Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia.
Lung cancer mimicking organizing pneumonia (LCOP) is a novel radiological entity of lung adenocarcinoma that could be misdiagnosed as inflammatory lesions. However, the characteristic biological and genetic features of LCOP are not fully clarified. We used thin-section CT images to select cases of (LCOP) among surgically resected lung adenocarcinoma patients. We compared the clinicopathological characteristics and the immunophenotypes of LCOP (n=44) and other lepidic-predominant adenocarcinomas (non-LCOP, n=56). We also analyzed the genomic mutation features of LCOP (n=4) by whole-exome sequencing (WES). All LCOP lesions were lepidic-predominant invasive adenocarcinoma. Patients with LCOP had significantly superior recurrence-free survival, compared to non-LCOP patients (95.5% and 74.4%; P=0.006, respectively). Vascular invasion and lymph node metastasis were less frequent in LCOP than in non-LCOP patients (P=0.001 and P=0.03, respectively). The cancer cell expression levels of aggressiveness-related molecules, including ezrin, ALDH-1, laminin-5 were similar between LCOP and non-LCOP. On the contrary, the number of tumor promoting stromal cells, i.e., podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor associated macrophages, was significantly lower in LOCP (P=0.021 and P=0.037, respectively). WES revealed that ABCB1, DNAH3, MSI2, and SLITRK2 were specifically mutated in LCOP. Our results indicate that LCOP is characterized by fewer tumor-promoting stromal cells, which may contribute to the better prognosis of LCOP patients. Moreover, recognition of specific somatic mutations of LCOP patients may provide information regarding the development and progression of this type of lung cancer.


Exercise to preserve beta cell function in recent-onset type 1 diabetes mellitus (EXTOD)--a study protocol for a pilot randomized controlled trial.
Exercise has a beta cell preserving effect in patients with type 2 diabetes. This benefit of exercise has not been examined in type 1 diabetes. Significant beta cell function is present at the time of diagnosis of type 1 diabetes and therefore studies of beta cell preservation are ideally conducted immediately after diagnosis.Many of the variables required to design and power such a study are currently unknown. The aim of EXTOD is to obtain the information required to design a formal study of exercise and beta cell preservation in newly diagnosed patients with type 1 diabetes. Barriers to exercise will initially be assessed in a qualitative study of newly diagnosed patients. Then, sixty newly diagnosed adult type 1 diabetes patients will be randomized to either conventional treatment or exercise, stratified on beta cell function and fitness. The exercise group will be encouraged to increase their level of activity to a minimum of 150 minutes of moderate to vigorous intensity exercise per week, aiming for 240 minutes per week of exercise for 12 months. Beta cell function will be measured by meal-stimulated C peptide. Primary outcomes are recruitment, adherence to exercise, loss to follow-up, and exercise levels in the non-intervention arm (contamination). The secondary outcome of the study is rate of loss of beta cell function. The outcomes of the EXTOD study will help define the barriers, uptake and benefits of exercise in adults newly diagnosed with type 1 diabetes. This information will enable design of a formal study to assess the effect of exercise on beta cell preservation in newly diagnosed patients with type 1 diabetes. Current controlled trials ISRCTN91388505.


Secretion of FK506/FK520 and rapamycin by Streptomyces inhibits the growth of competing Saccharomyces cerevisiae and Cryptococcus neoformans.
FK506 and rapamycin are immunosuppressants that inhibit signalling cascades required for T-cell activation, yet both are natural products of Streptomyces that live in the soil. FK506 and rapamycin also have potent antimicrobial activity against yeast and pathogenic fungi, suggesting a natural role in inhibiting growth of competing micro-organisms. The immunosuppressive and antimicrobial activities of FK506 and rapamycin are mediated by binding to the FKBP12 prolyl isomerase and the resulting FKBP12/FK506 and FKBP12/rapamycin complexes inhibit conserved protein targets, either the phosphatase calcineurin or the TOR (target of rapamycin) kinases, respectively. Streptomyces sp., 'Streptomyces hygroscopicus subsp. ascomyceticus' and Streptomyces hygroscopicus, which produce FK506, FK520 (also known as ascomycin, a C21 ethyl derivative of FK506) and rapamycin, respectively, produced toxins that inhibited the growth of competing cells of the yeast Saccharomyces cerevisiae and the pathogenic fungus Cryptococcus neoformans. Yeast and fungal mutants lacking FKBP12 or expressing dominant drug-resistant calcineurin or TOR mutants were resistant to FK506 and rapamycin, and to the toxins produced by Streptomyces. Streptomyces strains with mutations in the FK506 or rapamycin biosynthetic enzymes were impaired in toxin production. Finally, the toxins secreted by 'S. hygroscopicus subsp. ascomyceticus' and S. hygroscopicus promoted formation of FKBP12/calcineurin and FKBP12/TOR complexes in a two-hybrid assay and mutations that rendered calcineurin or TOR drug-resistant prevented interaction. These observations support the hypothesis that Streptomyces evolved to secrete FK506, FK520 and rapamycin as toxins to inhibit the growth of competing yeast and fungi.


Helping patients lose weight--what works?
Over one in two Australians are now overweight or obese. Weight loss is difficult for patients to achieve and maintain in the current 'obesogenic' environment. However, new developments have resulted in a number of strategies and methods with a good evidence base. A 5-10% reduction in weight can result in a 35% decrease in health risk. This article discusses the evidence base behind weight loss strategies for use in clinical practice. Obesity treatments with good evidence include counselling and behavioural approaches, exercise based programs, pre-prepared low energy meals, meal replacement, and bariatric surgery (the most effective for long term weight loss). Medication can be useful in some settings. Limited data suggests commercial diets and self help may be of some benefit. Alternative noningestible treatments (eg. creams and body wrapping) and the majority of over-the-counter medications (with the notable exception of orlistat) have no convincing evidence for efficacy. All successful strategies include some form of lifestyle change resulting in a reduction in energy consumed versus energy expended. The most effective treatments are likely to involve combining and matching strategies to the characteristics of the patient.


Electrospun Nanofibers: Shaping the Future of Controlled and Responsive Drug Delivery.
Electrospun nanofibers for drug delivery systems (DDS) introduce a revolutionary means of administering pharmaceuticals, holding promise for both improved drug efficacy and reduced side effects. These biopolymer nanofiber membranes, distinguished by their high surface area-to-volume ratio, biocompatibility, and biodegradability, are ideally suited for pharmaceutical and biomedical applications. One of their standout attributes is the capability to offer the controlled release of the active pharmaceutical ingredient (API), allowing custom-tailored release profiles to address specific diseases and administration routes. Moreover, stimuli-responsive electrospun DDS can adapt to conditions at the drug target, enhancing the precision and selectivity of drug delivery. Such localized API delivery paves the way for superior therapeutic efficiency while diminishing the risk of side effects and systemic toxicity. Electrospun nanofibers can foster better patient compliance and enhanced clinical outcomes by amplifying the therapeutic efficiency of routinely prescribed medications. This review delves into the design principles and techniques central to achieving controlled API release using electrospun membranes. The advanced drug release mechanisms of electrospun DDS highlighted in this review illustrate their versatility and potential to improve the efficacy of medical treatments.


The alpha2-adrenergic receptor agonist UK 14,304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats.
Secretin stimulates ductal secretion by activation of cAMP --> PKA --> CFTR --> Cl(-)/HCO(3)(-) exchanger in cholangiocytes. We evaluated the expression of alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenergic receptors in cholangiocytes and the effects of the selective alpha(2)-adrenergic agonist UK 14,304, on basal and secretin-stimulated ductal secretion. In normal rats, we evaluated the effect of UK 14,304 on bile and bicarbonate secretion. In bile duct-ligated (BDL) rats, we evaluated the effect of UK 14,304 on basal and secretin-stimulated 1) bile and bicarbonate secretion; 2) duct secretion in intrahepatic bile duct units (IBDU) in the absence or presence of 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of the Na(+)/H(+) exchanger isoform NHE3; and 3) cAMP levels, PKA activity, Cl(-) efflux, and Cl(-)/HCO(3)(-) exchanger activity in purified cholangiocytes. alpha(2)-Adrenergic receptors were expressed by all cholangiocytes in normal and BDL liver sections. UK 14,304 did not change bile and bicarbonate secretion of normal rats. In BDL rats, UK 14,304 inhibited secretin-stimulated 1) bile and bicarbonate secretion, 2) expansion of IBDU luminal spaces, and 3) cAMP levels, PKA activity, Cl(-) efflux, and Cl(-)/HCO(3)(-) exchanger activity in cholangiocytes. There was decreased lumen size after removal of secretin in IBDU pretreated with UK 14,304. In IBDU pretreated with EIPA, there was no significant decrease in luminal space after removal of secretin in either the absence or presence of UK 14,304. The inhibitory effect of UK 14,304 on ductal secretion is not mediated by the apical cholangiocyte NHE3. alpha(2)-Adrenergic receptors play a role in counterregulating enhanced ductal secretion associated with cholangiocyte proliferation in chronic cholestatic liver diseases.


Challenging behaviour in older people: nurses' attitudes.
An investigation was undertaken to look at nurses' attitudes to challenging behaviour in hospitalised older adults. It was predicted that nurses would make internal rather than external or medical attributions for challenging behaviour and that negative emotions towards the patient would result in negative responses, for example, reprimanding the patient. Findings revealed that nurses did not make significantly more internal rather than external or medical attributions, and that no significant differences were associated with age or grade (p > 0.05). A correlation coefficient showed that negative emotions were associated with an internal attribution style (r = .40, p < 0.005). A simple regression analysis revealed that negative behaviour could be significantly predicted from negative emotion (f = 10.68, p < 0.01). The research concludes that efforts should be made to reduce negative effect via staff training and that further research should focus upon staff and patient interactions within real life settings.


Dissection of DNA damage and repair pathways in live cells by femtosecond laser microirradiation and free-electron modeling.
Understanding and predicting the outcome of the interaction of light with DNA has a significant impact on the study of DNA repair and radiotherapy. We report on a combination of femtosecond pulsed laser microirradiation at different wavelengths, quantitative imaging, and numerical modeling that yields a comprehensive picture of photon-mediated and free-electron-mediated DNA damage pathways in live cells. Laser irradiation was performed under highly standardized conditions at four wavelengths between 515 nm and 1,030 nm, enabling to study two-photon photochemical and free-electron-mediated DNA damage in situ. We quantitatively assessed cyclobutane pyrimidine dimer (CPD) and γH2AX-specific immunofluorescence signals to calibrate the damage threshold dose at these wavelengths and performed a comparative analysis of the recruitment of DNA repair factors xeroderma pigmentosum complementation group C (XPC) and Nijmegen breakage syndrome 1 (Nbs1). Our results show that two-photon-induced photochemical CPD generation dominates at 515 nm, while electron-mediated damage dominates at wavelengths ≥620 nm. The recruitment analysis revealed a cross talk between nucleotide excision and homologous recombination DNA repair pathways at 515 nm. Numerical simulations predicted electron densities and electron energy spectra, which govern the yield functions of a variety of direct electron-mediated DNA damage pathways and of indirect damage by •OH radicals resulting from laser and electron interactions with water. Combining these data with information on free electron-DNA interactions gained in artificial systems, we provide a conceptual framework for the interpretation of the wavelength dependence of laser-induced DNA damage that may guide the selection of irradiation parameters in studies and applications that require the selective induction of DNA lesions.


The role of amino acids surrounding tyrosine 1062 in ret in specific binding of the shc phosphotyrosine-binding domain.
We investigated the role of the I-E-N-K-L (amino acids 1057-1061) sequence amino-terminal to Tyr1062 in Ret for binding of the Shc phosphotyrosine-binding (PTB) domain. Substitution of Ser for Ile1057 (I1057S), Ala for Asn1059 (N1059A), or Pro for Leu1061 (L1061P) in this sequence significantly decreased the transforming activity of Ret with the multiple endocrine neoplasm type 2A (MEN2A) mutation as well as the binding affinity of Shc to it in vivo and in vitro, indicating that these three amino acids play a role in Shc binding. In addition, as the RET protooncogene is translated as three isoforms of 1114 amino acids (Ret 51), 1106 amino acids (Ret 43), and 1072 amino acids (Ret 9) that differ from one another in the sequence carboxyl-terminal to Tyr1062, we examined whether these sequence differences influence the binding affinity of Shc to Ret. As a result, we found that the transforming activity of Ret 43 isoform with the MEN2A mutation and the binding affinity of Shc to it were very low, although the consensus sequence for the binding of the Shc PTB domain is conserved in the Ret 43 isoform. This finding suggested that the sequence carboxyl-terminal to Tyr1062 in Ret could also influence the binding affinity to Shc.


High-throughput physical mapping of chromosomes using automated in situ hybridization.
Projects to obtain whole-genome sequences for 10,000 vertebrate species and for 5,000 insect and related arthropod species are expected to take place over the next 5 years. For example, the sequencing of the genomes for 15 malaria mosquitospecies is currently being done using an Illumina platform. This Anopheles species cluster includes both vectors and non-vectors of malaria. When the genome assemblies become available, researchers will have the unique opportunity to perform comparative analysis for inferring evolutionary changes relevant to vector ability. However, it has proven difficult to use next-generation sequencing reads to generate high-quality de novo genome assemblies. Moreover, the existing genome assemblies for Anopheles gambiae, although obtained using the Sanger method, are gapped or fragmented. Success of comparative genomic analyses will be limited if researchers deal with numerous sequencing contigs, rather than with chromosome-based genome assemblies. Fragmented, unmapped sequences create problems for genomic analyses because: (i) unidentified gaps cause incorrect or incomplete annotation of genomic sequences; (ii) unmapped sequences lead to confusion between paralogous genes and genes from different haplotypes; and (iii) the lack of chromosome assignment and orientation of the sequencing contigs does not allow for reconstructing rearrangement phylogeny and studying chromosome evolution. Developing high-resolution physical maps for species with newly sequenced genomes is a timely and cost-effective investment that will facilitate genome annotation, evolutionary analysis, and re-sequencing of individual genomes from natural populations. Here, we present innovative approaches to chromosome preparation, fluorescent in situ hybridization (FISH), and imaging that facilitate rapid development of physical maps. Using An. gambiae as an example, we demonstrate that the development of physical chromosome maps can potentially improve genome assemblies and, thus, the quality of genomic analyses. First, we use a high-pressure method to prepare polytene chromosome spreads. This method, originally developed for Drosophila, allows the user to visualize more details on chromosomes than the regular squashing technique. Second, a fully automated, front-end system for FISH is used for high-throughput physical genome mapping. The automated slide staining system runs multiple assays simultaneously and dramatically reduces hands-on time. Third, an automatic fluorescent imaging system, which includes a motorized slide stage, automatically scans and photographs labeled chromosomes after FISH. This system is especially useful for identifying and visualizing multiple chromosomal plates on the same slide. In addition, the scanning process captures a more uniform FISH result. Overall, the automated high-throughput physical mapping protocol is more efficient than a standard manual protocol.


Tenacibaculum agarivorans sp. nov., an agar-degrading bacterium isolated from marine alga Porphyra yezoensis Ueda.
A novel Gram-stain-negative, aerobic, rod-shaped, non-flagellated and agar-digesting marine bacterium, designated as HZ1T, was isolated from the marine alga Porphyra yezoensis Ueda (AST58-103) collected from the coastal area of Weihai, PR China. Phylogenetic analysis based on 16S rRNA gene sequences placed HZ1T in the genus Tenacibaculum, and it formed a distinct clade in the phylogenetic tree with the type strains of Tenacibaculum amylolyticum and Tenacibaculum skagerrakense, with 97.0 % and 96.7 % 16S rRNA gene sequence similarities, respectively. The DNA G+C content of the isolate was 31.8 mol%. HZ1T contained MK-6 as the predominant menaquinone and iso-C15 : 0, summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), iso-C17 : 0 3-OH and iso-C15 : 1G as the major fatty acids. The major polar lipids were phosphatidylethanolamine, four unidentified lipids and five unidentified aminolipids. On the basis of the results of the phylogenetic analysis and phenotypic properties, it is concluded that HZ1T represents a novel species of the genus Tenacibaculum, for which the name Tenacibaculumagarivorans sp. nov. is proposed. The type strain is HZ1T (=MCCC 1H00174T=KCTC 52476T).


Is nitric oxide really important for regulation of the cerebral circulation? Yes or no?
Since endothelium-dependent relaxation of cerebral vessels was first identified in 1980, the pivotal role of the endothelium has become evident not only in dilator responses but also in constrictor responses to various kinds of stimulation. Involvement of endothelium-derived relaxing factors (EDRFs) as well as endothelium-derived contracting factors (EDCFs) has been postulated in such vascular responses. In 1987, one of the EDRFs was determined to be nitric oxide (NO), a simple and very labile molecule, whereas endothelin composed of 21 amino acid residues was identified as one of the EDCFs in 1988. Since 1990, numerous studies which exclusively employed L-arginine analogues as specific NO synthase (NOS) inhibitors, have been undertaken to examine the role of NO in the regulation of the cerebral circulation. However, some conflicting data have emerged. The few points of consensus among the researchers may be summarized as follows: (1) NO, probably produced in the endothelium, plays an important role in the maintenance of the basal cerebral blood flow, (2) NO is not directly involved in hypoxic vasodilation, and (3) NO mediates a functional coupling of metabolism and cerebral blood flow in certain types of neural activation. Hypercapnic vasodilation and autoregulatory responses are still the main topics providing conflicting data with substantial areas of controversy. Besides ensuring appropriate experimental protocols, future studies require the precise monitoring of the degree and cellular specificity (endothelium, perivascular nerve fibers, neurons, etc.) of NOS inhibition in order to obtain concrete and reliable experimental data.


Lesson of the month 2: Dry skin, yellow nails and breathlessness.
Interstitial lung disease (ILD) is a common clinical problem, representing a group of diseases consisting of inflammation and progressive fibrosis of the lung. In some cases, an underlying cause is not identified; however, a significant proportion of ILD is associated with connective tissue disease (CTD). A detailed history and examination is the most important part of the assessment of patients with suspected ILD and will direct further investigation. This case illustrates the importance of identifying the symptoms and signs of CTD when assessing a patient with ILD. In addition, we describe an unusual presenting manifestation of yellow nails, which is not a recognised feature of CTD-ILD, but improved following immunomodulatory treatment for the overall condition.


Metal-driven operation of the human large-conductance voltage- and Ca2+-dependent potassium channel (BK) gating ring apparatus.
Large-conductance voltage- and Ca(2+)-dependent K(+) (BK, also known as MaxiK) channels are homo-tetrameric proteins with a broad expression pattern that potently regulate cellular excitability and Ca(2+) homeostasis. Their activation results from the complex synergy between the transmembrane voltage sensors and a large (>300 kDa) C-terminal, cytoplasmic complex (the "gating ring"), which confers sensitivity to intracellular Ca(2+) and other ligands. However, the molecular and biophysical operation of the gating ring remains unclear. We have used spectroscopic and particle-scale optical approaches to probe the metal-sensing properties of the human BK gating ring under physiologically relevant conditions. This functional molecular sensor undergoes Ca(2+)- and Mg(2+)-dependent conformational changes at physiologically relevant concentrations, detected by time-resolved and steady-state fluorescence spectroscopy. The lack of detectable Ba(2+)-evoked structural changes defined the metal selectivity of the gating ring. Neutralization of a high-affinity Ca(2+)-binding site (the "calcium bowl") reduced the Ca(2+) and abolished the Mg(2+) dependence of structural rearrangements. In congruence with electrophysiological investigations, these findings provide biochemical evidence that the gating ring possesses an additional high-affinity Ca(2+)-binding site and that Mg(2+) can bind to the calcium bowl with less affinity than Ca(2+). Dynamic light scattering analysis revealed a reversible Ca(2+)-dependent decrease of the hydrodynamic radius of the gating ring, consistent with a more compact overall shape. These structural changes, resolved under physiologically relevant conditions, likely represent the molecular transitions that initiate the ligand-induced activation of the human BK channel.


An integrated exploration into the social and environmental determinants of health: the Saskatchewan Population Health and Evaluation Research Unit (SPHERU).
The Saskatchewan Population Health and Evaluation Research Unit (SPHERU) is a new interdisciplinary research institute established by the Universities of Saskatchewan and Regina. SPHERU developed four of its research programs using a hierarchic model of health determining conditions and contexts. In descending order these programs include: Economic and Environmental Globalization, Governance and Health Community/Environment as a Health Determinant Multiple Roles, Gender and Health Determinants of Healthy Childhood Development A fifth program researching the determinants of health of indigenous peoples spans all four levels. Two research projects, one on power, control and health, and another on community capacity building approaches to human service programs, assist SPHERU in developing the theoretical linkages between its programs. This article describes SPHERU's research model and the Unit's approach to research and summarizes each of its current research programs and projects.


Brief report: pervasive developmental disorder can evolve into ADHD: case illustrations.
Despite prominent attentional symptoms in Pervasive Developmental Disorders (PDD) the relationship between PDD and Attention Deficit Hyperactivity Disorder (ADHD) has received little direct examination. In addition, outcome studies of children with PDD often focus on language, educational placement, or adaptive skills, but seldom on loss of the PDD diagnosis or change to another clinical syndrome. We present three cases in detail, and tabular data on eight more, that illustrate a clinical presentation in which prototypical cases of PDD evolve into clear-cut cases of ADHD from early to middle childhood.


Atom probe tomography: a technique for nanoscale characterization.
Atom probe tomography is a technique for the nanoscale characterization of microstructural features. Analytical techniques have been developed to estimate the size, composition, and other parameters of features as small as 1 nm from the atom probe tomography data. These methods are outlined and illustrated with examples of yttrium-, titanium-, and oxygen-enriched particles in a mechanically alloyed, oxide-dispersion-strengthened steel.


Pneumonia With Scedosporium apiospermum and Lomentospora prolificans in a Patient After Bilateral Lung Transplantation for Pulmonary Hypertension: A Case Report.
Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum β-D-glucan elevated without any sign of fungal infection by other tests. The serum β-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum β-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.


Frequencies of neuronal autoantibodies in healthy controls: Estimation of disease specificity.
To provide an extensive overview on the prevalence of antibodies against neuronal surfaces (neuronal surface antibody [NSAb]) in healthy participants and disease controls. We searched the PubMed database (1974 to October 2016) for studies that analyzed frequencies of 22 different NSAbs in serum or CSF and included controls. Antibody prevalence was calculated for patients with NSAb-mediated disease and controls, including healthy participants, and those with neurologic and nonneurologic diseases. Different assays for antibody detection were compared. In 309 articles, 743,299 antibody tests for 22 NSAbs were performed, including 30,485 tests for 19 NSAbs in healthy controls (HCs). Of these, 26,423 (86.7%) were tested with current standard methods, usually cell-based assays. Prevalence was very low in HCs (mean 0.23%, absent for 9/19 antibodies), and test numbers ranged from 21 to 3,065 per antibody. One study reported >1,000 healthy participants, and the others contained 21-274 samples. CSF samples were virtually not available from HCs. NSAb prevalence was considerably higher (1.5%) in 69,850 disease controls, i.e., patients not initially suspected to have NSAb-mediated diseases. Antibody determination in controls using nonstandard assays (such as ELISA) resulted in 6% positivity. NSAbs are rarely found in healthy participants, particularly with standard detection methods, suggesting high disease specificity and supporting their diagnostic usefulness. Conversely, positive titers in atypical patients might point to the still expanding phenotypic spectrum. Future studies should include more CSF samples, data from HCs, and experimental evidence for antibody pathogenicity.


Associations of cardiorespiratory fitness, physical activity, and obesity with metabolic syndrome in Hong Kong Chinese midlife women.
Several studies have simultaneously examined physical activity (PA) and cardiorespiratory fitness (CRF) with metabolic syndrome (MS). However, the independent roles of both PA and CRF with MS are less firmly established. The combined contributions of PA and CRF with MS are less studied, particularly among Chinese women. There is uncertainty over the extent to which metabolically healthy but overweight/obese individuals have a higher CRF level. The sample included 184 Chinese women aged 55 to 69 years with available metabolic data and lifestyle factors. PA was assessed by self-reported questionnaire; CRF was assessed by maximal oxygen consumption (VO2max) during a symptom-limited maximal exercise test on a cycle ergometer. Metabolically healthy/abnormal was defined on the basis of absence or presence of MS. Overweight was defined as a body mass index (BMI) of ≥ 23 kg/m2 and obese was defined as a BMI of ≥ 25 kg/m2. The prevalence of MS was 21.7%. PA was inversely associated with the prevalence of MS after adjustment for age, BMI, and dietary total calories intake, but the association was eliminated after further adjustment for CRF. CRF was inversely associated with the prevalence of MS independent of age, BMI, and dietary total calories intake, and the association remained significant after further adjustment for PA. In the PA and CRF combined analysis, compared with those in the lowest tertile of PA (inactive) and lowest tertile of CRF (unfit), the OR (95%CI) of having MS was 0.31 (0.09-1.06) for subjects in the higher tertiles (2nd-3rd) of PA (active) but were unfit, 0.23 (0.06-0.88) for subjects who were inactive but in the higher tertiles (2nd-3rd) of CRF (fit), and 0.14 (0.04-0.45) for subjects who were active and fit. Metabolically healthy but overweight/obese subjects had a higher CRF level than their metabolically abnormal and overweight/obese peers. However, the difference did not reach statistically significance. CRF has greater association with the prevalence of MS compared with PA in Chinese midlife women. The interrelationships between CRF, obesity, and MS needs further study.


Cerebrospinal fluid and serum levels of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 in patients with severe head injury.
The aim of this study is to present time course of insulin like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in both cerebrospinal fluid (CSF) and serum of patients after severe head injury (SHI) and to compare with controls. Our trauma and control groups included 11 consecutive patients with isolated SHI and 9 patients with hydrocephalus (one with normotensive and eight with hydrocephalus due to aqueduct stenosis), respectively. Both serum and cerebrospinal fluid levels of IGF-1 and IGFBP-3 were measured during post-traumatic days and we compared the levels with controls. Patients and controls showed undetectable levels of both IGF-1 and IGFBP-3 in their CSF. When considering serum levels, patients with SHI had always lower levels of both molecules than that of controls. Administration of IGF-1 during acute, as well as chronic phase of severe head trauma may provide beneficial effects and may decrease both mortality and morbidity in humans with SHI.


Properties of antibacterial polypropylene/nanometal composite fibers.
Melt spinning of polypropylene fibers containing silver and zinc nanoparticles was investigated. The nanometals were generally uniformly dispersed in polypropylene, but aggregation of these materials was observed on fiber surface and in fiber cross-sections. The mechanical properties of the resulted composite fibers with low concentration of nanometal were comparable to those for the control PP yarns. Extruded composite fibers that contained 0.72% silver and 0.60% zinc nanoparticles had outstanding antibacterial efficacy as documented by the percentage count reduction growth of Escherichia coli and Staphylococcus aureus. Fibers containing silver particles had improved antistatic properties.


[New physiological records for Turiamo Bay, Henri Pittier National Park, Aragua, Venezuela].
Turiamo Bay is a natural refuge area for marine species, where it is possible to find different environments that allow the growth of a rich phycoflora. Although this bay is located in Henri Pittier National Park between human settlements, studies are scarce in this area. It is a reservoir of high diversity in flora as well as fauna. In this work we present 11 new records of macroalgae that grow over dead coral plataforms east of the bay. These species are: Ulva fasciata Delile, Enteromorpha flexuosa subsp. flexuosa (Wulfen) J. Agardh, Chaetomorpha antennina (Bory de St. Vicent) Kützing, Chaetomorpha linum (Müller) Kützing and Phyllodicyton anastomosans (Harvey) Kraft & M.J. Wynne (Chlorophyta); Dictyopteris delicatula Lamouroux (Phaeophyta); Galaxaura marginata (Ellis & Solander) Lamouroux, Grateloupia doryphora J. Agardh, Gymnogongrus tenuis J. Agardh, Hypnea musciformis (Wulfen) Lamouroux and Martensia fragilis Harvey (Rhodophyta).


Interneurons between giant axons and motoneurons in crayfish escape circuitry.
1. Crayfish giant fibers are generally believed to generate tailflip movements by means of direct connections to two classes of phasic flexor muscle motoneurons, the motor giants (MoGs) and the nongiant fast flexor motoneurons (FFs). It is shown here that the giants also stimulate a network of interneurons that make connections with the FFs. 2. This network includes an intraganglionic neuron, the segmental giant (SG), in each abdominal hemisegment and a number of intersegmental neurons, two of which (I2 and I3) were studied in detail. 3. The SGs are driven reliably by the giant fibers and they in turn drive the FFs of their hemisegment about as effectively as do the giant fibers themselves; it is possible that the giant fibers excite the FFs mainly by way of the SGs. The SGs also have an efferent first root axon whose peripheral targets we have been unable to determine. 4. I2 and I3 originate in the second and third abdominal ganglia, respectively, and descend to the last ganglion. In their ganglia of origin they are reliably driven by the giant fibers and by the SGs. In addition, I2 weakly excites I3 and both receive weak, apparently direct, excitatory input from FFs as well as less direct excitatory and inhibitory input from unidentified afferent sources. Both weakly excite most FFs in ganglia behind the one in which they originate. This excitation adds to that produced directly by giant fibers and SGs and, we believe, is sometimes decisive in causing FF firing. Their firing also causes inhibition involved in suppressing effects of reafference, as do the giant fibers themselves. 5. I3 strongly excites the motoneurons of certain tail fan muscles (the ventral and posterior telson flexors). However, the contraction of these muscles would be maladaptive during some giant fiber-mediated tailflips. Accordingly, when the giant fibers, which always recruit I3, fire, they cause an inhibition of the motoneurons that nullifies the excitatory input from I3. At a formal level this means that the giants, viewed as command neurons, not only drive but also alter or modulate the subordinate motor pattern-generating network that they control. 6. Tailflips that are less stereotyped than those mediated by giant fibers are known to occur without participation of the giants. It is suggested that the presence of complex circuitry mediating between giant fibers and FFs may be related to the use of portions of this circuitry as well as the FFs themselves in production of nongiant tailflips.


The water-energy-food nexus: a systematic bibliometric analysis.
Adequate water, electricity, and food are essential for sustainable development. Regional conflicts intensified by global water, energy, and food shortages necessitate a rethinking of the security and interdependence of these resources. However, most earlier scholars concentrated on the subsystems of the water-energy-food nexus (WEF nexus), lacking holistic studies. Therefore, to understand the history and current state of research on the WEF nexus and predict future research directions, this study analyzed 1313 journal articles from the Web of Science database between 2007 and 2022 using the bibliometric analysis and Citespace software. The findings in this study indicate that (1) the progress of the WEF nexus research can be classified into three stages between 2007 and 2022: the early stage (2007-2010), the fast-developing stage (2011-2015), and the steady and in-depth stage (2016-2022). The WEF nexus has become a hot zone for academic research. (2) Map of the network of countries, institutions, and author collaborations implies tight academic collaboration among countries, institutions, and writers. (3) Climate change, integrated WEF nexus, sustainable development, and security are research hotspots in this field. Meanwhile, energy security, circular economy, and resource allocation are advanced subjects in this field. These key findings can provide managers and researchers with valuable information for decision-making.


Presumed ocular histoplasmosis.
Six patients showing typical manifestations and some rare features of the presumed ocular histoplasmosis syndrome are presented and discussed in the light of present knowledge. Krypton laser photocoagulation was used in one patient with encouraging results. Histoplasmin skin testing was negative in all cases. HLA typing supported the previous findings of an association with HLA B7 but not DRw2. Although the presumed ocular histoplasmosis syndrome is not uncommon outside America the true aetiology of this condition remains obscure.


High variability in serum estradiol measurements in men and women.
To reduce the variability in estradiol (E2) testing and to assure better patient care, standardization of E2 measurements has been recommended. This study aims to assess the accuracy and variability of E2 measurements performed by 11 routine immunological methods and 6 mass spectrometry methods using single donor serum materials and to compare the results to a reference method. The contribution of calibration bias, specificity or matrix effects, and imprecision on the overall variability of individual assays was evaluated. This study showed substantial variability in serum E2 measurements in samples from men and pre- and post-menopausal women. The mean bias across all samples, for each participant, ranged between -2.4% and 235%, with 3 participants having a mean bias of over 100%. The data suggest that calibration bias is the major contributor to the overall variability for nine assays. The analytical performances of most assays measuring E2 concentrations do not meet current needs in research and patient care. Three out of 17 assays would meet performance criteria derived from biological variability of ±12.5% bias at concentrations ≥20 pg/mL, and a maximum allowable bias of ±2.5 pg/mL at concentrations <20 pg/mL. The sensitivity differs highly between assays. Most assays are not able to measure E2 levels below 10 pg/mL. Standardization, specifically calibration to a common standard by using panels of individual patient samples, can reduce the observed variability and improve the utility of E2 levels in clinical settings.


[Verification of amplified DNA profiles by electrophoresis in various gels].
Differentiation of genotypical mixtures resultant from amplification analysis of mixed DNA preparations and false multi-strip profiles, which can result from amplification typing of individual DNA under certain conditions and simulate mixtures, impedes the molecular genetic identification expert evaluations. This paper offers an effective method for verification of amplification profiles of DNA, which is based on the use of alternative gel electrophoretic systems. This methodological approach helps detect the polymerase chain reaction artefacts without using additional expert material and promotes correct interpretation of expert findings even in difficult cases.


Is arginine charged in a membrane?
"Charged" amino acids play countless important roles in protein structure and function. Yet when these side chains come into contact with membranes we do not fully understand their behavior. This is highlighted by a recent model of voltage-gated ion channel activity and translocon-based experiments that suggest small penalties to expose these side chains to lipids, opposing the prevailing view in membrane biophysics. Here we employ a side chain analog as well as a transmembrane helix model to determine the free energy as a function of protonation state and position for a lipid-exposed arginine (Arg) residue across a membrane. We observe high free energy barriers for both the charged and neutral states. Due to the stabilizing influence of membrane deformations for the protonated form, the Arg side chain experiences a pK(a) shift of <or=4.5 units and remains mostly protonated. The cost for exposing Arg to lipid hydrocarbon is prohibitively high with implications for many membrane translocating processes and the activation mechanisms of voltage-gated ion channels.


Migraine headache and obesity in women aged 40-74 years: a population-based study.
This study investigates the associations between obesity and migraine. A neurologist clinically assessed 684 women aged 40-74 years attending a population-based mammography screening programme. Body height and weight were measured and body mass index (BMI) calculated. Obesity was defined as a BMI > or = 30 kg/m2. The proportion of obesity did not differ between women with active migraine, women with inactive migraine or women who had never experienced migraine (P = 0.96). The distribution of frequency, intensity, duration or severity of attacks did not differ between obese and non-obese women with migraine. In this study there were no significant associations between migraine or migraine characteristics on the one hand and obesity on the other.


Removable-suture closure of the lamellar scleral flap in trabeculectomy.
Removable-suture closure of the lamellar scleral flap was attempted in trabeculectomy, with the goal of increasing the degree of filtration during the immediate postoperative period by removing the suture so as to undo the closure whenever the need arose. The incorporation of the removable-suture closure of the lamellar scleral flap resulted in an additional mechanism of control over the degree of filtration after trabeculectomy. Furthermore, the availability of such a mechanism allowed the surgeon to close the lamellar scleral flap relatively tightly; this resulted in a decreased incidence of postoperative complications.


Air Pollution as a Potential Determinant of Rheumatoid Arthritis: A Population-based Cohort Study in Taiwan.
Limited studies have explored the relationship between air pollution and rheumatoid arthritis (RA), with the results being somewhat inconsistent. This was a retrospective cohort study that included 322,301 subjects aged 30-50 years, selected from the National Health Insurance Research Database in Taiwan, were followed from 2001 to 2010. We used a time-dependent extended Cox model and incorporated time-dependent variables to estimate the associations between the annual mean concentrations of air pollutants with RA, including carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), particles with an aerodynamic diameter less than 10 μm (PM10), and sulfur dioxide (SO2), and reported the hazard ratio (HR) and 95% confidence interval (CI). Newly diagnosed RA was positively associated with a 100-ppb increase in CO (adjusted HR = 1.17 [95% CI = 1.16, 1.18]), a 10-ppb increase in NO2 (1.54 [1.45, 1.64]), a 10-ppb increase in O3 (1.37 [1.33, 1.41]), and a 1 ppb in SO2 (1.02 [1.00, 1.04]). There was no association between a 10-μg/m increase in PM10 and RA (1.02 [0.99, 1.05]). Our finding suggests that O3 and traffic-related air pollutants (CO and NO2) may be positively associated with incident RA. This is an important finding given that many individuals are exposed to similar levels of O3 and NO2 globally.


Psychosocial distress and stroke risk in older adults.
To investigate the association of psychosocial distress with risk of stroke mortality and incident stroke in older adults. Data were from the Chicago Health and Aging Project, a longitudinal population-based study conducted in 3 contiguous neighborhoods on the south side of Chicago, IL. Participants were community-dwelling black and non-Hispanic white adults, aged 65 years and older (n=4120 for stroke mortality; n=2649 for incident stroke). Psychosocial distress was an analytically derived composite measure of depressive symptoms, perceived stress, neuroticism, and life dissatisfaction. Cox proportional hazards models examined the association of distress with stroke mortality and incident stroke over 6 years of follow-up. Stroke deaths (151) and 452 incident strokes were identified. Adjusting for age, race, and sex, the hazard ratio (HR) for each 1-SD increase in distress was 1.47 (95% confidence interval [CI]=1.28-1.70) for stroke mortality and 1.18 (95% CI=1.07-1.30) for incident stroke. Associations were reduced after adjustment for stroke risk factors and remained significant for stroke mortality (HR=1.29; 95% CI=1.10-1.52) but not for incident stroke (HR=1.09; 95% CI=0.98-1.21). Secondary analyses of stroke subtypes showed that distress was strongly related to incident hemorrhagic strokes (HR=1.70; 95% CI=1.28-2.25) but not ischemic strokes (HR=1.02; 95% CI=0.91-1.15) in fully adjusted models. Increasing levels of psychosocial distress are related to excess risk of both fatal and nonfatal stroke in older black and white adults. Additional research is needed to examine pathways linking psychosocial distress to cerebrovascular disease risk.


Effective cardiac radiotherapy relieved life-threatening heart failure caused by advanced small cell lung cancer with cardiac metastasis: a case report.
Cardiac radiotherapy is rarely used in clinical practice because of concern of adverse effects on the heart. We present a case of a 64-year-old man with advanced small cell lung cancer (SCLC) treated with chemo-radiotherapy who attained partial remission initially but had disease progression to bulky cardiac metastasis and significant pericardial effusion. Severe heart failure with hepatic failure was found. Chemotherapy and pericardiocentesis were contraindicated because of the associated high risk and bleeding tendency. Emergent palliative cardiac radiotherapy resulted in rapid improvements of dyspnea, liver function, and urine output. Pericardiocentesis was performed 5 days later and effusion cytology confirmed metastatic SCLC. To our knowledge, this is the first case of effective cardiac radiotherapy for SCLC with life-threatening cardiac metastasis. Palliative cardiac radiotherapy may be an effective alternative treatment for radiosensitive malignancy with cardiac metastasis in cases of multiple organ dysfunction and unsuitability for chemotherapy and pericardiocentesis.


A macrophage invasion mechanism of pathogenic mycobacteria.
Tuberculosis is the leading cause of death due to an infectious organism, killing an estimated 3 million people annually. Mycobacterium tuberculosis, the causative agent of tuberculosis, and other pathogenic mycobacteria require entry into host macrophages to initiate infection. An invasion mechanism was defined that was shared among pathogenic mycobacteria including M. tuberculosis, M. leprae, and M. avium but not by nonpathogenic mycobacteria or nonmycobacterial intramacrophage pathogens. This pathway required the association of the complement cleavage product C2a with mycobacteria resulting in the formation of a C3 convertase. The mycobacteria-associated C2a cleaved C3, resulting in C3b opsonization of the mycobacteria and recognition by macrophages.


Spatial attention and environmental information.
Navigating through our perceptual environment requires constant selection of behaviorally relevant information and irrelevant information. Spatial cues guide attention to information in the environment that is relevant to the current task. How does the amount of information provided by a location cue and irrelevant information influence the deployment of attention and what are the processes underlying this effect? To address these questions, we used a spatial cueing paradigm to measure the relationship between cue predictability (measured in bits of information) and the voluntary attention effect, the benefit in reaction time (RT) because of cueing a target. We found a linear relationship between cue predictability and the attention effect. To analyze the cognitive processes producing this effect, we used a simple RT model, the Linear Ballistic Accumulator model. We found that informative cues reduced the amount of evidence necessary to make a response (the threshold), regardless of the presence of irrelevant information (i.e., distractors). However, a change in the rate of evidence accumulation occurred when distractors were present in the display. Thus, the mechanisms underlying the deployment of attention are exquisitely tuned to the amount and behavioral relevancy of statistical information in the environment. (PsycINFO Database Record


GyrA ser83 and ParC trp106 Mutations in Salmonella enterica Serovar Typhi Isolated from Typhoid Fever Patients in Tertiary Care Hospital.
Typhoid fever is endemic in India and other developing countries, causing major public health problems with high morbidity and mortality. The resistance of Salmonella enterica serovar Typhi (S. Typhi) towards commonly prescribed antimicrobials is increasing in developing countries. However, there have been several reports of the therapeutic failure of fluoroquinolones in patients with Salmonella infection. Resistance to quinolones/ fluoroquinolones commonly arises due to target site mutation. The present study was planned to analyze mutation in Quinolone Resistance Determining Region (QRDR) of quinolone resistant Salmonella isolates. A total of 133 S. Typhi isolates (blood (n = 131), stool (n=1) and bone marrow aspirate (n=1)) from tertiary care hospitals in Chennai and Puducherry, were included in this study. Minimum Inhibitory Concentrations (MIC) were carried out according to the Clinical Laboratory Standard Institute (CLSI)guidelines 2014. Mutations in gyrA and parC genes were analyzed by PCR-RFLP (Restriction Fragment Length Polymorphism) method followed by DNA sequencing. Of the 133 S. Typhi, 99.2% were resistant to nalidixic acid and 21% were resistant to ciprofloxacin by MIC method. 94% of isolates showed Ser 83 mutation in gyrA and 21.8% of isolates showed Trp106-Gly mutation in parC. Mutations in gyrA and parC genes are highly prevalent among Salmonella species. Irrational use of fluoroquinolones may increase the accumulation of mutations in the DNA gyrase and topoisomerase encoding genes, which lead to the emergence of high level fluoroquinolone-resistant Salmonella strains in future.


Evaluation of the wound healing potentials of two subspecies of Hypericum perforatum on cultured NIH3T3 fibroblasts.
For centuries, Hypericum perforatum has been used in folk medicine to treat wounds. In the present study, the wound healing activities of extracts of H. perforatum ssp. perforatum (HPP) and H. perforatum ssp. veronense (HPV) were evaluated by comparing with a titrated extract of Centella asiatica (TECA) on NIH3T3 fibroblasts. The cells were incubated with the extracts. Using microscopical methods by staining cells, mitotic ability, morphological changes and collagen production in the fibroblasts were evaluated as parameters to approach possible wound repair mechanism(s). The wound healing activity caused an increase in the percentage of polygonal fibroblasts and in collagen granule numbers in fibroblasts of HPP and HPV. At 1 µg/mL, HPP caused a greater increase in mitotic cell numbers than HPV. The most increases in polygonal cell numbers were observed with HPV at 1 and 10 µg/mL. The number of collagen granules was increased with 1 µg/mL HPV being higher than HPP. As an indication of cytotoxic effects, round cells in response to HPV and HPP extracts, were found to be increased in concentrations higher than 10-50 µg/mL. The results indicated that the two subspecies of H. perforatum have different wound healing profiles as a result of the fibroblast migration and stimulation of collagen synthesis.


Selective Anchoring by Surface Sulfur Species Coupled with Rapid Interface Electron Transfer for Ultrahigh Capacity Extraction of Uranium from Seawater.
Improving the adsorption selectivity, enhancing the extraction capacity, and ensuring the structural stability of the adsorbent are the key to realize the high efficiency recovery of uranium. In this work, we utilized the strong Lewis acid-base interaction between S2- and U(VI)O22+ coupling rapid electron transfer at the MnS/U(VI)O22+ solid-liquid interface to achieve excellent selectivity, high adsorption capacity, and rapid extraction of uranium. The as-synthesized MnS adsorbent exhibited an ultrahigh uranium extraction capacity (2457.05 mg g-1) and a rapid rate constant (K = 9.11 × 10-4 g h-1 mg-1) in seawater with 100.7 ppm of UO2(NO3)2 electrolyte. The kinetic simulation reveals that this adsorption process is a chemical adsorption process and conforms to a pseudo-second-order kinetic model, indicating electron transfer at the MnS/U(VI)O22+ solid-liquid interface. The relevant (quasi) in situ spectroscopic characterization and theoretical calculation results further revealed that the outstanding uranium extraction property of MnS could be attributed to the highly selective UO22+ adsorption of MnS with lower adsorption energy as a result of the strong interaction between S2- and UO22+ and the rapid mass transfer and interface electron transfer from S2- and low-valent Mn(II) to U(VI)O22+.


Responses of microbial community from northern Gulf of Mexico sandy sediments following exposure to Deepwater Horizon crude oil.
In the present study, microbial community responses to exposure to unweathered Macondo Well crude oil and conventional diesel in a sandy beach environment were determined. Biodegradation was assessed in mesocosm experiments with differing fuel amounts (2,000 and 4,000 mg/kg) and with or without inorganic nutrient amendment. Carbon dioxide production was measured daily for 42 d. Aerobic alkane, total hydrocarbon, and polycyclic aromatic hydrocarbon (PAH) degraders were enumerated in treated and control mesocosms and changes in their abundances were measured weekly. Hydrocarbon mineralization occurred in all treatments. In the inorganic nutrient-amended treatments, the degradation rates were 2.31 and 2.00 times greater in the 2,000 mg/kg diesel and crude oil treatments, respectively, and 3.52 (diesel) and 4.14 (crude) times higher for the fuel types at the 4,000 mg/kg fuel concentrations compared to unamended treatments. Microbial lag phases were short (<3 d) and alkane and total hydrocarbon degrader numbers increased by five orders of magnitude compared to the uncontaminated treatments within 7 d in most treatments. Hydrocarbon degrader numbers in diesel and in crude oil treatments were similar; however, the PAH degraders were more abundant in the crude oil relative to diesel treatment. These findings indicate that hydrocarbon degradation by extant microbial populations in the northern Gulf of Mexico sandy beach environments can be stimulated and enhanced by inorganic nutrient addition.


Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.
A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 microM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.


Student leadership in interprofessional education: benefits, challenges and implications for educators, researchers and policymakers.
Context Interprofessional collaboration is gaining increasing prominence as a team-based approach to health care delivery that synergistically maximises the strengths of each health professional to enhance patient care, decrease medical errors and optimise efficiency. The often neglected role that student leaders have in preparing their peers, as the health professionals of the future, for collaboration in health care should not be overlooked. Objective This paper offers the foundational arguments supporting the integral role that student leadership in interprofessional education (IPE) can play and its comparative advantages. Methods Evidence from previous literature and the National Health Science Students' Association in Canada was reviewed and a questionnaire on student-initiated IPE was administered among Canada's top student leaders in this area. Results Student leadership is essential to the success of IPE because it enhances students' willingness to collaborate and facilitates the longterm sustainability of IPE efforts. Student-initiated IPE, a subset of student leadership, is particularly important to achieving the aforementioned goals and offers a number of benefits, comparative advantages and associated challenges. Conclusions Successful student leadership in IPE will yield significant benefits for everyone in the years to come. However, it requires the support of educators, researchers and policymakers in fostering an enabling environment that will facilitate the efforts and contributions of student leaders.


Racial/Ethnic Differences in the Association between Arrest and Unprotected Anal Sex among Young Men Who Have Sex with Men: The P18 Cohort Study.
This analysis aimed to determine whether the relationship between a history of arrest and unprotected anal sex (UAS) is the same for Black/Latino gay, bisexual, and other young men who have sex with men (YMSM) as compared to White/Asian/Pacific Islander (API) YMSM in New York City (NYC). Baseline audio-computer-assisted self-interview (ACASI) and interviewer-administered survey data from a sample of 576 YMSM aged 18-19 years old who self-reported being HIV-negative were analyzed. Data included history of arrest and incarceration as well as UAS in the past 30 days. Race/ethnicity was an effect modifier of the association between arrest and UAS among YMSM: White/API YMSM with a lifetime arrest history were more than three times as likely to report UAS, and Black/Latino YMSM with a lifetime history of arrest were approximately 70 % less likely to report UAS as compared with White/API YMSM with no reported arrest history. Race/ethnicity may modify the relationship between arrest and sexual risk behavior because the etiology of arrest differs by race, as partially evidenced by racial/ethnic disparities in police stop, arrest, and incarceration rates in NYC. Arrest could not only be an indicator of risky behavior for White/API YMSM but also an indicator of discrimination for Black/Latino YMSM. Further research is needed to assess whether the differential associations observed here vis-à-vis race/ethnicity are robust across different populations and different health outcomes.


The Dutch Heart Health Community Intervention 'Hartslag Limburg': effects on smoking behaviour.
A pretest-posttest control group design with two posttests was used to evaluate the effects of a regional Dutch Heart Health Community Intervention on smoking behaviour and its determinants. At baseline, a cohort research population of 1,200 smokers was recruited in the intervention region and in a control region. Data was gathered by means of short structured telephone interviews. No significant differences were found between the intervention region and the control region on smoking behaviour and its determinants. It is concluded that the regional intervention was unable to exceed secular trends in smoking cessation.


'Something for something': the importance of talking about transactional sex with youth in South Africa using a resilience-based approach.
Transactional sex is a common feature of sexual relationships in South Africa but has severe health implications for those who engage in it. This paper presents perspectives on transactional sex based on interviews and focus group discussions with young people in Gauteng and Limpopo, South Africa. The discussions were part of an evaluation of a peer education programme promoting HIV prevention called Vhutshilo, aimed at 14-16 year olds. The session on transactional sex entitled 'Something for Something' evoked strong responses from youth. Youth recognised transactional sex as a common phenomenon in their communities and associated it with many risks. However, when comparing young people's qualitative responses to the impact of the session as measured by the quantitative impact survey, no significant differences were discernible between youth in the programme and those in a control group who were not exposed to the session. Further analysis showed that the content of the session was limited to the negative consequences and health risks of transactional sex and focused mostly on the adverse contexts in South Africa that force youth into such relationships. The session did little to situate transactional relationships within the everyday realities of sexual decision making and youth values of peer status and consumerism. We argue that the session's findings reveal a narrow understanding of the dynamic contexts under which transactional sex occurs and fails to take into account the resilience of youth to make choices of whether or not to engage in such relationships, and how they can engage in these types of relationships safely. We conclude that HIV prevention curriculums need to leverage youth resilience and protective skills within the confines of difficult economic and social circumstances to allow them to successfully navigate safer sexual relationships.


Density-induced plant size reduction and size inequalities in ethylene-sensing and ethylene-insensitive tobacco.
Plant competition for light is a commonly occurring phenomenon in natural and agricultural vegetations. It is typically size-asymmetric, meaning that slightly larger individuals receive a disproportionate share of the light, leaving a limited amount of light for the initially smaller individuals. As a result, size inequalities of such stands increase with competition intensity. A plant's ability to respond morphologically to the presence of neighbour plants with enhanced shoot elongation, the so-called shade avoidance response, acts against the development of size inequalities. This has been shown experimentally with transgenic plants that cannot sense neighbours and, therefore, show no shade avoidance responses. Stands of such transgenic plants showed a much stronger development of size inequalities at high plant densities than did wild type (WT) stands. However, the transgenic plants used in these experiments displayed severely hampered growth rates and virtually no response to neighbours. In order to more precisely study the impact of this phenotypic plasticity on size inequality development, experiments required plants that have normal growth rates and reduced, but not absent, shade avoidance responses. We made use of an ethylene-insensitive, transgenic tobacco genotype (Tetr) that has wild type growth rates and moderately reduced shade avoidance responses to neighbours. Here, we show that the development of size inequalities in monocultures of these plants is not affected unambiguously different from wild type monocultures. Plots of Tetr plants developed higher inequalities for stem length than did WT, but monocultures of the two genotypes had identical CV (Coefficient of Variance) values for shoot biomass that increased with plant density. Therefore, even though reduced shade avoidance capacities led to the expected higher size inequalities for stem length, this does not necessarily lead to increased size inequalities for shoot biomass.


Relaunching the Policy and Management section.
Follow the money, the saying goes, and you will understand why things are the way they are. Serving as coeditors for Families, Systems, and Health's Policy and Management section, we seek to do just that. As new models of payment offer hope for improved delivery of integrated care for families, this newly relaunched section of the journal will highlight both the opportunities and the deeply rooted challenges in the evolving US payment system. While many of the challenges associated with integrated care payment are driven by public policy, others are driven by management and leadership decisions. We wish to explore both this year. Drawing on our combined experience in health care policy and management-nearly 70 years and counting-our aim is to offer readers timely, thoughtful, and promising insights into payment policy reforms and cost reduction opportunities that impact the spread and sustainability of integrated care. We invite your opinions, case studies, and research as we follow the money, and explore how to best pay for integrated care. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Quasi-cellular systems: stochastic simulation analysis at nanoscale range.
The wet-lab synthesis of the simplest forms of life (minimal cells) is a challenging aspect in modern synthetic biology. Quasi-cellular systems able to produce proteins directly from DNA can be obtained by encapsulating the cell-free transcription/translation system PURESYSTEM(PS) in liposomes. It is possible to detect the intra-vesicle protein production using DNA encoding for GFP and monitoring the fluorescence emission over time. The entrapment of solutes in small-volume liposomes is a fundamental open problem. Stochastic simulation is a valuable tool in the study of biochemical reaction at nanoscale range. QDC (Quick Direct-Method Controlled), a stochastic simulation software based on the well-known Gillespie's SSA algorithm, was used. A suitable model formally describing the PS reactions network was developed, to predict, from inner species concentrations (very difficult to measure in small-volumes), the resulting fluorescence signal (experimentally observable). Thanks to suitable features specific of QDC, we successfully formalized the dynamical coupling between the transcription and translation processes that occurs in the real PS, thus bypassing the concurrent-only environment of Gillespie's algorithm. Simulations were firstly performed for large liposomes (2.67µm of diameter) entrapping the PS to synthetize GFP. By varying the initial concentrations of the three main classes of molecules involved in the PS (DNA, enzymes, consumables), we were able to stochastically simulate the time-course of GFP-production. The sigmoid fit of the GFP-production curves allowed us to extract three quantitative parameters which are significantly dependent on the various initial states. Then we extended this study for small-volume liposomes (575 nm of diameter), where it is more complex to infer the intra-vesicle composition, due to the expected anomalous entrapment phenomena. We identified almost two extreme states that are forecasted to give rise to significantly different experimental observables. The present work is the first one describing in the detail the stochastic behavior of the PS. Thanks to our results, an experimental approach is now possible, aimed at recording the GFP production kinetics in very small micro-emulsion droplets or liposomes, and inferring, by using the simulation as a reverse-engineering procedure, the internal solutes distribution, and shed light on the still unknown forces driving the entrapment phenomenon.


Enhanced thermoelectric performance in ternary spinel Cu4Mn2Te4via the synergistic effect of tellurium deficiency and chlorine doping.
The chemistry of copper-based chalcogenides has received considerable attention due to their diverse structures and potential applications in the area of thermoelectric (TE) materials. In this communication, a series of spinel-type Cu4Mn2Te4-based samples have been successfully prepared and their high TE performances are attributed to the enhanced power factor and low thermal conductivity via the synergistic effect of Te deficiency and Cl doping. Consequently, a maximum TE figure of merit (ZT) of ∼0.4 was achieved for the Cu4Mn2Te3.93Cl0.03 sample at 700 K, which was about 100% enhanced in comparison with the undoped Cu4Mn2Te4 sample and one of the highest ZT values reported for p-type spinel tellurides.


Axonal transection in the lesions of multiple sclerosis.
Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system and is the most common cause of neurologic disability in young adults. Despite antiinflammatory or immunosuppressive therapy, most patients have progressive neurologic deterioration that may reflect axonal loss. We conducted pathological studies of brain tissues to define the changes in axons in patients with multiple sclerosis. Brain tissue was obtained at autopsy from 11 patients with multiple sclerosis and 4 subjects without brain disease. Fourteen active multiple-sclerosis lesions, 33 chronic active lesions, and samples of normal-appearing white matter were examined for demyelination, inflammation, and axonal pathologic changes by immunohistochemistry and confocal microscopy. Axonal transection, identified by the presence of terminal axonal ovoids, was detected in all 47 lesions and quantified in 18 lesions. Transected axons were a consistent feature of the lesions of multiple sclerosis, and their frequency was related to the degree of inflammation within the lesion. The number of transected axons per cubic millimeter of tissue averaged 11,236 in active lesions, 3138 at the hypocellular edges of chronic active lesions, 875 in the hypocellular centers of chronic active lesions, and less than 1 in normal-appearing white matter from the control brains. Transected axons are common in the lesions of multiple sclerosis, and axonal transection may be the pathologic correlate of the irreversible neurologic impairment in this disease.


Protein kinase C mediates the mitogenic action of thrombopoietin in c-Mpl-expressing UT-7 cells.
Protein kinase C (PKC) has been implicated in signal transduction events elicited by several hematopoietic growth factors. Thrombopoietin (TPO) is the major regulator of megakaryocytic lineage development, and its receptor, c-Mpl, transduces signals for the proliferation and differentiation of hematopoietic progenitors. In this study we have examined the effect of TPO on the subcellular distribution of PKC (a measure of enzyme activation) in a growth factor-dependent pluripotent hematopoietic cell line that was engineered to express the c-Mpl receptor (UT-7/mpl). In addition, we have assessed the significance of this activation for the induction of both mitogenesis and differentiation. Using a PKC translocation assay, TPO was found to stimulate a time- and dose-dependent increase in the total content of PKC activity present in the membrane fraction of UT-7/mpl cells (maximum increase = 2.3-fold above basal level after 15 minutes with 40 ng/mL TPO, EC50 = 7 ng/mL). Accordingly, a decrease of PKC content in the cytosolic fraction was observed. Immunoblot analysis using PKC isotype-specific antibodies showed that TPO treatment led to a marked increase of the Ca2+/diacylglycerol-sensitive PKC isoforms alpha and beta found in the membrane fraction. In contrast, the subcellular distribution of these isoforms did not change after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). Exposure of UT-7/mpl cells to the selective PKC inhibitor GF109203X completely inhibited the PKC activity associated to the membrane fraction after TPO treatment, and blocked the mitogenic effect of TPO. In contrast, GF109203X had no effect on the TPO-induced expression of GpIIb, a megakaryocytic differentiation antigen. Downregulation of PKC isoforms alpha and beta to less than 25% of their initial level by treatment with phorbol 12,13-dibutyrate also abolished the TPO-induced mitogenic response, but had no significant effect when this response was induced by GM-CSF. Taken together, these findings suggest that (1) TPO stimulates the activation of PKC, (2) PKC activation mediates the mitogenic action of TPO, and (3) PKC activation is not required for TPO-induced expression of megakaryocytic surface markers.


Zero-inflated generalized Dirichlet multinomial regression model for microbiome compositional data analysis.
There is heightened interest in using high-throughput sequencing technologies to quantify abundances of microbial taxa and linking the abundance to human diseases and traits. Proper modeling of multivariate taxon counts is essential to the power of detecting this association. Existing models are limited in handling excessive zero observations in taxon counts and in flexibly accommodating complex correlation structures and dispersion patterns among taxa. In this article, we develop a new probability distribution, zero-inflated generalized Dirichlet multinomial (ZIGDM), that overcomes these limitations in modeling multivariate taxon counts. Based on this distribution, we propose a ZIGDM regression model to link microbial abundances to covariates (e.g. disease status) and develop a fast expectation-maximization algorithm to efficiently estimate parameters in the model. The derived tests enable us to reveal rich patterns of variation in microbial compositions including differential mean and dispersion. The advantages of the proposed methods are demonstrated through simulation studies and an analysis of a gut microbiome dataset.


The effect of vitamin B12 on idiopathic tinnitus.
Tinnitus is one of the most important challenges in the field of ear, nose and throat diseases. The aim of this study was to evaluate the effect of vitamin B12 on idiopathic tinnitus. In this double-blind clinical trial study, 140 patients with idiopathic tinnitus were divided into two groups, the group receiving vitamin B12 and the group receiving placebo. The first group received vitamin B12 for a month and the other group received placebo. All patients filled a THI questionnaire before the participation, one month and three months after the participation. VAS evaluation questionnaires were also filled for the patients before the participation, one month and three months after the participation. The effect of vitamin B12 on tinnitus was also assessed according to hearing loss status. The two groups were also compared regarding the side effects. There was no significant differences between two groups regarding age (p.value = 0.523), gender (females (p.value = 0.810) and males (p.value = 0.789), and hearing loss status (p value = 0.651). According to VAS score, there was no significant statistical differences in tinnitus severity in each group (B12 group, p.value = 0.851 and placebo group, p.value = 0.386). There was no significant statistical differences in tinnitus severity based on VAS score between two groups before the participation (p.value = 0.560), one month (p.value = 0.485) and three months (p.value = 0.254) after the participation. According to THI criterion, there was no significant statistical differences in tinnitus severity in each group (B12 group, p.value = 0.259 and placebo group, p.value = 0.521). There was no significant statistical differences in tinnitus severity based on THI score between two groups before the participation (p.value = 0.651), one month (p.value = 0.125) and three months (p.value = 0.089) after the participation. None of the patients of the two groups had any noticeable side effects. The mean of VAS and THI also had no statistically significant difference before and after the intervention in term of hearing loss status (p.value>0.05). These results were not significantly different between the two groups in term of hearing loss status (p value>0.05). The result of this study indicated that vitamin B12 has no distinctive effect on reducing tinnitus severity.


Retinal function in best macular dystrophy: relationship between electrophysiological, psychophysical, and structural measures of damage.
To establish structure-function correlations across the visual field, to investigate disease progression in Best macular dystrophy (BMD), by correlating structural damage with retinal function as assessed by the combination of psychophysics and multifocal electrophysiology. Spatial achromatic and chromatic contrast sensitivities (probing red-green and blue-yellow pathways) were assessed using custom-made psychophysical software to evaluate retinal damage in BMD and age-matched control eyes (n = 19 and n = 22, respectively). Neurosensory retinal dysfunction was also evaluated by means of multifocal electroretinography (mfERG). Correlation analysis was performed between functional parameters in BMD, clinical measures, and morphologic data obtained by optical coherence tomography (OCT). Significant peripheral impairment of retinal function, as measured by mfERG and spatial achromatic contrast sensitivity (CS) methods, was found in BMD. Furthermore, changes in thickness of the neurosensory retina, as measured by OCT, and reduced mfERG responses were also indicators of early loss in BMD and often occurred even with preserved visual acuity. Disease duration was significantly correlated with psychophysical deterioration in chromatic and achromatic tasks but not with mfERG measures. Interestingly, partial correlation analysis revealed a significant independent correlation with our CS measures. Novel topographic achromatic and chromatic CS methods can detect and quantify functional impairment in early stages of BMD, including the involvement of the peripheral retina and the central chromatic pathway, and can provide new pathophysiological information with added value in relation to electrophysiological and structural measures of damage.


Dissipation and Dietary Risk Assessment of Pydiflumetofen Residues in Soybean.
In this study, the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method, combined with high-performance liquid chromatography−tandem mass spectrometry, was chosen for detecting pydiflumetofen residues in soybean plants, soybeans and soil, and assessing the risk of short- and long-term dietary intake. Pydiflumetofen concentrations ranging from 0.001−0.5 mg/L exhibited good linearity (r > 0.997). At varying doses, the average pydiflumetofen recovery rates and relative standard deviations among soybean plants, soybeans, and soil ranged from 83.9 ± 1.1% to 99.5 ± 3.3% and from 0.77 to 7.77%, respectively. The sensitivity, accuracy, and precision of the chosen methodology met the requirements of pesticide residue analysis. The results of the degradation dynamics test showed that the half-life of pydiflumetofen (t1/2) in soybean plants and in soil were 3.6 to 5.7 and from 7.9 to 25.7 d, respectively. Assessment of the concentration of pydiflumetofen residues in soybeans revealed acute and chronic dietary exposure risks of 0.06 and 7.54%, respectively. As these values are very low, pydiflumetofen residues in soybeans present an acceptable risk to public health. The results of this study will help to guide the practical application of pydiflumetofen and minimize the environmental risks associated with its use.


Modulation of murine in vitro erythroid and granulopoietic colony formation by ouabain, digoxin and theophylline.
Ouabain has been shown to increase the number of clonally derived erythroid stem cells, CFUE and BFUE, from normal murine bone marrow. We report here that digoxin and theophylline also enhance erythroid stem cell colony formation, in the presence of suboptimal concentrations of erythropoietin (Ep) (0.01 IU/ml) in methylcellulose culture. Both digoxin and theophylline increased CFUE colony formation optimally at 10(-8) M (29-81% respectively). The increase in BFUE colony formation occurred at 10(-10) M (35-76% respectively), suggesting that BFUE are more sensitive to the enhancing properties of these compounds. In addition, digoxin theophylline and ouabain were effective inhibitors of clonally derived granulocyte-macrophage progenitor cells, CFUC, from normal murine marrow plated in double layer agar in the presence of 10% L-cell conditioned medium (LCM). The degree of reduction in colony formation by CFUC ranged from 11% to 100%. Digoxin and theophylline were inhibitory for CFUC in the range of 10(-2) to 10(-12) M; however, ouabain was inhibitory over a broader concentration range of 10(-4) to 10(-18) M, suggesting that ouabain has a greater influence on committed hematopoietic progenitor cell colony formation. Both ouabain and digoxin have the property of binding to Na+/K+ATPase. This may mediate the alteration of hematopoietic differentiation. Theophylline, an adenyl cyclase inhibitor, may act through alterations in cyclic nucleotide levels. These studies further indicate that digoxin, theophylline and ouabain may serve as useful tools in elucidating the underlying mechanisms of how specific growth factors influence hematopoietic growth and differentiation.


Evidence for precipitation on Mars from dendritic valleys in the Valles Marineris area.
Dendritic valleys on the plateau and canyons of the Valles Marineris region were identified from Thermal Emission Imaging System (THEMIS) images taken by Mars Odyssey. The geomorphic characteristics of these valleys, especially their high degree of branching, favor formation by atmospheric precipitation. The presence of inner channels and the maturity of the branched networks indicate sustained fluid flows over geologically long periods of time. These fluvial landforms occur within the Late Hesperian units (about 2.9 to 3.4 billion years old), when Mars was thought to have been cold. Our results suggest a period of warmer conditions conducive to hydrological activity.


Association of Metformin With the Development of Age-Related Macular Degeneration.
Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD. To investigate the association between metformin use and age-related macular degeneration (AMD). The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. Prevalence of AMD in the treatment arms. Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02). These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.


New Direct-Acting Antiviral Therapies for Treatment of Chronic Hepatitis C Virus Infection.
The treatment of hepatitis C virus infection has been advancing at breakneck speeds over the past few years. This article provides an update on the newest drugs available and those currently in development, including newer-generation protease inhibitors, RNA-dependent RNA polymerase, and nonstructural component inhibitors. Also discussed in this article are the regimens developed and the genotypes they target. Treatment of cirrhotic patients and patients who have failed prior therapy is also addressed, as are special populations, such as patients with harder-to-treat genotypes, patients with HIV coinfection, patients who have undergone liver transplantation, and patients with chronic kidney disease. Future developments and economic considerations are also mentioned.


Mixed-affinity binding in humans with 18-kDa translocator protein ligands.
11C-PBR28 PET can detect the 18-kDa translocator protein (TSPO) expressed within macrophages. However, quantitative evaluation of the signal in brain tissue from donors with multiple sclerosis (MS) shows that PBR28 binds the TSPO with high affinity (binding affinity [Ki], ∼4 nM), low affinity (Ki, ∼200 nM), or mixed affinity (2 sites with Ki, ∼4 nM and ∼300 nM). Our study tested whether similar binding behavior could be detected in brain tissue from donors with no history of neurologic disease, with TSPO-binding PET ligands other than 11C-PBR28, for TSPO present in peripheral blood, and with human brain PET data acquired in vivo with 11C-PBR28. The affinity of TSPO ligands was measured in the human brain postmortem from donors with a history of MS (n=13), donors without any history of neurologic disease (n=20), and in platelets from healthy volunteers (n=13). Binding potential estimates from thirty-five 11C-PBR28 PET scans from an independent sample of healthy volunteers were analyzed using a gaussian mixture model. Three binding affinity patterns were found in brains from subjects without neurologic disease in similar proportions to those reported previously from studies of MS brains. TSPO ligands showed substantial differences in affinity between subjects classified as high-affinity binders (HABs) and low-affinity binders (LABs). Differences in affinity between HABs and LABs are approximately 50-fold with PBR28, approximately 17-fold with PBR06, and approximately 4-fold with DAA1106, DPA713, and PBR111. Where differences in affinity between HABs and LABs were low (∼4-fold), distinct affinities were not resolvable in binding curves for mixed-affinity binders (MABs), which appeared to express 1 class of sites with an affinity approximately equal to the mean of those for HABs and LABs. Mixed-affinity binding was detected in platelets from an independent sample (HAB, 69%; MAB, 31%), although LABs were not detected. Analysis of 11C-PBR28 PET data was not inconsistent with the existence of distinct subpopulations of HABs, MABs, and LABs. With the exception of 11C-PK11195, all TSPO PET ligands in current clinical application recognize HABs, LABs, and MABs in brain tissue in vitro. Knowledge of subjects' binding patterns will be required to accurately quantify TSPO expression in vivo using PET.


Fibrinogen binding is affected by amino acid substitutions in C-terminal repeat region of fibronectin binding protein A.
Fibronectin-binding protein A (FnBPA), a protein displayed on the outer surface of Staphylococcus aureus, has a structured A-domain that binds fibrinogen (Fg) and a disordered repeat-region that binds fibronectin (Fn). Amino acid substitutions in Fn-binding repeats (FnBRs) have previously been linked to cardiovascular infection in humans. Here we used microtiter and atomic force microscopy (AFM) to investigate adhesion by variants of full-length FnBPA covalently anchored in the outer cell wall of Lactococcus lactis, a Gram-positive surrogate that otherwise lacks adhesins to mammalian ligands. Fn adhesion increased in five of seven FnBPA variants under static conditions. The bond targeting Fn increased its strength with load under mechanical dissociation. Substitutions extended bond lifetime (1/koff) up to 2.1 times for FnBPA-Fn. Weaker adhesion was observed for Fg in all FnBPA variants tested with microtiter. However, mechanical dissociation with AFM showed significantly increased tensile strength for Fg interacting with the E652D/H782Q variant. This is consistent with a force-induced mechanism and suggests that the dock, lock, and latch (DLL) mechanism is favored for Fg-binding under mechanical stress. Collectively, these experiments reveal that FnBPA exhibits bimodal, ligand-dependent adhesive behavior. Amino acid substitutions in the repeat-region of FnBPA impact binding to both ligands. This was unexpected for Fg since all variants have the same A-domain sequence, and the Fg-binding site is distant from the repeat region. This indicates that FnBRs may fold back on the A-domain in a way that impacts the DLL binding mechanism for Fg.


[Intensification of neurogenic spasms of the cerebral vessels by naloxone].
Naloxone was shown to induce a slight increase of the blood supply to the brain, an elevation of blood pressure and an enhancement of the bioelectrical activity in the sympathetic nerves. Unlike opioid peptides, naloxone was found to exert a marked alleviating effect on the nervous control of the cerebral circulation. The drug increases neurogenic spasms of the cerebral vessels that is followed by an enhancement of vasomotor and somatosympathetic reflexes. The data obtained indicate the role of the opioid system in the central regulation of the cerebral circulation.


A narrative review on tumor microenvironment in oligometastatic and oligoprogressive non-small cell lung cancer: a lot remains to be done.
In this review, we aim to collect and discuss available data about the role and composition of tumor microenvironment (TME) in oligometastatic (OMD) and oligoprogressive (OPD) non-small cell lung cancer (NSCLC). Furthermore, we aim to summarize the ongoing clinical trials evaluating as exploratory objective the TME composition, through tissue and/or blood samples, in order to clarify whether TME and its components could explain, at least partially, the oligometastatic/oligoprogressive process and could unravel the existence of predictive and/or prognostic factors for local ablative therapy (LAT). OMD/OPD NSCLC represent a heterogeneous group of diseases. Several data have shown that TME plays an important role in tumor progression and therefore in treatment response. The crucial role of several types of cells and molecules such as immune cells, cytokines, integrins, protease and adhesion molecules, tumor-associated macrophages (TAMs) and mesenchymal stem cells (MSCs) has been widely established. Due to the peculiar activation of specific pathways and expression of adhesion molecules, metastatic cells seem to show a tropism for specific anatomic sites (the so-called "seed and soil" hypothesis). Based on this theory, metastases appear as a biologically driven process rather than a random release of cancer cells. Although the role and the function of TME at the time of progression in patients with NSCLC treated with tyrosine-kinase inhibitors and immune checkpoint inhibitors (ICIs) have been investigated, limited data about the role and the biological meaning of TME are available in the specific OMD/OPD setting. Through a comprehensive PubMed and ClinicalTrials.gov search, we identified available and ongoing studies exploring the role of TME in oligometastatic/oligoprogressive NSCLC. Deepening the knowledge on TME composition and function in OMD/OPD may provide innovative implications in terms of both prognosis and prediction of outcome in particular from local treatments, paving the way for future investigations of personalized approaches in both advanced and early disease settings.


Serotonin-related tryptophan in children with insulin-dependent diabetes.
In the course of the present research in school children with insulin-dependent diabetes mellitus, we observed that the free fraction of L-tryptophan, the free fraction of L-tryptophan/total L-tryptophan, and the free fraction of L-tryptophan/neutral amino acids ratios, are significantly reduced. The decrease of free fraction of L-tryptophan in plasma with a concomitant decrease of the free fraction of L-tryptophan/neutral amino acids ratio suggest a decrease in the transport of the precursor amino acid to the brain and in the serotonin synthesis rate, similar to that observed in diabetic animals. This finding may be of relevance in the pathophysiology and in the clinical picture, which could be related to an alteration of serotonin metabolism and neurotransmission in the brain and may be possibly related to neuropsychiatric disorders in diabetic school children. Thus we propose that the free fraction of L-tryptophan and the free fraction of L-tryptophan/neutral amino acids ratios may be clinically useful as indicators of brain serotonergic activity in these patients. In our laboratory, we are currently obtaining additional data on the functional role of the brain serotonergic system in humans to further support the relevance of our results.


Recreational cannabis: Profile of cannabinoids present in marijuana samples supplied by the consuming population.
As cannabis/marijuana is one of the most consumed psychoactive substances in the world, knowing the composition and type of cannabis sold in urban environments is a necessary input for the design of public health policies based on scientific evidence. This study characterized the main phytocannabinoids of marijuana samples (cigarettes or buds) obtained in urban and rural areas of the city of Medellín in October 2021. Non-probabilistic convenience sampling was carried out in which 87 marijuana samples donated by consumers were collected at different collection points throughout the city, and gas chromatography-mass spectrometry and flame ionization techniques were employed for the characterization of phytocannabinoids. Tetrahydrocannabinol (THC) was found to be the main constituent of circulating marijuana in Medellín, where 67.8% of the samples had a high or higher toxicological range for THC; the foregoing in a context where the deregulated market in practice limits the possibility that consumers have to calibrate or decide the concentration of cannabinoids in their doses.