic derived from marine actinomycetes, and it possesses various biological activities. Prostate cancer cells (PC3) were treated with resistomycin (IC12.5: 0.65 or IC25: 1.3 µg/mL) or 5-fluorouracil (5-FU; IC25: 7 µg/mL) for 24 h. MTT assay and flow cytometry were utilized to assess cell viability and apoptosis. Oxidative stress, apoptotic-related markers, and cell cycle were also assessed. The results revealed that the IC50 of resistomycin and 5-FU on PC3 cells were 2.63 µg/mL and 14.44 µg/mL, respectively. Furthermore, treated cells with the high dose of resistomycin showed an increased number of apoptotic cells compared to those treated with the lower dose. Remarkable induction of reactive oxygen species generation and lactate dehydrogenase (LDH) leakage with high malondialdehyde (MDA), carbonyl protein (CP), and 8-hydroxyguanosine (8-OHdG) contents were observed in resistomycin-treated cells. In addition, marked declines in glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in PC3 cells subjected to resistomycin therapy were observed. Resistomycin triggered observable cell apoptosis by increasing Bax, caspase-3, and cytosolic cytochrome c levels and decreasing Bcl-2 levels. In addition, notable downregulation of proliferating cell nuclear antigen (PCNA) and cyclin D1 was observed in resistomycin-treated cancerous cells. According to this evaluation, the antitumor potential of resistomycin, in a concentration-dependent manner, in prostate cancer cells was achieved by triggering oxidative stress, mitochondrial apoptosis, and cell cycle arrest in cancer cells. In conclusion, our investigation suggests that resistomycin can be considered a starting point for developing new chemotherapeutic agents for human prostate cancer.


Methylation of DNA.
The methylated bases of DNA are formed by the transfer of the methyl group from S-adenosylmethionine to a polynucleotide acceptor. This transfer is catalyzed by highly specific enzymes which recognize a limited number of available sites in the DNA. The mechanism for the recognition is presently unknown. In some instances, there is evidence that other cellular components, such as lipopolysaccharides, can influence the methylation reaction. Certain bacteriophages induce new methylases upon infection of their hosts. Phage T3 is unique in establishing an environment in which methylation of neither the phage nor the host nucleic acid can occur. By superinfecting T3-infected cells with other phages, the latter can be obtained with methyl-deficient DNA. Although a great deal is known about the enzymology of the methylation reaction, and there appears to be a strong correlation between the in vitro and in vivo reactions, studies in which DNA is either supermethylated or totally unmethylated have not yielded any insight as to what the possible function of the methylated bases may be.


MICU1 and MICU2 potentiation of Ca2+ uptake by the mitochondrial Ca2+ uniporter of Trypanosoma cruzi and its inhibition by Mg2.
The mitochondrial Ca2+ uptake, which is important to regulate bioenergetics, cell death and cytoplasmic Ca2+ signaling, is mediated via the calcium uniporter complex (MCUC). In animal cells the MCUC is regulated by the mitochondrial calcium uptake 1 and 2 dimer (MICU1/MICU2), which has been proposed to act as gatekeeper preventing mitochondrial Ca2+ overload at low cytosolic Ca2+ levels. In contrast to animal cells, knockout of either MICU1 or MICU2 in Trypanosoma cruzi, the etiologic agent of Chagas disease, did not allow Ca2+ uptake at low extramitochondrial Ca2+ concentrations ([Ca2+]ext) and it was though that in the absence of one MICU the other would replace its role. However, previous attempts to knockout both genes were unsuccessful. Here, we designed a strategy to generate TcMICU1/TcMICU2 double knockout cell lines using CRISPR/Cas9 genome editing. Ablation of both genes was confirmed by PCR and Southern blot analyses. The absence of both proteins did not allow Ca2+ uptake at low [Ca2+]ext, significantly decreased the mitochondrial Ca2+ uptake at different [Ca2+]ext, without dissipation of the mitochondrial membrane potential, and increased the [Ca2+]ext set point needed for Ca2+ uptake, as we have seen with TcMICU1-KO and TcMICU2-KO cells. Mg2+ was found to be a negative regulator of MCUC-mediated mitochondrial Ca2+ uptake at different [Ca2+]ext. Occlusion of the MCUC pore by Mg2+ could partially explain the lack of mitochondrial Ca2+ uptake at low [Ca2+]ext in TcMICU1/TcMICU2-KO cells. In addition, TcMICU1/TcMICU2-KO epimastigotes had a lower growth rate, while infective trypomastigotes have a reduced capacity to invade host cells and to replicate within them as amastigotes.


c-kit+ precursors support postinfarction myogenesis in the neonatal, but not adult, heart.
We examined the myogenic response to infarction in neonatal and adult mice to determine the role of c-kit(+) cardiovascular precursor cells (CPC) that are known to be present in early heart development. Infarction of postnatal day 1-3 c-kit(BAC)-EGFP mouse hearts induced the localized expansion of (c-kit)EGFP(+) cells within the infarct, expression of the c-kit and Nkx2.5 mRNA, myogenesis, and partial regeneration of the infarction, with (c-kit)EGFP(+) cells adopting myogenic and vascular fates. Conversely, infarction of adult mice resulted in a modest induction of (c-kit)EGFP(+) cells within the infarct, which did not express Nkx2.5 or undergo myogenic differentiation, but adopted a vascular fate within the infarction, indicating a lack of authentic CPC. Explantation of infarcted neonatal and adult heart tissue to scid mice, and adoptive transfer of labeled bone marrow, confirmed the cardiac source of myogenic (neonate) and angiogenic (neonate and adult) cells. FACS-purified (c-kit)EGFP(+)/(αMHC)mCherry(-) (noncardiac) cells from microdissected infarcts within 6 h of infarction underwent cardiac differentiation, forming spontaneously beating myocytes in vitro; cre/LoxP fate mapping identified a noncardiac population of (c-kit)EGFP(+) myocytes within infarctions, indicating that the induction of undifferentiated precursors contributes to localized myogenesis. Thus, adult postinfarct myogenic failure is likely not due to a context-dependent restriction of precursor differentiation, and c-kit induction following injury of the adult heart does not define precursor status.


Distribution of the GABAA receptor alpha 1- and gamma 2-subunit mRNAs in chick brain.
We have used sequence-specific oligonucleotide probes and in situ hybridisation histochemistry to examine the distribution of the GABAA receptor alpha 1- and gamma 2-subunit mRNAs in serial sections of 1-day-old chick brain. Both transcripts are present together, at high levels, in many brain regions. Differences are found, however, in the relative amounts of these mRNAs in two isthmic nuclei of the optic lobe, the deep cerebellar nuclei, and the dorsal thalamus. We therefore conclude that while the alpha 1 and gamma 2 subunits predominantly occur together in the same receptor complex, they may also be found separately in other GABAA receptor subtypes.


The use of Complementary and Alternative Medicine by women experiencing menopausal symptoms in Bologna.
The present study describes Complementary and Alternative Medicine (CAM) use amongst Italian women transitioning through menopause. Popularity and perceived effectiveness of CAM treatments, use of pharmaceutical medications, characteristics of CAM users, the extent of communication between medical practitioners and women about their use of CAM, and variables associated with CAM use were also investigated. Women, aged 45-65 years attending Family Planning and Women's Health clinics or Menopause Centres in Bologna were invited to complete a voluntary, anonymous, self administered questionnaire, which was used in a previous study in Sydney. The questionnaire was translated and adapted for use amongst Italian women. Data on general demographic and health characteristics, menopause related symptoms and the use of CAM and pharmaceutical treatments during the previous 12 months were collected. In total, 1,203 women completed the survey, of which 1,106 were included in the final sample. Of women who had symptoms linked with menopause and/or used remedies to alleviate symptoms, 33.5% reported to have used CAM. Among these, 23.5% had consulted one or more practitioners and 24% had used at least one CAM product.Approximately nine out of ten respondents reported medical practitioners did not seek information about their use of CAM; while one third of CAM users did not disclose the use of CAM to their physician. Nevertheless, medical practitioners were the most popular source of information. From the multivariate analysis, variables associated with CAM use were: professional employment, time since the last natural menses, use of CAM for conditions other than menopause, and presence of some severe symptoms. The relatively high prevalence of CAM use by women transitioning through menopause should encourage research initiatives into determining which CAM treatments are the safest and effective. The increasing and likely concomitant use of CAM with HRT and other pharmaceuticals underlines the need for the implementation of a surveillance system to report and monitor possible drug-herb adverse events. The discrepancy between women preferring to seek information about CAM from their medical doctor and the difficulties noted in communication between doctor and patient should encourage educational initiatives on CAM by health-care agencies and institutions.


Cloning the bacterial bphC gene into Nicotiana tabacum to improve the efficiency of phytoremediation of polychlorinated biphenyls.
The aim of this work was to construct transgenic plants with increased capabilities to degrade organic pollutants, such as polychlorinated biphenyls. The environmentally important gene of bacterial dioxygenase, the bphC gene, was chosen to clone into a plant of Nicotiana tabacum. The chosen bphC gene encodes 2,3-dihydroxybiphenyl-1,2-dioxygenase, which cleaves the aromatic ring of dihydroxybiphenyl, and we cloned it in fusion with the gene for β-glucuronidase (GUS), luciferase (LUC) or with a histidine tail. Several genetic constructs were designed and prepared and the possible expression of desired proteins in tobacco plants was studied by transient expression. We used genetic constructs successfully expressing dioxygenase's genes we used for preparation of transgenic tobacco plants by agrobacterial infection. The presence of transgenic DNA , mRNA and protein was determined in parental and the first filial generation of transgenic plants with the bphC gene. Properties of prepared transgenic plants will be further studied.


Rationale and Design of Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health (FAMILIA).
The 2020 American Heart Association Impact Goal aims to improve cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease and stroke by 20%. A large step toward this goal would be to better understand and take advantage of the significant intersection between behavior and biology across the entire life-span. In the proposed FAMILIA studies, we aim to directly address this major knowledge and clinical health gap by implementing an integrated family-centric health promotion intervention and focusing on the intersection of environment and behavior, while understanding the genetic and biologic basis of cardiovascular disease. We plan to recruit 600 preschool children and their 600 parents or caregivers from 12-15 Head Start schools in Harlem, NY, and perform a 2:1 (2 intervention/1 control) cluster randomization of the schools. The preschool children will receive our intensive 37-hour educational program as the intervention for 4 months. For the adults, those in the "intervention" group will be randomly assigned to 1 of 2 intervention programs: an "individual-focused" or "peer-to-peer based." The primary outcome in children will be a composite score of knowledge (K), attitudes (A), habits (H), related to body mass index Z score (B), exercise (E), and alimentation (A) (KAH-BEA), using questionnaires and anthropometric measurements. For adults, the primary outcome will be a composite score for behaviors/outcomes related to blood pressure, exercise, weight, alimentation (diet) and tobacco (smoking; Fuster-BEWAT score). Saliva will be collected from the children for SNP genotyping, and blood will be collected from adults for RNA sequencing to identify network models and predictors of primary prevention outcomes. The FAMILIA studies seek to demonstrate that targeting a younger age group (3-5 years) and using a family-based approach may be a critical strategy in promoting cardiovascular health across the life-span.


Addressing the Pediatric Mental Health Crisis in Emergency Departments in the US: Findings of a National Pediatric Boarding Consensus Panel.
In 2021, several professional organizations declared a national state of emergency in child and adolescent mental health. Rising volume and acuity of pediatric mental health emergencies, coupled with reduced access to inpatient psychiatric care, has caused tremendous downstream pressures on EDs resulting in long lengths of stay, or "boarding", for youth awaiting psychiatric admission. Nationally, boarding times are highly heterogeneous, with medical / surgical patients experiencing much shorter boarding times compared to patients with primary mental health needs. There is little guidance on best practices in the care of the pediatric patient with significant mental health need "boarding" in the hospital setting. There is a significant increase in the practice of "boarding" pediatric patients within emergency departments and inpatient medical floors while awaiting psychiatric admission. This study aims to provide consensus guidelines for the clinical care of this population. Twenty-three panel participants of fifty-five initial participants (response rate 41.8%) committed to completing four successive rounds of questioning using Delphi consensus gathering methodology. Most (70%) were child psychiatrists and represented 17 health systems. Thirteen participants (56%) recommended maintaining boarded patients in the emergency department, while 78% indicated a temporal limit on boarding in the emergency department should prompt transfer to an inpatient pediatric floor. Of this group, 65% recommended a 24-hour threshold. Most participants (87%) recommended not caring for pediatric patients in the same space as adults. There was unanimous agreement that emergency medicine or hospitalists maintain primary ownership of patient care, while 91% agreed that child psychiatry should maintain a consultative role. Access to social work was deemed most important for staffing, followed by behavioral health nursing, psychiatrists, child life, rehabilitative services, and lastly, learning specialists. There was unanimous consensus that daily evaluation is necessary with 79% indicating vitals should be obtained every 12 hours. All agreed that if a child psychiatric provider is not available on-site, a virtual consultation is sufficient to provide mental health assessment. This study highlights findings of the first national consensus panel regarding the care of youth boarding in hospital-based settings and provides promising beginnings to standardizing clinical practice while informing future research efforts.


A Rare Association of Monosomy 18p Syndrome and Polyglandular Autoimmune Syndrome Type IIIA.
We report a monosomy 18p syndrome in a male patient with polyglandular autoimmune syndrome (PAS) type IIIA. A 34-year-old mentally retarded diabetic male patient with short stature, wide earlaps, old-looking face, straight nasal bone, atrophic mouth, drooping cheeks, full teeth loss, and soft, weak and sparse white hair was admitted to the outpatient endocrinology clinic. Chromosome analysis of the patient revealed 46,XY,del(18)(p11.2). He was also diagnosed with autoimmune thyroiditis, primary hypothyroidism and diabetes mellitus type 1. We concluded that monosomy 18p syndrome may be associated with autoimmune diseases and if this is suspected, patients should be examined for an endocrine deficiency.


Effect of bulky lesions on DNA: solution structure of a DNA duplex containing a cholesterol adduct.
The three-dimensional solution structure of two DNA decamers of sequence d(CCACXGGAAC)-(GTTCCGGTGG) with a modified nucleotide containing a cholesterol derivative (X) in its C1 '(chol)alpha or C1 '(chol)beta diastereoisomer form has been determined by using NMR and restrained molecular dynamics. This DNA derivative is recognized with high efficiency by the UvrB protein, which is part of the bacterial nucleotide excision repair, and the alpha anomer is repaired more efficiently than the beta one. The structures of the two decamers have been determined from accurate distance constraints obtained from a complete relaxation matrix analysis of the NOE intensities and torsion angle constraints derived from J-coupling constants. The structures have been refined with molecular dynamics methods, including explicit solvent and applying the particle mesh Ewald method to properly evaluate the long range electrostatic interactions. These calculations converge to well defined structures whose conformation is intermediate between the A- and B-DNA families as judged by the root mean square deviation but with sugar puckerings and groove shapes corresponding to a distorted B-conformation. Both duplex adducts exhibit intercalation of the cholesterol group from the major groove of the helix and displacement of the guanine base opposite the modified nucleotide. Based on these structures and molecular dynamics calculations, we propose a tentative model for the recognition of damaged DNA substrates by the UvrB protein.


Functional metabolic mapping during forelimb movement in rat. I. Stimulation of motor cortex.
The quantitative 14C-deoxyglucose (DG) autoradiographic technique has been used to study changes in cerebral metabolism during forelimb movements induced by graded stimulation of motor cortex. Experiments were directed at studying basic physiologic and anatomic aspects of the metabolic changes. Single shocks caused movement without metabolic change, whereas low-frequency trains caused seizures. Repetitive high-frequency train stimuli of short duration (500 Hz for 20 msec) caused jerk movements coupled with DG uptake in pathways. With stimulation of the forelimb motor zone at frequencies of 15-30/min there was prominent activation of cortical columns and strips in ipsilateral SI, SII, and MII, and contralateral MI and SI. Higher frequencies (120/min) were required to cause significant changes in DG in subcortical circuits. The most prominent changes occurred within a longitudinal corridor in dorsal thalamus and a ventral corridor in second-order sites in basal ganglia. Metabolic activation also occurred in contralateral cerebellum, the cuneate nucleus, and dorsal horn of the cervical spinal cord. Changes in these latter two sites were largely eliminated by removing feedback sensory activity. Stimulation of the forelimb sensory zone activated different sites in caudatoputamen and thalamus but similar zones in midbrain and cerebellum. The magnitude of the metabolic response in distant sites depended on the frequency of cortical stimulation. Different frequency-response relationships in different sites seemed to reflect the nature of the cortical input as well as differential effects of anesthesia. The pattern of the metabolic response was studied by comparing sites of activation with sites of the anatomic projections from motor and sensory cortical zones. 3H- and 14C-labeled amino acids were used to map the site and relative strength of pathways. Results revealed good correlation between the site of anatomic projection and the site of DG uptake but no consistent relationship between the relative strength of a projection and the magnitude of metabolic change within its field. Changes in glucose utilization with metabolic mapping experiments depend on the nature, strength, and frequency of stimulation; the site and nature of anatomic projection; the effects of anesthesia; and the strength of sensory feedback associated with the induced behavior.


Literature Review of Sex Differences in mTBI.
Traumatic brain injury (TBI) remains a significant source of morbidity worldwide and is of particular concern for the military. Scientific literature examining sex differences in TBI is highly contradictory with some reporting better outcomes in men, others reporting better outcomes in women, and others reporting mixed results or no difference. While the exact cause is currently debated, the existence of such differences has important implications for surveillance techniques, treatment options, and management of long-term consequences. As the number of women within the U.S. military ranks increases and with the opening of combat roles to women in 2013, increased awareness of probable sex differences regarding TBI responses will enable better standard of care. Using the PubMed database, a keyword search using gender, "sex factors", "sex dependent", "gender disparity", TBI, "traumatic brain injury", mTBI (mild TBI), and "cranial trauma" was used to identify articles of interest. Results were filtered for written in the last 5 years, English, and free full text. References of relevant articles were cross-checked for additional publications. Articles familiar to the authors were also included. We review literature that includes analysis of age as an interaction in TBI, hypothesized mechanisms to explain variations in outcomes between men and women, and the need for inclusion of sex as a criterion in future studies. Emerging studies underscore the complexity of interpreting sex differences in TBI. The long-held belief that women have a neuroprotective advantage compared to men based on higher levels of sex hormones is being re-evaluated. Past conclusions have relied extensively on clinical studies that include a disproportionate number of men or do not stratify results based on sex. While sex hormones may be neuroprotective, underlying mechanisms are far from clarified. Future TBI studies must include women and gonadal hormone levels should be measured to address potential variables. Given the significant number of TBIs within the military, an improved understanding of TBI pathophysiology and outcomes is important considerations for mission success and servicemember longevity.


Planar optical tweezers using tapered-waveguide junctions.
We demonstrate planar optical tweezers using the evanescent field of a silicon nitride tapered-waveguide junction between a singlemode waveguide and a multimode waveguide. Our experiments show that the junction embedded in a fluidic channel holds up to one and two polystyrene particles of sizes of 2.2 μm and 1 μm, respectively. The trapped particles are successively substituted by the incoming particles. Our experiments and numerical modeling reveal that the junction particle trapping depends on particle size and number.


Flow measurement in MRI using arterial spin labeling with cumulative readout pulses--theory and validation.
This article systematically examines arterial spin labeling (ASL) as a flow quantification technique through theoretical simulation, in vitro, and in vivo experiment. The authors present a novel imaging pulse sequence design consisting of a single ASL magnetization preparation followed by Look-Locker-like image readouts. Bloch-equation-based modeling has been developed and validated using a hemodialyzer as a tissue-mimicking flow phantom. After the single in-plane slice-selective double inversion magnetization preparation, multiple TFL readouts are acquired with linear k-space ordering, causing a signal variation that depends on through-slice flow velocity. Computer simulations were performed to assess the behavior of the flow-dependent ASL signal as a function of varying imaging parameters. The signal was optimized by choosing imaging parameters that maximize the simulated flow-sensitive signal. Furthermore, a hemodialyzer which mimics blood flow in human tissues was tested with a wide range of flow rates. An exponential curve fitting of the flow-sensitive dynamics to the model derived from Bloch equations provides a method to estimate through-slice velocity for varying flow rates on the hemodialyzer and in vivo human brain. The flow dependency of the ASL signal and the sensitivity of the ASL signal to imaging parameters were demonstrated. Experimental results from a hemodialyzer when fitted with a Bloch-equation-based model provide flow measurements that are consistent with ground truth velocities. Human brain velocity mapping was obtained as well. The results provide evidence that the proposed pulse sequence design is an effective technique to measure total fluid flow through image voxels. The unique combination of the two main features, multiple-image readout after a single ASL preparation and linear acquisition ordering in the phase encoding direction in TFL imaging, make this technique an appealing flow imaging method to quantify through-plane flow in a time-efficient manner.


An evaluation of hospices in the New York State Hospice Demonstration Program.
In response to a New York State legislative directive, the study reported herein was undertaken to evaluate the use of hospice care within the state's Hospice Demonstration Program. Twelve hospice programs, each providing one of three different models of hospice care, were studied. The community-based programs were found to be considerably less costly than both the hospital-based scattered-bed programs and the hospital-based autonomous-unit programs. The costs of all three programs, however, were less than the costs of conventional terminal care. Although satisfaction with all three models was high, it was higher for both kinds of hospital-based programs than for the community-based programs.


Disease burden-research match? Registered trials in child health from low- and middle-income and high-income countries.
The aim of this study was to determine whether there is a match between the health problems that children face and the clinical trials that are being conducted, especially in low- and middle-income countries (LMICs). All trials on the World Health Organisation International Clinical Trials Registry Platform registered from 2005 to 2013 were reviewed. The disease-specific focus of registered trials for children was compared to the global burden of disease for 2011 using World Health Organisation disability-adjusted life-year data. Children account for 34% of the global disease burden, but were represented in only 15% (29 899/203 726) of registered trials. Although the number of trials in children registered annually has increased over time (from 3174 in 2005 to 3392 in 2013), the proportion of trials involving children has decreased (from 18 to 13%). LMICs account for 98% of the disease burden among children world-wide, but only 22% of trials. More trials were registered in high-income countries than in LMICs for the majority of the disease categories. There was moderate correlation between the number of trials and the burden of each disease within each region (Spearman's correlation r = 0.6, P = 0.007 and r = 0.55, P = 0.02 in LMICs and high-income countries, respectively). Overall, children continue to be under-represented in clinical trials, particularly children from LMICs where disease burden is greatest. Clinical trial activity correlates moderately with disease burden among the world's children. A more evidence-informed approach for prioritising trials to specifically address the health-care needs of children is required.


A potential inflammatory role of IL-31 in psoriatic arthritis: A correlation with Th17 cytokine profile.
The goals of our study were to determine the possible association of interleukin (IL)-31 with Th17 cytokine profile in serum and to quantify retinoic acid-related orphan receptor C (RORC) mRNA expression in psoriatic arthritis (PsA) patients. This cross-sectional study was conducted in 50 patients with PsA and 30 control subjects (CS) matched by age and gender. The cytokine serum levels were quantified by magnetic bead-based assay using the Bio-Plex MAGPIX system, and RORC mRNA expression was determined by quantitative polymerase chain reaction (qPCR). As a result, significant differences in IL-31 were observed between study groups (77.23 pg/mL in PsA vs 64.4 pg/mL in CS, P < 0.001) and Th17 cytokine profile serum levels (IL-17A: 6.36 pg/mL in PsA vs 2.97 pg/mL in CS, P = 0.02; IL-17F: 44.15 pg/mL in PsA vs 23.36 pg/mL in PsA, P = 0.01; IL-17E: 3.03 pg/mL in PsA vs 0.82 pg/mL in CS, P < 0.001; IL-21: 36.45 pg/mL in PsA vs 12.44 pg/mL in CS, P = 0.02); however, significant differences were not observed for IL-23 (31.2 pg/mL in PsA vs 53.26 pg/mL in CS, P = 0.58). Furthermore, positive correlations between IL-31 and Th17 cytokine profile serum levels were found (IL-17A: rs = 0.64, P < 0.001; IL-17F: rs = 0.73, P < 0.001; IL-17E: rs = 0.70, P < 0.001; IL-21: rs = 0.54, P = 0.002; IL-23: rs = 0.5, P < 0.01). Regarding RORC gene expression, the PsA group showed an increase of 6.85-fold compared to the CS group. We did not find any association between the serum levels of cytokines and RORC gene expression. In conclusion, in PsA, there are increased serum levels of IL-31, IL-17A, IL-17F, IL-17E, and IL-21, but not IL-23. Moreover, there was a positive correlation of IL-31 with the Th17 cytokine profile and a high RORC gene expression. Altogether, these findings suggest a proinflammatory contribution of IL-31 in close association with the Th17 cytokine profile in PsA.


Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis.
Among its many roles in development, retinoic acid determines the anterior-posterior identity of differentiating motor neurons by activating retinoic acid receptor (RAR)-mediated transcription. RAR is thought to bind the genome constitutively, and only induce transcription in the presence of the retinoid ligand. However, little is known about where RAR binds to the genome or how it selects target sites. We tested the constitutive RAR binding model using the retinoic acid-driven differentiation of mouse embryonic stem cells into differentiated motor neurons. We find that retinoic acid treatment results in widespread changes in RAR genomic binding, including novel binding to genes directly responsible for anterior-posterior specification, as well as the subsequent recruitment of the basal polymerase machinery. Finally, we discovered that the binding of transcription factors at the embryonic stem cell stage can accurately predict where in the genome RAR binds after initial differentiation. We have characterized a ligand-dependent shift in RAR genomic occupancy at the initiation of neurogenesis. Our data also suggest that enhancers active in pluripotent embryonic stem cells may be preselecting regions that will be activated by RAR during neuronal differentiation.


THE EFFECT OF HYPERGLYCEMIA ON HYPOTHALAMIC GOLD UPTAKE AND HYPERPHAGIA IN GOLDTHIOGLUCOSE-TREATED MICE.
The accumulation of gold in the hypothalamus and the development of hyperphagia and obesity were studied in mice given a single intravenous injection of goldthioglucose at various levels of blood glucose concentration. It was found that the glucose concentration prevailing at the time of goldthioglucose injection was correlated directly with the level of free and bound goldthioglucose in the blood 3 minutes later, with the hypothalamic uptake of gold, with the extent of the hypothalamic lesion, and with the severity of the subsequent hyperphagia and obesity. Hyperglycemia was associated with an increased gold deposition throughout the brain. A gold content of 88 +/- 12 microg/mg wet tissue in the hypothalamus of fasted animals was associated with clearcut lesions in all animals studied, whereas a similar gold content in the control brain lobes of hyperglycemic animals was not associated with lesions in any animal. This finding indicates that some regions in the brain (e.g. the ventral hypothalamus) are more susceptible than others to damage by goldthioglucose.


[One case of acute severe nitrite poisoning with massive pulmonary thromboembolism].
This paper reported a case of acute severe nitrite poisoning with massive pulmonary thromboembolism (PTE), discussed the pathogenesis and summarized the treatment experience. Common symptoms of nitrite poisoning include headache, abdominal pain, shortness of breath, cyanosis, etc., which can be followed by encephalopathy, neurological dysfunction, hemolysis, etc. However, the cases of PTE are rare in clinical practice and are prone to missed diagnosis. Nitrite and methemoglobin may lead to vascular endothelial damage and promote thrombosis. In the diagnosis and treatment of acute severe nitrite poisoning patients, the targeted preventive measures should be taken.


Varicella seroepidemiology in United States air force recruits: A retrospective cohort study comparing immunogenicity of varicella vaccination and natural infection.
Infection with varicella zoster virus (VZV) produces lifelong immunity, but duration of post-vaccination immunity has not been established. The purpose of this study is to determine if a difference exists in the long-term seropositivity of anti-VZV antibodies in a cohort of young adults who were vaccinated against varicella as compared to a similar cohort with a history of chickenpox disease, and to determine which variables best predict waning seropositivity following varicella vaccination. This retrospective cohort study captures immunization and serology data from approximately 10,000 recruits who entered basic military training between January 1, 2008, and December 31, 2015, and who have childhood immunization records in the Air Force Aeromedical Services Information Management System. Varicella vaccine immunogenicity was determined relative to the immunogenicity of chickenpox disease, as measured by multiplex flow immunoassay. Among vaccine recipients, waning seroimmunity was modeled and adjusted for several important covariates. Basic military trainees who received varicella vaccine in childhood were 24% less likely to be seropositive to VZV than trainees who were exempt from vaccine due to a history of chickenpox disease. There was no significant difference in seropositivity between male and female trainees. The odds of a vaccinated trainee being seropositive to VZV decreased by 8% with each year elapsed since vaccination. Seroprevalence declined below estimated herd immunity thresholds in vaccinated trainees born after 1994, and in the cohort as a whole for trainees born after 1995. Despite prior vaccination, seroimmunity in a large cohort of young adults unexposed to wild-type VZV failed to meet the estimated threshold for herd immunity. If vaccination in accordance with the current US VZV vaccination schedule is inadequate to maintain herd immunity, young adults not previously exposed to wild-type VZV may be at increased risk for varicella outbreaks.


Growth control of the rat skull. Differential effects of undernourishment and of altered behaviour in experimental bipedia.
Experimental bipedia results in retarded general development and in a change of skull form. The present study was undertaken to investigate the precise cause(s) of the changes of skull growth. Skull growth was restudied in experimentally bipedal male rats and compared to that in control rats that were reared in extra large litters, thereby creating undernutrition during the pre-weaning period. In addition, another category of control rats were reared in litters of standard size. The animals were sacrificed at the age of either 30 or 46 weeks. The following observations were made. In bipedal as well as in large-litter rats the cranial base was different to that of the standard-litter rats with respect to the following aspects: the basisphenoid bone was reduced in length, and the cranial base was more dorsally flexed at the spheno-occipital synchondrosis. Both differences, therefore, do not seem to be specific for the bipedal condition, but must be the consequence of general growth retardation during early life. The supra-occipital bone, on the other hand, was rotated backward in the large-litter rats, but rotated forward in the bipedal rats. This phenomenon seems to be the only change observed so far that is specific for the bipedal condition.


Work performance decrements are associated with Australian working conditions, particularly the demand to work longer hours.
To demonstrate the importance of including a range of working conditions in models exploring the association between health- and work-related performance. The Australian Work Outcomes Research Cost-benefit study cross-sectional screening data set was used to explore health-related absenteeism and work performance losses on a sample of approximately 78,000 working Australians, including available demographic and working condition factors. Data collected using the World Health Organization Health and Productivity Questionnaire were analyzed with negative binomial logistic regression and multinomial logistic regressions for absenteeism and work performance, respectively. Hours expected to work, annual wage, and job insecurity play a vital role in the association between health- and work-related performance for both work attendance and self-reported work performance. Australian working conditions are contributing to both absenteeism and low work performance, regardless of health status.


Dysregulation of trophic factors contributes to diabetic retinopathy in the Ins2Akita mouse.
Diabetic retinopathy (DR) is considered as a diabetes-related complication that can lead to severe visual impairments. By 2030, it is expected that 1 in 5 adults will suffer from the disease. Suitable animal models for chronic DR are essential for a better understanding of the pathophysiology and to further develop new treatments. The Ins2Akita mouse is a type 1 diabetes model that shows signs of both early and late stages of DR, including pericyte loss, increased vascular permeability, increased acellular capillaries and neovascularization. To further characterize DR in the Ins2Akita mouse model, we have evaluated the protein levels of the angiogenesis inducers vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and the angiogenesis inhibitor pigment epithelium-derived factor (PEDF). Additionally, we have analyzed the protein expression profile of the glial markers ionized calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) as well as of the chemokine monocyte chemoattractant protein 1 (MCP-1). In this study we demonstrate that, with disease progression, there is the development of an inflammatory response and an unbalanced expression of pro- and antiangiogenic factors in the neural retina and in the retinal pigment epithelium (RPE) of Ins2Akita mice. Therefore, our data provide support for the diabetic retinopathy features detected in the Ins2Akita retina, reflecting what is observed in the human pathology.


Curative resection of advanced esophageal cancer with metachronous stage IV breast cancer: A case report.
Recent studies have shown the safety and efficacy of curative resection of esophageal cancer with multiple primary cancers. However, our literature search revealed no curative surgery cases for esophageal cancer in patients with multiple primary cancers with distant metastasis. A 75-year-old woman visited our hospital with dysphagia. She had a history of breast cancer with multiple bone metastasis. Esophagogastroduodenoscopy revealed a circumferential mass in the upper intrathoracic esophagus. Histopathological examination of the biopsy showed squamous cell carcinoma. Other imaging findings revealed multiple nodules in the liver. The nodules were thought to have originated from the breast, but metastasis of esophageal cancer was considered a possibility. Intraoperative frozen sections of the liver and peritoneal nodules showed adenocarcinoma. Thoracoscopic esophagectomy was then performed. Following surgery, the patient received fulvestrant therapy, followed by capecitabine therapy, and the liver tumors decreased in size. She is currently alive after 1.5 years of the surgery without local recurrence of esophageal cancer. Although the patient had metastatic breast cancer, her relapse-free interval of 20 years and good response to hormone therapy for 15 years were favorable prognostic factors. Her life expectancy was estimated to be a few years and surgery was performed. Curative resection could be considered for patients with esophageal cancer who have an additional cancer with distant metastasis when the prognosis of the additional cancer is not poor.


Epithelial and mucosal preparations of canine proximal colon in ussing chambers: comparison of responses.
A novel epithelial preparation from proximal canine colon, devoid of its underlying muscularis mucosa, was studied in Ussing chambers and its responses to added agonists compared with those of a conventional full mucosal preparation. We assumed that the responses elicited from the former would reflect direct action of agonists on epithelial cells, and from the latter both direct and indirect effects mediated by functioning nerves in the attached submucosal plexus. Responses of the two preparations to tetrodotoxin, ouabain, scorpion venom, and field stimulation were different, the differences being explicable on the basis of functioning nerves in the mucosal preparation. Histamine stimulated both preparations; the increase in short-circuit current seen with the mucosal but not the epithelial preparation was inhibited by tetrodotoxin. Serotonin was a better stimulant of the epithelial preparation. Basal absorptions of both Na+ and Cl- were seen in both mucosa and epithelium, but net absorptions were significantly greater in the latter, suggesting tonic neuronal inhibition of absorption in the mucosa. These two preparations would prove useful in analysing direct and indirect effects of agonists on colonic transport.


Underestimation of atypical ductal hyperplasia at MRI-guided 9-gauge vacuum-assisted breast biopsy.
The purposes of this study were to determine the frequency of diagnosis of atypical ductal hyperplasia (ADH) at MRI-guided 9-gauge vacuum-assisted breast biopsy and to assess the rate of underestimation of ADH at subsequent surgical excision. We conducted a retrospective review of medical records of 237 lesions consecutively detected with MRI and then subjected to MRI-guided 9-gauge vacuum-assisted breast biopsy during a 33-month period. Underestimated ADH was defined as a lesion yielding ADH at vacuum-assisted biopsy and cancer at surgery. Scientific tables were used to calculate 95% CI. Histologic analysis of MRI-guided vacuum-assisted breast biopsy specimens yielded ADH without cancer in 15 (6%) of 237 lesions. Among 15 patients in whom vacuum-assisted breast biopsy yielded ADH, the median age was 52 years (range, 46-68 years). The median number of specimens obtained was nine (range, 8-18 lesions). Median MRI lesion diameter was 1.3 cm (range, 0.7-7.0 cm). Among 15 MRI lesions, 10 (67%) were nonmasslike enhancement and five (33%) were masses. Surgical excision was performed on 13 lesions. Surgical histologic findings were malignancy in five (38%) of the cases, all ductal carcinoma in situ; high-risk lesion in six (46%) of the cases, including ADH without other high-risk lesions (n = 2), ADH and lobular carcinoma in situ (LCIS) (n = 1), ADH, LCIS, and papilloma (n =1), ADH and papilloma (n = 1), and LCIS (n = 1); and benign in two (15%) of the cases. These data indicated an ADH underestimation rate of 38% (95% CI, 14-68%). ADH without cancer was encountered in 6% of MRI-guided 9-gauge vacuum-assisted breast biopsies. ADH at MRI-guided vacuum-assisted breast biopsy is an indication for surgical excision because of the high (38%) frequency of underestimation of these lesions.


Branched-chain alpha-keto acid catabolism via the gene products of the bkd operon in Enterococcus faecalis: a new, secreted metabolite serving as a temporary redox sink.
Recently the bkd gene cluster from Enterococcus faecalis was sequenced, and it was shown that the gene products constitute a pathway for the catabolism of branched-chain alpha-keto acids. We have now investigated the regulation and physiological role of this pathway. Primer extension analysis identified the presence of a single promoter upstream of the bkd gene cluster. Furthermore, a putative catabolite-responsive element was identified in the promoter region, indicative of catabolite repression. Consistent with this was the observation that expression of the bkd gene cluster is repressed in the presence of glucose, fructose, and lactose. It is proposed that the conversion of the branched-chain alpha-keto acids to the corresponding free acids results in the formation of ATP via substrate level phosphorylation. The utilization of the alpha-keto acids resulted in a marked increase of biomass, equivalent to a net production of 0.5 mol of ATP per mol of alpha-keto acid metabolized. The pathway was active under aerobic as well as anaerobic conditions. However, under anaerobic conditions the presence of a suitable electron acceptor to regenerate NAD(+) from the NADH produced by the branched-chain alpha-keto acid dehydrogenase complex was required for complete conversion of alpha-ketoisocaproate. Interestingly, during the conversion of the branched-chain alpha-keto acids an intermediate was always detected extracellularly. With alpha-ketoisocaproic acid as the substrate this intermediate was tentatively identified as 1, 1-dihydroxy-4-methyl-2-pentanone. This reduced form of alpha-ketoisocaproic acid was found to serve as a temporary redox sink.


Statin use and risk of new-onset diabetes: A meta-analysis of observational studies.
Meta-analyses of randomized control trials investigating the association between incident diabetes and statin use showed an increased risk of new-onset diabetes (NOD) from 9% to 13% associated with statins. However, short follow-up period, unpowered sample size, and lack of pre-specified diagnostic criteria for diabetes detection could be responsible of an underestimation of this risk. We conducted a meta-analysis of published observational studies to evaluate the association between statins use and risk of NOD. PubMed, EMBASE and MEDLINE databases were searched from inception to June 30, 2016 for cohort and case-control studies with risk of NOD in users vs nonusers, on ≥1000 subjects followed-up for ≥1 year. Two review authors assessed study eligibility and risk of bias and undertook data extraction independently. Pooled estimates were calculated by a random-effects model and between-study heterogeneity was tested and measured by I2 index. Furthermore, stratified analyses and the evaluation of publication bias were performed. Finally, the meta-analysis included 20 studies, 18 cohort and 2 case-control studies. Overall, NOD risk was higher in statin users than nonusers (RR 1.44; 95% CI 1.31-1.58). High between-study heterogeneity (I2 = 97%) was found. Estimates for all single statins showed a class effect, from rosuvastatin (RR 1.61; 1.30-1.98) to simvastatin (RR 1.38; 1.19-1.61). The present meta-analysis confirms and reinforces the evidence of a diabetogenic effect by statins utilization. These observations confirm the need of a rigorous monitoring of patients taking statins, in particular pre-diabetic patients or patients presenting with established risk factors for diabetes.


Active genes are sensitive to deoxyribonuclease I during metaphase.
The active exogenous murine leukemia virus sequences of mouse cells growing in culture are preferentially digested by deoxyribonuclease I in metaphase chromosomes. As determined by nuclear nick translation, all of the gene sequences of these cells active during interphase are in a deoxyribonuclease I-sensitive conformation during metaphase. This method of nick translation can therefore be used to label chromosomes in situ in order to visualize the active regions of the genome.


Protective efficacy of a human endogenous retrovirus envelope-coated, nonreplicable, baculovirus-based hemagglutin vaccine against pandemic influenza H1N1 2009.
Despite the advantages of DNA vaccines, overcoming their lower efficacy relative to that of conventional vaccines remains a challenge. Here, we constructed a human endogenous retrovirus (HERV) envelope-coated, nonreplicable, baculovirus-based HA vaccine against swine influenza A/California/04/2009(H1N1) hemagglutin (HA) (AcHERV-sH1N1-HA) as an alternative to conventional vaccines and evaluated its efficacy in two strains of mice, BALB/c and C57BL/6. A commercially available, killed virus vaccine was used as a positive control. Mice were intramuscularly administered AcHERV-sH1N1-HA or the commercial vaccine and subsequently given two booster injections. Compared with the commercial vaccine, AcHERV-sH1N1-HA induced significantly higher levels of cellular immune responses in both BALB/c and C57BL/6 mice. Unlike cellular immune responses, humoral immune responses depended on the strain of mice. Following immunization with AcHERV-sH1N1-HA, C57BL/6 mice showed HA-specific IgG titers 10- to 100-fold lower than those of BALB/c mice. In line with the different levels of humoral immune responses, the survival of immunized mice after intranasal challenge with sH1N1 virus (A/California/04/2009) depended on the strain. After challenge with 10-times the median lethal dose (MLD50) of sH1N1 virus, 100% of BALB/c mice immunized with the commercial vaccine or AcHERV-sH1N1-HA survived. In contrast, C57BL/6 mice immunized with AcHERV-sH1N1-HA or the commercial vaccine showed 60% and 70% survival respectively, after challenge with sH1N1 virus. In all mice, virus titers and results of histological analyses of lung tissues were consistent with the survival data. Our results indicate the importance of humoral immune response as a major defense system against influenza viral infection. Moreover, the complete survival of BALB/c mice immunized with AcHERV-sH1N1-HA after challenge with sH1N1 virus suggests the potential of baculoviral vector-based vaccines to achieve an efficacy comparable to that of killed virus vaccines.


Nuclear insulin-like growth factor-1 receptor (IGF1R) displays proliferative and regulatory activities in non-malignant cells.
The insulin-like growth factor-1 receptor (IGF1R) mediates the biological actions of IGF1 and IGF2. The IGF1R is involved in both physiological and pathological activities and is usually overexpressed in most types of cancer. In addition to its classical mechanism of action, recent evidence has shown a nuclear presence of IGF1R, associated with novel genomic/transcriptional types of activities. The present study was aimed at evaluating the hypothesis that nuclear IGF1R localization is not restricted to cancer cells and might constitute a novel physiologically relevant regulatory mechanism. Our data shows that nuclear translocation takes place in a wide array of cells, including normal diploid fibroblasts. In addition, we provide evidence for a synergistic effect of a nuclear translocation blocker along with selective IGF1R inhibitors in terms of decreasing cell proliferation. Given the important role of the IGF1R in mitogenesis, the present results may be of translational relevance in cancer research. In conclusion, results are consistent with the concept that nuclear IGF1R fulfills important physiological and pathological roles.


Regulation of rabbit alpha 1-acid glycoprotein gene expression in acute-phase liver. Identification of inducible and constitutive proteins like CCAAT-enhancer binding protein that interact with the 5'-proximal promoter elements.
To identify the cis-acting DNA sequences responsible for inducible transcription of rabbit alpha 1-acid glycoprotein gene, 5'-flanking region containing 529 bp of this gene and its various 5'-deletions were linked to the reporter gene coding for the bacterial chloramphenicol acetyltransferase (CAT) and analyzed for their ability to confer cytokine-mediated inducibility to the reporter CAT gene in liver cells. Deletion analysis has identified a 151-bp region from the sequence -186 to -35, that contains the regulatory promoter element(s) responsible for stimulation mediated by cytokines present in the conditioned-medium. Using mobility shift assays, we have identified highly inducible nuclear factors in acute liver nuclear extract that interact with this regulatory promoter region. DNase I footprint analysis has revealed two adjacent nuclear factor binding sites and competition of DNA-binding activity has indicated that the distal element of these two sites has higher affinity for nuclear factors than the proximal one. Both of these two regions have been found to be capable of directing conditioned-medium-induced transcription. Studies on the characterization of nuclear factors binding to these elements have shown that they belong to a class of transcription factors called CCAAT-enhancer binding protein (C/EBP). Our results indicate that binding of C/EBP-like factors to the inducible promoter elements of rabbit alpha 1-acid glycoprotein gene is highly specific and the induction of this gene under acute-phase conditions may involve their participation.


Sleep networks and the anatomic and physiologic connections with respiratory control.
A central neuronal network regulates airway functions from the nares to the bronchioles and is an integral component of a regulatory system for brain control of breathing and airway patency during wakefulness and sleep. This network, components of which include sleep generating sites and monoaminergic neurons in particular, is characterized by reciprocal interconnections, parallel organization, and state-dependent activity patterns, which can be influenced by both genes and environment. Sleep generating neurons are interconnected with the monoaminergic containing cells to the extent that sleep-related changes in upper and lower airway patency could be due to inhibitory influences of sleep-activated neurons on serotonergic and noradrenergic producing cells. Neurochemical studies and physiologic experiments show that serotonergic and noradrenergic producing cells can make parallel pathways, directly innervating the hypoglossal motor cells regulating upper airway dilating muscles, and vagal preganglionic neurons providing cholinergic outflow to the airways. Activation of serotonergic and noradrenergic cell groups preferentially increases activity of the genioglossus muscle, but diminishes cholinergic outflow to the airways. Hence, inhibition of monoaminergic neurons during sleep may lead to a decrease in upper airway dilating forces and an elevation of cholinergic outflow to the airways. Qualitatively different responses of hypoglossal and airway-related vagal preganglionic neurons (AVPNs) occur in response to endogenously released serotonin or norepinephrine and could be related to its simultaneous action on different serotonin or norepinephrine receptor subtypes. Dysfunction of monaminergic cell groups during sleep may predispose to upper airway occlusion as well as bronchoconstriction. Pharmacological corrections of alterations of these transmitter specific converging systems might be an avenue for treatment of sleep related airway disorders such as sleep apnea and worsening of asthma.


Clean bioprinting - Fabrication of 3D organ models devoid of animal components
Bioprinting is a rapidly developing technology that enables the exact positioning of living cells embedded in bio-materials in precise spatial arrangements to fabricate engineered tissues and organs. While the ultimate goal of bioprinting approaches is to produce organs for transplantation purposes, bioprinted organ models also hold great potential for research purposes to serve as alternatives to animal experiments. By using human cells, humanized organ models can be generated that may produce more relevant results for human (patho-)physiology than animal models. However, standard bioprinting procedures currently use numerous hidden animal components. Virtually all studies published in the field to date make use of cells grown in media with fetal bovine serum (FBS). In addition, Matrigel, the extracellular matrix (ECM) harvested from Engelbreth-Holm-Swarm sarcoma grown in mice, is widely employed to cultivate stem cells and 3D organ models. Finally, most bioinks currently in use contain gelatin or comparable animal components to improve cell viability and adhesion. The present review will give an introduction to the potential of bioprinting to fabricate 3D models that may be substituted for animal experiments and will go on to describe strategies to replace animal components currently included in standard procedures of bioprinting. These approaches comprise the adaptation of cells to FBS-free media, the use of bioinks composed of synthetic or plant material, and the replacement of animal ingredients by materials of human origin. We propose denoting bioprinting strategies devoid of animal components as clean bioprinting.


USP38 promotes deubiquitination of K11-linked polyubiquitination of HIF1α at Lys769 to enhance hypoxia signaling.
HIF1α is one of the master regulators of the hypoxia signaling pathway and its activation is regulated by multiple post-translational modifications (PTMs). Deubiquitination mediated by deubiquitylating enzymes (DUBs) is an essential PTM that mainly modulates the stability of target proteins. USP38 belongs to the ubiquitin-specific proteases (USPs). However, whether USP38 can affect hypoxia signaling is still unknown. In this study, we used quantitative real-time PCR assays to identify USPs that can influence hypoxia-responsive gene expression. We found that overexpression of USP38 increased hypoxia-responsive gene expression, but knockout of USP38 suppressed hypoxia-responsive gene expression under hypoxia. Mechanistically, USP38 interacts with HIF1α to deubiquitinate K11-linked polyubiquitination of HIF1α at Lys769, resulting in stabilization and subsequent activation of HIF1α. In addition, we show that USP38 attenuates cellular ROS and suppresses cell apoptosis under hypoxia. Thus, we reveal a novel role for USP38 in the regulation of hypoxia signaling.


Family perceptions of support interventions in the intensive care unit.
Family needs of critically ill patients have been well documented in nursing literature. However, few researchers have examined support interventions intended to meet these needs. This study examines which interventions provide the greatest benefit to critically ill patients' families and recommends nursing actions to meet families' support needs.


Immunohistochemical study of seminiferous epithelium in adult bovine testis using monoclonal antibodies against Ki-67 protein and proliferating cell nuclear antigen (PCNA).
The distribution pattern of proliferating cell nuclear antigen (PCNA) and Ki-67 protein was studied in adult bovine seminiferous epithelium by means of immunohistochemistry using monoclonal antibodies. Tailoring the methodological protocol for each of the two proliferation markers was a necessary prerequisite for obtaining optimal results in tubular sections and whole-mounts. A-, I- and B-spermatogonia displayed PCNA-positive nuclei, except during meta-, ana- and telophases of mitosis. PCNA-negative nuclei in the basal tubular compartment, excluding those from non-cycling Sertoli cells, belonged to the spermatogonia precursor cell line. However, only about 30%, 45% and 47% of the respective A-, I-, B-spermatogonia had positive nuclei after exposure to the MIB-1 antibody directed against the Ki-67 protein. Spermatogonia with MIB-1-negative nuclei represented cells in the G1-phase. Both antibodies reacted intensely with the nuclei of preleptotene primary spermatocytes. PCNA reactivity was also present during leptotene through pachytene. Ki-67 protein expression was absent during leptotene and zygotene but was again encountered during pachytene and meiosis I and II. Anti-PCNA/anti-protein gene product 9.5 double-labelling indicated that the transition from spermatogonia precursor cells into A1-spermatogonia is not strictly synchronized in a given tubular segment, a possible reason for the flexibility in A-spermatogonial propagation seen in bovine seminiferous tubules.


Self-Assembled Core-Satellite Gold Nanoparticle Networks for Ultrasensitive Detection of Chiral Molecules by Recognition Tunneling Current.
Chirality sensing is a very challenging task. Here, we report a method for ultrasensitive detection of chiral molecule l/d-carnitine based on changes in the recognition tunneling current across self-assembled core-satellite gold nanoparticle (GNP) networks. The recognition tunneling technique has been demonstrated to work at the single molecule level where the binding between the reader molecules and the analytes in a nanojunction. This process was observed to generate a unique and sensitive change in tunneling current, which can be used to identify the analytes of interest. The molecular recognition mechanism between amino acid l-cysteine and l/d-carnitine has been studied with the aid of SERS. The different binding strength between homo- or heterochiral pairs can be effectively probed by the copper ion replacement fracture. The device resistance was measured before and after the sequential exposures to l/d-carnitine and copper ions. The normalized resistance change was found to be extremely sensitive to the chirality of carnitine molecule. The results suggested that a GNP networks device optimized for recognition tunneling was successfully built and that such a device can be used for ultrasensitive detection of chiral molecules.


Becoming a Clinical Teacher: Identity Formation in Context.
Most clinical teachers have not been trained to teach, and faculty development for clinical teachers is undermined by poor attendance, inadequate knowledge transfer, and unsustainability. A crucial question for faculty developers to consider is how clinicians become teachers "on the job." Such knowledge is important in the design of future workplace-based faculty development initiatives. The authors conducted a scoping review of research on the relationship between becoming a clinical teacher and the clinical environments in which those teachers work. In June 2017, using the scoping review design described by Levac et al (2010), the authors searched 12 databases. They subjected the articles discovered to four phases of screening, using iteratively developed inclusion/exclusion criteria. They charted data from the final selection of articles and used thematic analysis to synthesize findings. Thirty-four research reports met the inclusion criteria. Most (n = 24) took an individualist stance toward identity, focusing on how teachers individually construct their teacher identity in tension with their clinician identities. Only 10 studies conceptualized clinical teacher identity formation as a social relational phenomenon, negotiated within hierarchical social structures. Twenty-nine of the included studies made little or no use of explicit theoretical frameworks, which limited their rigor and transferability. Clinicians reconciled their identities as teachers with their identities as clinicians by juggling the two, finding mutuality between them, or forging merged identities that minimized tensions between educational and clinical roles. They did so in hierarchical social settings where patient care and research were prioritized above teaching.


Diffusional dynamics of an active rhodamine-labeled 1,4-dihydropyridine in sarcolemmal lipid multibilayers.
A "membrane bilayer pathway" model, involving ligand partition into the bilayer, lateral diffusion, and receptor binding has been invoked to describe the 1,4-dihydropyridine (DHP) calcium channel antagonist receptor binding mechanism. In an earlier study (Chester et al. 1987. Biophys. J. 52:1021-1030), the diffusional component of this model was examined using an active fluorescence labeled DHP calcium channel antagonist, nisoldipine-lissamine rhodamine B (Ns-R), in purified cardiac sarcolemmal (CSL) lipid multibilayers. Diffusion coefficient measurements on membrane-bound drug and phospholipid at maximum bilayer hydration yielded similar values (3.8 x 10(-8) cm2/s). However, decreases in bilayer hydration resulted in dramatically reduced diffusion coefficient values for both probes with substantially greater impact on Ns-R diffusion. These data suggested that hydration dependent diffusional differences could be a function of relative probe location along the bilayer normal. In this communication, we have addressed the relative effect of the rhodamine substituent on Ns-R diffusion complex by examining the diffusional dynamics of free rhodamine B under the same conditions used to evaluate Ns-R complex and phospholipid diffusion. X-ray diffraction studies were performed to determine the Ns-R location in the membrane and model the CSL lipid bilayer profile structure to give a rationale for the differences in probe diffusional dynamics as a function of interbilayer water space.


Advancing peristalsis deciphering in mouse small intestine by multi-parameter tracking.
Assessing gastrointestinal motility lacks simultaneous evaluation of intraluminal pressure (ILP), circular muscle (CM) and longitudinal muscle (LM) contraction, and lumen emptying. In this study, a sophisticated machine was developed that synchronized real-time recordings to quantify the intricate interplay between CM and LM contractions, and their timings for volume changes using high-resolution cameras with machine learning capability, the ILP using pressure transducers and droplet discharge (DD) using droplet counters. Results revealed four distinct phases, BPhase, NPhase, DPhase, and APhase, distinguished by pressure wave amplitudes. Fluid filling impacted LM strength and contraction frequency initially, followed by CM contraction affecting ILP, volume, and the extent of anterograde, retrograde, and segmental contractions during these phases that result in short or long duration DD. This comprehensive analysis sheds light on peristalsis mechanisms, understand their sequence and how one parameter influenced the other, offering insights for managing peristalsis by regulating smooth muscle contractions.


Exploration of the relationship among roadway characteristics, operating speed, and crashes for city streets using path analysis.
Estimating the speed-crash relationship has long been a focus area of interest in roadway safety analysis. Because of many confounding factors that may influence both speeds and crashes, the relationship cannot be appropriately established without considering the corresponding roadway contexts and accounting for their effects on speeds and crashes. This paper investigates the speed-crash relationship for city streets by jointly modeling speed, roadway characteristics, and crashes using a path analysis approach that has been recently introduced into safety analysis while incorporating a wide range of roadway and traffic related variables and additional speed measures. The results from the coherent path analysis identified multiple speed measures of interest that have a statistically significant association with crashes as well as having intuitive and useful interpretation. The results also supported a positive relationship between speed variability and crash occurrence (i.e., larger spread/variability in operational speed is associated with more crashes).


Mechanical characteristics of zirconia produced additively by 3D printing in dentistry - A systematic review with meta-analysis of novel reports.
This study was aimed at comparing the mechanical parameters of ceramics made using the addition and subtraction technique. A search was performed on four search engines on 5th April 2023. Quality assessment was performed using study type-specific scales. Where possible, a meta-analysis was performed. Data were extracted from four search engines: PubMed, PubMed Central, Embase, Web of Science, Scopus. The search strategy identified 686 potential articles. 19 papers were subject to qualitative analysis, and data from 11 papers were meta-analysed. The included studies were of high or medium quality. All included papers were in-vitro studies. No clinical trials were found in the literature. Ceramics made in the additive technology in terms of mechanical parameters can compete with ceramics made in the milling technology. There are no clinical studies yet that would indicate the use of this type of material for permanent restorations in patients. Studies presented in the literature vary greatly in terms of study design and reporting of results. The research did not receive external funding.


Comparison of RIA and conventional reamed nailing for treatment of femur shaft fractures.
The standard of care for femoral diaphysis fractures is sequentially reamed, locked, intramedullary nails. However, in the polytraumatized patient perioperative complications such as fat embolism syndrome (FES) and acute respiratory distress (ARDS) are well chronicled. The reamer irrigator aspirator (RIA)has been theorized to minimize such phenomena. A retrospective study comparing conventional reamed nailing for femur fractures versus those treated with the RIA was conducted. From January 2005 to September 2006, 156 patients treated at our institution with an intramedullary nail met inclusion criteria. There were sixty-six patient treated with conventional reaming (group A) and ninety patients treated with the RIA (group B). The main outcome measures included length of hospital stay, rate of ARDS, pneumonia, ventilatory failure, overall pulmonary complications, healing rate and death. No significant differences were found between groups with regard to patient demographics, injury severity and the incidence of head/chest trauma. In addition, no differences were found in length of hospital stay, length of ICU stay or mechanical ventilation. Overall pulmonary complications occurred in 11% (group A) and 16% (group B) respectively (p = 0.48). No fatalities were found in group A while there were four in group B, 4% (p = 0.14). No significant differences were found in delayed union versus nonunion rate between groups, while overall healing complications were seen in 7% and 14% of patients (p = 0.35) in groups A and B respectively. No statistical significance was reached with regard to pulmonary complications, healing rates or death. However, we were unable to demonstrate favorable physiologic lung parameters with RIA use compared to conventional reaming as has been described in previous animal studies. We found a trend toward more healing complications in the RIA group, but this was not statistically significant. Further study is warranted.


Peripheral endothelium-dependent flow-mediated vasodilatation is associated with left ventricular mass in older persons with hypertension.
Increased left ventricular (LV) mass is associated with greater cardiovascular disease risk. Recent studies have also shown an association of increased LV mass with attenuated endothelium-dependent coronary flow reserve. Less is known about the association between LV mass and endothelium-dependent flow-mediated dilatation (FMD) in peripheral arteries, a noninvasive measure of endothelial function. Sixty-two subjects with untreated mild hypertension, aged 55 to 75 years and otherwise healthy, were examined. Resting blood pressure was obtained by the average of 4 to 5 visits, each at least 1 week apart. LV mass was determined from magnetic resonance imaging and was indexed by body surface area, height and height(2.7). Body composition was assessed with dual energy x-ray absorptiometry. FMD was measured as the percent change of brachial artery diameter during reactive hyperemia by use of high-resolution ultrasound. Median LV mass index was 63 g/m2 (interquartile range, 58-73). In bivariate analysis, LV mass was correlated to lean body mass (r = 0.63, P <.001), diastolic blood pressure (r = 0.35, P <.01), and FMD (r = -0.27, P <.05). In multivariate analysis, 44% of the variance in log-LV mass was explained by lean body mass. An additional 6% of the variance was explained by FMD (P <.05). For each 1% point decrease in FMD, LV mass increased by 1.1%. In addition to the expected influences of body size, impairment of brachial artery FMD was independently related to LV mass in elderly subjects with mild hypertension who did not yet have LV hypertrophy. Whether mild hypertension is the common mechanism linking LV mass and endothelial function has yet to be determined.


Pharmacogenetics of tardive dyskinesia in schizophrenia: The role of CHRM1 and CHRM2 muscarinic receptors.
Objectives: Acetylcholine M (muscarinic) receptors are possibly involved in tardive dyskinesia (TD). The authors tried to verify this hypothesis by testing for possible associations between two muscarinic receptor genes (CHRM1 and CHRM2) polymorphisms and TD in patients with schizophrenia.Methods: A total of 472 patients with schizophrenia were recruited. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale. Fourteen allelic variants of CHRM1 and CHRM2 were genotyped using Applied Biosystems amplifiers (USA) and the MassARRAY System by Agena Bioscience.Results: The prevalence of the rs1824024*GG genotype of the CHRM2 gene was lower in TD patients compared to the group without it (χ2 = 6.035, p = 0.049). This suggested that this genotype has a protective effect for the development of TD (OR = 0.4, 95% CI: 0.19-0.88). When age, gender, duration of schizophrenia and dosage of antipsychotic treatment were added as covariates in regression analysis, the results did not reach statistical significance.Conclusions: This study did identify associations between CHRM2 variations and TD; the results of logistic regression analysis with covariates suggest that the association is, however, likely to be secondary to other concomitant factors.


[Validation of a short questionnaire on frequency of dietary intake: reproducibility and validity].
Knowledge on dietary intake in individuals is an essential tool to know the dietary patterns and explore their association with the disease risk. One of the current methods most currently used are dietary intake questionnaires. The main drawback of their use is the need for previous validation. Our objective was to validate a short questionnaire on the frequency of dietary intake. Reus (Catalonia), Spain. 71 adolescents and adults from both genders, with different socio-cultural levels and professional categories. The questionnaire was administered two times within an approximated period of one year to assess the reproducibility. Through this time, 9 24-hour recalls (gold standard method) were administered to determine the validity. Spearman's correlation coefficients for the reproducibility analysis varied 0.49-0.75 for foods and 0.44-0.78 for energy and nutrients. Most of intra-class correlation coefficients varied 0.53-0.96 for foods and 0.49-0.78 for energy and nutrients. In the validity analysis, the correlations varied 0.27-0.59 for foods, and 0.30-0.49 for energy and nutrients. The correlation coefficients in the validity study varied 0.41-0.67 for foods, and 0.29-0.47 for energy and nutrients. The questionnaire allows assessing the consumption of groups of foods, energy and macronutrients with adequate reproducibility and validity.


Global prediction of gross primary productivity under future climate change.
The ecosystem gross primary productivity (GPP) is crucial to land-atmosphere carbon exchanges, and changes in global GPP as well as its influencing factors have been well studied in recent years. However, identifying the spatio-temporal variations of global GPP under future climate changes is still a challenging issue. This study aims to develop data-driven approach for predicting the global GPP as well as its monthly and annual variations up to the year 2100 under changing climate. Specifically, Catboost was employed to examine the potential relationship between the GPP and environmental factors, with climate variables, CO2 concentration and terrain attributes being selected as environmental factors. The predicted monthly and annual GPP from Coupled Model Intercomparison Project phase 6 (CMIP6) under future SSP1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5 scenarios were analyzed. The results indicate that the global GPP is predicted to increase under the future climate change in the 21st century. The annual GPP is expected to be 115.122 Pg C, 116.537 Pg C, 117.626 Pg C, and 120.097 Pg C in 2100 under four future scenarios, and the predicted monthly GPP shows seasonal difference. Meanwhile, GPP tends to increase in the northern mid-high latitude regions and decrease in the equatorial regions. For the climate zones form Köppen-Geiger classification, the arid, cold, and polar zones present increased GPP, while GPP in the tropical zone will decrease in the future. Moreover, the high importance of climate variables in GPP prediction illustrates that the future climate change is the main driver of the global GPP dynamics. This study provides a basis for predicting how global GPP responds to future climate change in the coming decades, which contribute to understanding the interactions between vegetation and climate.


The importance of region 2.1 in sustaining the functional structure of the Bacillus subtilis sigma(A) factor.
Region 2.1 of the sigma factor is once proposed to be involved in core binding, and certain bulky hydrophobic amino acids in region 2.1 are thought to make contact with the conserved isoleucine residues in the promoter -10 binding region on the same protein. To examine the roles of the contact between these two regions in sigma(A) structure and function, sigma(A )factor with L145A, I149A, or Y153A was created, and the effects of each substitution on the growth of Bacillus subtilis and on the structural and functional properties of sigma(A) were analyzed. Our data revealed that the growth potential of B. subtilis was significantly affected by each of the substitutions of sigma(A) at elevated temperature. The growth defect was most pronounced with the strain containing L145A-sigma(A); it possessed a low growth potential even at 37 degrees C. In parallel, changes in the structural stability and core-binding activity of sigma(A) and in the promoter-binding and transcription activities of sigma(A)-RNA polymerase were observed for each of the substitutions, with the most drastic effects exerted by L145A. Clearly, region 2.1 of sigma(A) has extra functions, such as the binding of RNA polymerase to promoter DNA, other than the known core-binding ability. Moreover, the multiple effects of each of the substitutions on sigma(A) demonstrate that the contacts between the hydrophobic amino acids in region 2.1 and those in the promoter -10 binding region are critical to the maintenance of the functional sigma(A) structure and that L145 in region 2.1 plays an important role in this respect.


Landmark identification error in posteroanterior cephalometric radiography. A systematic review.
To evaluate the reliability of landmark identification in posteroanterior cephalometrics. A literature search was conducted to identify all articles concerning landmark identification error in the frontal radiograph. Electronic databases (PubMed, Web of Science, Cochrane Database, PubMed Central, and HubMed) were searched. Abstracts that appeared to fulfill the initial selection criteria were selected, and the full-text original articles were then retrieved and analyzed. Only articles that fulfilled the initial selection criteria were finally considered. Their references were also hand searched for possible missing articles from the database searches. Twelve abstracts met the initial inclusion criteria, and these articles were retrieved. From these, eight were immediately rejected because of methodological issues. Only the four articles remaining seemed to fulfill the selection criteria, but two articles were later rejected, one because no landmark identification error mean values were provided and the other because of the sample. Only one article fulfilled the inclusion and exclusion criteria of this study. Midline landmarks were more reproducible than bilateral skeletal landmarks. Only one study fulfilled the additional inclusion and exclusion criteria. Few studies exist about the random error in localization of landmarks in posteroanterior cephalograms, and several methodological issues affected these few studies. Thus, future well-designed studies are needed to allow the orthodontist to choose the most appropriate cephalometric analysis.


Protein Kinase C (Pkc)-δ Mediates Arginine-Induced Glucagon Secretion in Pancreatic α-Cells.
The pathophysiology of type 2 diabetes involves insulin and glucagon. Protein kinase C (Pkc)-δ, a serine-threonine kinase, is ubiquitously expressed and involved in regulating cell death and proliferation. However, the role of Pkcδ in regulating glucagon secretion in pancreatic α-cells remains unclear. Therefore, this study aimed to elucidate the physiological role of Pkcδ in glucagon secretion from pancreatic α-cells. Glucagon secretions were investigated in Pkcδ-knockdown InR1G9 cells and pancreatic α-cell-specific Pkcδ-knockout (αPkcδKO) mice. Knockdown of Pkcδ in the glucagon-secreting cell line InR1G9 cells reduced glucagon secretion. The basic amino acid arginine enhances glucagon secretion via voltage-dependent calcium channels (VDCC). Furthermore, we showed that arginine increased Pkcδ phosphorylation at Thr505, which is critical for Pkcδ activation. Interestingly, the knockdown of Pkcδ in InR1G9 cells reduced arginine-induced glucagon secretion. Moreover, arginine-induced glucagon secretions were decreased in αPkcδKO mice and islets from αPkcδKO mice. Pkcδ is essential for arginine-induced glucagon secretion in pancreatic α-cells. Therefore, this study may contribute to the elucidation of the molecular mechanism of amino acid-induced glucagon secretion and the development of novel antidiabetic drugs targeting Pkcδ and glucagon.


A stochastic simulation model of African swine fever transmission in domestic pig farms in the Red River Delta region in Vietnam.
The main objectives of this study were to model various scenarios of African swine fever (ASF) virus transmission among farms in Vietnam and to evaluate the impact of control strategies using North American Animal Disease Spread Model (NAADSM). A total of 7,882 pig farms in the Red River Delta (RRD) region were obtained from the General Statistics Office, and then, random points corresponding to the number of farms in each province were generated as exact farm locations were not available. A total of 10 models were developed, including movement control scenarios. In addition, we conducted sensitivity analysis to assess the impact of indirect contact transmission probability (TP). Overall, the indirect contact exhibited an important role in transmitting the ASF virus. In order to minimize ASF transmission between farms, we found that movement restriction needed to reach a certain level (approximately between 50% and 75%) and that the restriction had to be applied in a timely manner. This study offers valuable insight into how ASF virus can be transmitted via direct and indirect contact and controlled among farms under the various simulation scenarios. Our results suggest that the enforcement of movement restriction was an effective control measure as soon as the outbreaks were reported. In addition, this study provided evidence that high standards of biosecurity can contribute to the reduction of disease spread.


The power of partnership: Exploring collaboration dynamics in U.S. transplant research.
Collaboration is one of the hallmarks of academic research. This study analyzes collaboration patterns in U.S. transplant research, examining publication trends, productive institutions, co-authorship networks, and citation patterns in high-impact transplant journals. 4,265 articles published between 2012 and 2021 were analyzed using scientometric tools, logistic regression, VantagePoint software, and Gephi software for network visualization. 16,003 authors from 1,011 institutions and 59 countries were identified, with Harvard, Johns Hopkins, and University of Pennsylvania contributing the most papers. Odds of international collaboration significantly increased over time (OR 1.03; p = 0.040), while odds of citation in single-institution collaborations decreased (OR 0.99; p = 0.016). Five major scientific communities and central institutions (Harvard University and University of Pittsburgh) connecting them were identified, revealing interconnected research clusters. Collaboration enhances knowledge exchange and research productivity, with an increasing trend of institutional and international collaboration in U.S. transplant research. Understanding this community is essential for promoting research impact and forming strategic partnerships.