Cardiovascular MR imaging at 3 T: opportunities, challenges, and solutions.
Although 3-T magnetic resonance (MR) imaging is well established in neuroradiology and musculoskeletal imaging, it is in the nascent stages in cardiovascular imaging applications, and there is limited literature on this topic. The primary advantage of 3 T over 1.5 T is a higher signal-to-noise ratio (SNR), which can be used as such or traded off to improve spatial or temporal resolution and decrease acquisition time. However, the actual gain in SNR is limited by other factors and modifications in sequences adapted for use at 3 T. Higher resonance frequencies result in improved spectral resolution, which is beneficial for fat suppression and spectroscopy. The higher T1 values of tissues at 3 T aid in myocardial tagging, angiography, and perfusion and delayed-enhancement sequences. However, there are substantial challenges with 3-T cardiac MR imaging, including higher magnetic field and radiofrequency inhomogeneities and susceptibility effects, which diminish image quality. Off-resonance artifacts are particularly challenging, especially with steady-state free precession sequences. These artifacts can be managed by using higher-order shimming, frequency scouts, or low repetition times. B1 inhomogeneities can be managed by using radiofrequency shimming, multitransmit coils, or adiabatic pulses. Chemical shifts are also increased at 3 T. The higher radiofrequency results in higher radiofrequency deposition power and a higher specific absorption rate. MR angiography, dynamic first-pass perfusion sequences, myocardial tagging, and MR spectroscopy are more effective at 3 T, whereas delayed-enhancement, flow quantification, and black-blood sequences are comparable at 1.5 T and 3 T. Knowledge of the relevant physics helps in identifying artifacts and modifying sequences to optimize image quality. Online supplemental material is available for this article.


Coronaviridae and SARS-associated coronavirus strain HSR1.
During the recent severe acute respiratory (SARS) outbreak, the etiologic agent was identified as a new coronavirus (CoV). We have isolated a SARS-associated CoV (SARS-CoV) strain by injecting Vero cells with a sputum specimen from an Italian patient affected by a severe pneumonia; the patient traveled from Vietnam to Italy in March 2003. Ultrastructural analysis of infected Vero cells showed the virions within cell vesicles and around the cell membrane. The full-length viral genome sequence was similar to those derived from the Hong-Kong Hotel M isolate. By using both real-time reverse transcription-polymerase chain reaction TaqMan assay and an infectivity plaque assay, we determined that approximately 360 viral genomes were required to generate a PFU. In addition, heparin (100 microg/mL) inhibited infection of Vero cells by 50%. Overall, the molecular and biologic characteristics of the strain HSR1 provide evidence that SARS-CoV forms a fourth genetic coronavirus group with distinct genomic and biologic features.


Application of a Regenstrief RELMA V.6.6 to Map Russian Laboratory Terms to LOINC.
Manual mapping of laboratory data to Logical Observation Identifiers Names and Codes (LOINC) requires a major effort. Application of the LOINC mapping assistant RELMA V.6.6 can reduce the effort required for mapping. The goal of the paper is to perform a semi-automated mapping of Russian laboratory terms to LOINC. A semi-automated mapping of the 2563 terms from two clinics in Russia was performed. The first step was automatic mapping using RELMA V.6.6 and LOINC V.2.48 Russian translation by Yaroslavl state medical academy. The second step was a manual expert mapping. To evaluate the correctness of mapping all the mapped terms were reviewed by two experts. The paper presents the results of semi-automatic mapping of Russian laboratory terms to LOINC. Two clinics (A and B) and a laboratory service participated in the project. The following results were achieved: mapping of 86% terms from Clinic A and 87% from Clinic B. It has to be mentioned that 99% of terms used in 2014 were mapped. In total 2398 out of 2563 were mapped. The required effort was reasonable and the price of mapping and maintenance was considered as relatively low in comparison to manual methods. RELMA V.6.6 and LOINC V.2.48 offer the opportunity of a low effort LOINC mapping even for non-English languages. The study proved that the mapping effort is acceptable and mapping results are on the same level as the manual mapping.


Association Between MTHFR C677T Polymorphism and Congenital Heart Disease.
Many published studies have evaluated the association between the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) polymorphism and the risk of congenital heart disease (CHD); however, the specific conclusion is still controversial.To get a more accurate conclusion, we used a meta-analysis to evaluate the association between the MTHFR gene C677T polymorphism and the risk of CHD.Based on the design-based search strategy, a comprehensive literature search was conducted on PubMed, OVID, Cochrane Library, Embase, Wanfang, CNKI, and Web of Science. We selected the Newcastle-Ottawa Scale (NOS) to assess the quality of the included studies. We performed a heterogeneity test on the results of the study and calculated the combined odds ratios (ORs) and its corresponding 95% confidence intervals (95% CIs) under a random- or fixed-effect model. Subgroup analyses were conducted by ethnicity, source of controls, sample size, and genotyping method. Sensitivity analysis was used to insure authenticity of this meta-analysis result. Egger's test and Begg's funnel plot were performed to detect publication bias.Eventually, our meta-analysis included 15 eligible studies. We observed a significant correlation between the MTHFR C677T polymorphism and the development of CHD in the recessive model (OR: 1.35, 95% CI: 1.06-1.71, P = 0.006) for the overall population. In subgroups stratified by ethnicity and source of controls, subgroup analyses indicated similar associations in Asians and hospital-based groups, but not for Caucasians and population-based groups. Egger's test and Begg's funnel plot demonstrated no significant publication bias in our study.Our analysis identified that MTHFR C677T allele is a risk genetic for CHD development, especially in Asians compared with Caucasians.


Advances in novel drug delivery strategies for breast cancer therapy.
Breast cancer remains one of the world's most devastating diseases. However, better understanding of tumor biology and improved diagnostic devices could lead to improved therapeutic outcomes. Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Various nanocarriers have been introduced to improve the therapeutic efficacy of anticancer drugs, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. Recently, targeted drug delivery systems for anti-tumor drugs have demonstrated great potential to lower cytotoxicity and increase therapeutic effects. Various ligands/approaches have been explored for targeting breast cancer. This paper provides an overview of breast cancer, conventional therapy, potential of nanotechnology in management of breast cancer, and rational approaches for targeting breast cancer.


Dual interaction of JAM-C with JAM-B and alpha(M)beta2 integrin: function in junctional complexes and leukocyte adhesion.
The junctional adhesion molecules (JAMs) have been recently described as interendothelial junctional molecules and as integrin ligands. Here we show that JAM-B and JAM-C undergo heterophilic interaction in cell-cell contacts and that JAM-C is recruited and stabilized in junctional complexes by JAM-B. In addition, soluble JAM-B dissociates soluble JAM-C homodimers to form JAM-B/JAM-C heterodimers. This suggests that the affinity of JAM-C monomers to form dimers is higher for JAM-B than for JAM-C. Using antibodies against JAM-C, the formation of JAM-B/JAM-C heterodimers can be abolished. This liberates JAM-C from its vascular binding partner JAM-B and makes it available on the apical side of vessels for interaction with its leukocyte counter-receptor alpha(M)beta2 integrin. We demonstrate that the modulation of JAM-C localization in junctional complexes is a new regulatory mechanism for alpha(M)beta2-dependent adhesion of leukocytes.


Inhibition of Heat-Stable Toxin-Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors.
Many enterotoxigenic Escherichia coli strains produce the heat-stable toxin, STa, which, by activation of the intestinal receptor-enzyme guanylyl cyclase (GC) C, triggers an acute, watery diarrhea. We set out to identify GCC inhibitors that may be of benefit for the treatment of infectious diarrheal disease. Compounds that inhibit STa-induced cyclic guanosine 3',5'-monophosphate (cGMP) production were selected by performing cyclase assays on cells and membranes containing GCC, or the related GCA. The effect of leads on STa/GCC-dependent activation of the cystic fibrosis transmembrane conductance regulator anion channel was investigated in T84 cells, and in porcine and human intestinal tissue. Their effect on STa-provoked fluid transport was assessed in ligated intestinal loops in piglets. Four N-2-(propylamino)-6-phenylpyrimidin-4-one-substituted piperidines were shown to inhibit GCC-mediated cellular cGMP production. The half maximal inhibitory concentrations were ≤ 5 × 10(-7) mol/L, whereas they were >10 times higher for GCA. In T84 monolayers, these leads blocked STa/GCC-dependent, but not forskolin/adenylyl cyclase-dependent, cystic fibrosis transmembrane conductance regulator activity. GCC inhibition reduced STa-provoked anion secretion in pig jejunal tissue, and fluid retention and cGMP levels in STa-exposed loops. These GCC inhibitors blocked STa-provoked anion secretion in rectal biopsy specimens. We have identified a novel class of GCC inhibitors that may form the basis for development of future therapeutics for (infectious) diarrheal disease.


Formation of immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes.
Elevated levels of advanced glycosylation end products (AGEs) have been found in multiple tissues in association with diabetic vascular complications and during the microalbuminuric phase of diabetic nephropathy. In this study, we have used an AGE-specific enzyme-linked immunosorbent assay (ELISA) to measure skin AGEs to determine whether elevated levels can be detected before the onset of overt microangiopathy. Subjects with type I diabetes (n = 48) were graded for the degree of nephropathy (normal [23], microalbuminuria [12], or macroalbuminuria [12]) and retinopathy (none [13], background [20], or proliferative [15]). Subgroups with a premicroalbuminuric phase of albumin excretion (< or = 28 mg/24 h, n = 27) or with the earliest stages of retinopathy (n = 27) were identified. A significant increase in tissue AGEs was found as urinary albumin increased during the premicroalbuminuric phase of nephropathy even when the data were adjusted for age and duration of diabetes (P = 0.005). Immunoreactive AGEs also increased as normal renal status advanced to microalbuminuria and macroalbuminuria (P = 0.0001 across groups). Significant elevation of AGEs was also found in association with the earliest stages of clinically evident retinopathy (early background versus minimal grades). In addition, higher AGE levels were found in subjects with proliferative retinopathy when compared with those with less severe retinopathy (P < 0.004 across groups). In contrast, no significant differences were found in tissue AGE levels between groups with or without early retinopathy based on pentosidine or fluorescent AGE measurements, although fluorescent AGEs correlated with albumin excretion.(ABSTRACT TRUNCATED AT 250 WORDS)


Transcriptional mapping of a DNA replication gene cluster in bacteriophage T4. Sites for initiation, termination, and mRNA processing.
A phage T4 genetic cluster that encodes DNA polymerase, several other DNA replication proteins, transcriptional factors, and the translation repressor RegA has been shown to be controlled by overlapping modes of transcription which initiate at several promoters. The promoters were mapped by using a combination of assays including Northern blotting, S1-mapping, RNA sequencing, and analysis of products of radioactive labeling of 5' ends on T4-induced RNA in vitro via the reaction catalyzed by eukaryotic guanylyl transferase (RNA capping assay). The most proximal in the cluster are two promoters that do not require any phage-induced factors for activation, i.e. they are T4 early promoters. Initiation at these promoters yields several RNA species having overlapping 5'-terminal sequences, the largest of which is estimated to be about 15,000 nucleotides long and to include all the cistrons of the cluster. A third early promoter maps inside the protein encoding segment of one of the cistrons (T4 gene 47), while at least five additional promoters map in intercistronic regions and are T4 middle promoters, i.e. they require the T4-induced DNA-binding transcription factor MotA. Transcriptional readthrough at a termination site within the T4 gene 45-44 intercistronic region is required for synthesis of gp44 and gp62, two essential T4 DNA-polymerase (gp43) accessory proteins. In contrast, transcription of T4 gene 43 is serviced by readthrough across a termination site in the regA-43 intercistronic region as well as by a MotA-dependent promoter that maps downstream of the termination site, and the region contains a site for processing by a T4-induced enzyme that also cleaves elsewhere in the polycistronic mRNA from the cluster (i.e. in the Shine-Dalgarno sequence of the gene 45.2 mRNA). The termination events in the gene 45-44 and regA-43 intercistronic regions both occur downstream of RNA stem-loop structures containing the sequence 5'CUUCGG3' in the loop segments. Transcription termination in the 78-base-pair regA-43 intercistronic region occurs about 60 nucleotides away from the gp43 initiator AUG, transcription initiation occurs at 38-40 nucleotides upstream from the AUG, and T4-dependent RNA processing occurs at several sites (including a GGAG sequence) between the transcription termination and initiation sites. Thus, all gp43-encoding mRNAs contain the translational operator (residues -40 to -1 relative to the AUG) for autogenous repression by this DNA polymerase (Andrake et al., 1988).(ABSTRACT TRUNCATED AT 400 WORDS)


Is color vision deficiency an advantage under scotopic conditions?
To examine experimentally whether color vision deficiency confers a selective advantage under scotopic conditions. Red-green color-deficient subjects, monochromats, and age-matched color-normal control subjects were examined. In each subject the time course of dark adaptation, scotopic visual field sensitivity, and performance on a scotopic perceptual task were measured. No significant differences were found between red-green color-deficient subjects and control subjects on any of the three tests. Our small sample of monochromats had higher absolute thresholds than the corresponding control subjects, but their performance at the scotopic visual field test and perceptual task did not differ significantly from that of color-normal subjects. No evidence was found that red-green color deficiency or monochromatism confers a selective advantage under scotopic conditions.


Relationships between work-related factors and disorders in the neck-shoulder and low-back region among female and male ambulance personnel.
This cross-sectional study on a random sample of 1,500 ambulance personnel investigated the relationships between self-reported work-related physical and psychosocial factors, worry about work conditions, and musculoskeletal disorders among female and male ambulance personnel. Three different outcomes, complaints, activity limitation, and sick leave, for the neck-shoulder and low-back region, respectively, were chosen. Among the female personnel, physical demands was significantly associated with activity limitation in the neck-shoulder (OR 4.13) and low-back region (OR 2.17), and psychological demands with neck-shoulder (OR 2.37) and low-back (OR 2.28) complaints. Among the male personnel, physical demands was significantly associated with low-back complaints (OR 1.41) and activity limitation (OR 1.62). Psychological demands and lack of social support were significantly associated with neck-shoulder complaints (OR 1.86 and OR 1.58, respectively) and activity limitation (OR 3.46 and OR 1.71) as well as activity limitation due to low-back complaints (OR 2.22 and OR 1.63). Worry about work conditions was independently associated with activity limitation due to low-back complaints among the female (OR 5.28), and to both neck-shoulder and low-back complaints (OR 1.79 and OR 2.04, respectively) and activity limitation (OR 2.32 and OR 1.95) among the male personnel. In conclusion, the association patterns between physical and psychological demands and MSDs suggest opportunities for intervention.


Thyroid neoplasia in captive raccoons (Procyon lotor).
Two adult, spayed, female raccoons were diagnosed with thyroid neoplasia. One raccoon had a palpable, left-sided, nonfunctional thyroid adenocarcinoma which was treated with a thyroidectomy twice with local recurrence both times. After the second recurrence, pulmonary metastases were identified. A third thyroidectomy was performed, and a vascular access port was placed for administration of intravenous doxorubicin. The raccoon developed pancytopenia and became anorexic after chemotherapy, and the owner elected humane euthanasia. The second raccoon had nonpalpable, bilateral, functional follicular thyroid adenomatous hyperplasia and was treated with a right thyroidectomy and a partial left thyroidectomy, leaving behind the grossly normal portion of the left thyroid. However, the animal was still hyperthyroid after surgery and was then successfully managed with topical methimazole gel. Thyroid pathology has been documented in raccoons in Europe, but is not reported in the United States. Thyroid neoplasia in raccoons can occur as a nonfunctional adenocarcinoma, as is commonly reported in dogs, or as a functional adenoma, as is commonly reported in cats. Raccoons with adenocarcinomas should be evaluated for pulmonary metastasis. Methimazole gel may be a viable treatment option for raccoons with hyperthyroidism.


Intrinsic deviations in fluorescence yield detected x-ray absorption spectroscopy: the case of the transition metal L₂,₃ edges.
Fluorescence yield (FY) detected x-ray absorption spectra (XAS) of 3d transition metal ions are calculated from the integrated 2p3d resonant x-ray emission spectra. The resulting FY-XAS spectra are compared with the normal XAS spectra corresponding to the absorption cross section and significant deviations between the two spectra are found. This implies that the assumption that the FY-XAS spectrum identifies with the XAS spectrum is disproved. Especially for the early transition metal systems the differences between the FY-XAS and XAS are large, due to the opening of inelastic decay channels from selected x-ray absorption final states. The theoretical calculations show that the difference between FY detection and XAS is largest for the detection in depolarized geometry. The calculations are compared with experimental spectra for oxides and coordination compounds for Fe(2+), Co(2+) and Ni(2+) systems. The implications for the sum rules in XAS and magnetic circular dichroism experiments are discussed.


Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance.
Saquinavir is a widely used HIV-1 protease inhibitor drug for AIDS therapy. Its effectiveness, however, has been hindered by the emergence of resistant mutations, a common problem for inhibitor drugs that target HIV-1 viral enzymes. Three HIV-1 protease mutant species, G48V, L90M, and G48V/L90M double mutant, are associated in vivo with saquinavir resistance by the enzyme (Jacobsen et al., 1996). Kinetic studies on these mutants demonstrate a 13.5-, 3-, and 419-fold increase in Ki values, respectively, compared to the wild-type enzyme (Ermolieff J, Lin X, Tang J, 1997, Biochemistry 36:12364-12370). To gain an understanding of how these mutations modulate inhibitor binding, we have solved the HIV-1 protease crystal structure of the G48V/L90M double mutant in complex with saquinavir at 2.6 A resolution. This mutant complex is compared with that of the wild-type enzyme bound to the same inhibitor (Krohn A, Redshaw S, Richie JC, Graves BJ, Hatada MH, 1991, J Med Chem 34:3340-3342). Our analysis shows that to accommodate a valine side chain at position 48, the inhibitor moves away from the protease, resulting in the formation of larger gaps between the inhibitor P3 subsite and the flap region of the enzyme. Other subsites also demonstrate reduced inhibitor interaction due to an overall change of inhibitor conformation. The new methionine side chain at position 90 has van der Waals interactions with main-chain atoms of the active site residues resulting in a decrease in the volume and the structural flexibility of S1/S1' substrate binding pockets. Indirect interactions between the mutant methionine side chain and the substrate scissile bond or the isostere part of the inhibitor may differ from those of the wild-type enzyme and therefore may facilitate catalysis by the resistant mutant.


Induced fit and "lock and key" recognition of 5S RNA by zinc fingers of transcription factor IIIA.
Transcription factor IIIA (TFIIIA) is a Cys2His2 zinc finger protein that regulates expression of the 5 S ribosomal RNA gene by binding specifically to the internal control element. TFIIIA also functions in transport and storage of 5 S RNA by binding directly to the RNA transcript. To obtain insights into the mechanism by which TFIIIA recognizes 5 S RNA, we determined the solution structure of the middle three zinc fingers bound to the central core of 5 S RNA. Finger 4 utilizes "lock and key" recognition to bind in the widened major groove of the pre-structured RNA loop E motif. This interaction is mediated by direct hydrogen bonding interactions with bases. In contrast, recognition of loop A, a flexible junction of three helices, occurs by an induced fit mechanism that involves reorganization of the conserved CAUA motif and structuring of the finger 5-finger 6 interface to form a complementary RNA binding surface.


Rotator cuff calcific tendinopathy: from diagnosis to treatment.
Rotator cuff calcific tendinopathy (RCCT) is a very common condition caused by the presence of calcific deposits in the rotator cuff (RC) or in the subacromial-subdeltoid (SASD) bursa when calcification spreads around the tendons. The pathogenetic mechanism of RCCT is still unclear. It seems to be related to cell-mediated disease in which metaplastic transformation of tenocytes into chondrocytes induces calcification inside the tendon of the RC. RCCT is a frequent finding in the RC that may cause significant shoulder pain and disability. It can be easily diagnosed with imaging studies as conventional radiography (CR) or ultrasound (US). Conservative management of RCCT usually involves rest, physical therapy, and oral NSAIDs administration. Imaging-guided treatments are currently considered minimally-invasive, yet effective methods to treat RCCT with about 80% success rate. Surgery remains the most invasive treatment option in chronic cases that fail to improve with other less invasive approaches.


Detection and quantification of SARS-CoV-2 by droplet digital PCR in real-time PCR negative nasopharyngeal swabs from suspected COVID-19 patients.
Since SARS-CoV-2-based disease (COVID-19) spreads as a pandemic, the necessity of a highly sensitive molecular diagnosis that can drastically reduce false negatives reverse transcription PCR (rtPCR) results, raises as a major clinical need. Here we evaluated the performance of a ddPCR-based assay to quantify SARS-CoV-2 titer in 55 suspected COVID-19 cases with negative rtPCR results thanks to in-house ddPCR assay (targeting RdRp and host RNaseP). Samples were collected at ASST-GOM Niguarda between February and May 2020 at hospital admission. Clinical and imaging data were obtained for clinical staging and definition of disease severity. Patients were mainly female (45.5%) with a median age of 73 (57-84) years. ddPCR-based assay detected SARS-CoV-2 genome in nasopharyngeal samples of 19 (34.5%) patients (median viral-load: 128 copies/mL, IQR: 72-345). In 15 of them (78.9%), chest CT showed a classical COVID-19 bilateral interstitial pneumonia; 14 patients (73.7%) showed severe COVID-19 manifestations. ddPCR did not identify any trace of SARS-CoV-2 genome in the respiratory samples of the remaining 36 patients. The serological assay performed in a subgroup of 34 patients at the later stage of illness (from 3 days to 90 days after) confirmed the presence of SARS-CoV-2 antibodies in all patients tested positive for SARS-CoV-2 in ddPCR (100%). Contrariwise, negative tests were observed in 95.0% ddPCR negative patients (P<0.001). Thanks to a ddPCR-based assay, we achieved a rapid and accurate SARS-CoV-2 diagnosis in rtPCR-negative respiratory samples of individuals with COVID-19 suspect, allowing the rapid taking care and correct management of these patients.


Bayesian models of cognition revisited: Setting optimality aside and letting data drive psychological theory.
Recent debates in the psychological literature have raised questions about the assumptions that underpin Bayesian models of cognition and what inferences they license about human cognition. In this paper we revisit this topic, arguing that there are 2 qualitatively different ways in which a Bayesian model could be constructed. The most common approach uses a Bayesian model as a normative standard upon which to license a claim about optimality. In the alternative approach, a descriptive Bayesian model need not correspond to any claim that the underlying cognition is optimal or rational, and is used solely as a tool for instantiating a substantive psychological theory. We present 3 case studies in which these 2 perspectives lead to different computational models and license different conclusions about human cognition. We demonstrate how the descriptive Bayesian approach can be used to answer different sorts of questions than the optimal approach, especially when combined with principled tools for model evaluation and model selection. More generally we argue for the importance of making a clear distinction between the 2 perspectives. Considerable confusion results when descriptive models and optimal models are conflated, and if Bayesians are to avoid contributing to this confusion it is important to avoid making normative claims when none are intended. (PsycINFO Database Record


Primary relationships, HIV treatment adherence, and virologic control.
To identify factors associated with antiretroviral therapy (ART) adherence and virologic control among HIV-positive men on ART in primary relationships, data were collected from 210 male couples (420 men). Dyadic actor-partner analyses investigated associations with three levels of adherence-related dependent variables: self-efficacy (ASE), self-reported adherence, and virologic control. Results indicated that higher patient ASE was related to his own positive beliefs about medications, higher relationship autonomy and intimacy, and fewer depressive symptoms. Fewer depressive symptoms and less relationship satisfaction in the partner were linked to higher ASE in the patient. Better self-reported adherence was related to the patient's positive appraisal of the relationship and the partner's positive treatment efficacy beliefs. Greater medication concerns of both patient and partner were associated with less adherence. The partner's higher relationship commitment was associated with lower viral load in the patient. Findings suggest that depressive symptoms, treatment beliefs, and relationship quality factors of both partners may influence adherence-related outcomes.


Integrative Review of the Relationship Between Sleep Disturbances and Episodic Memory in Older Adults.
Impaired episodic memory in older adults has been linked to many factors. One of these factors is sleep disturbances, which are reported by more than 50% of older adults. The relationship between episodic memory and sleep disturbances remains unclear, however, because of the multiple types of measures of sleep and episodic memory used in previous studies. The purpose of this integrative literature review was to integrate and compare findings on this relationship in adults aged 65 years. An electronic search was conducted in PubMed, Cumulative Index to Nursing and Allied Health Literature, PsychINFO, and Medline for material published from the inception of the databases to December 2016. The literature search produced 13 data-based, peer-reviewed, and primary research articles that met eligibility criteria. The synthesized results from these articles provide evidence that older adults with 6-8 hr of self-reported total sleep time had better episodic memory than older adults with ≤5 hr or ≥9 hr of total sleep time. Shorter length and lower percentage of slow-wave sleep were associated with reduced episodic memory in older adults, but the results were controversial. Selection of different measurements and inconsistent variables across studies increased the difficulty of synthesizing and comparing the results. The diversity of covariates controlled in the included articles raise questions regarding which covariates should be controlled in such studies of sleep and episodic memory in older adults. The numerous study limitations were thus major barriers to understanding the relationship between sleep disturbances and episodic memory.


Destruction of the securin Pds1p occurs at the onset of anaphase during both meiotic divisions in yeast.
Sister chromatid cohesion is established during DNA replication and depends on a multiprotein complex called cohesin. At the onset of anaphase the cohesive structures that hold sisters together must be destroyed to allow segregation of sisters. In the budding yeast Saccharomyces cerevisiae loss of sister chromatid cohesion depends on a separating protein (separin) called Esp1. At the metaphase to anaphase transition, separin is activated by proteolysis of its inhibitory subunit (securin) called Pds1. This process is mediated by the anaphase promoting complex and an accessory protein Cdc20. In meiosis a single round of DNA replication is followed by two successive rounds of segregation. Thus loss of cohesion is spun out over two divisions. By studying the mechanisms that initiate anaphase in meiotic division we show that the yeast securin Pds1p is present in meiotic nuclei and is destroyed at the onset of each meiotic division. We also show that securin destruction depends on Cdc20p which accumulates within nuclei around the time of Pds1p's disappearance.


Type IV secretion systems: tools of bacterial horizontal gene transfer and virulence.
Type IV secretion systems (T4SSs) are multisubunit cell-envelope-spanning structures, ancestrally related to bacterial conjugation machines, which transfer proteins and nucleoprotein complexes across membranes. T4SSs mediate horizontal gene transfer, thus contributing to genome plasticity and the evolution of pathogens through dissemination of antibiotic resistance and virulence genes. Moreover, T4SSs are also used for the delivery of bacterial effector proteins across the bacterial membrane and the plasmatic membrane of eukaryotic host cell, thus contributing directly to pathogenicity. T4SSs are usually encoded by multiple genes organized into a single functional unit. Based on a number of features, the organization of genetic determinants, shared homologies and evolutionary relationships, T4SSs have been divided into several groups. Type F and P (type IVA) T4SSs resembling the archetypal VirB/VirD4 system of Agrobacterium tumefaciens are considered to be the paradigm of type IV secretion, while type I (type IVB) T4SSs are found in intracellular bacterial pathogens, Legionella pneumophila and Coxiella burnetii. Several novel T4SSs have been identified recently and their functions await investigation. The most recently described GI type T4SSs play a key role in the horizontal transfer of a wide variety of genomic islands derived from a broad spectrum of bacterial strains.


Unusual splenic B-cell lymphoma in two related Sumatran tigers (Panthera tigris sumatrae).
A 14-year-old 120-kg (264-lb) sexually intact male Sumatran tiger (Panthera tigris sumatrae) and its 10-year-old 130-kg (286-lb) sexually intact male offspring were housed separately and evaluated independently after experiencing weeks of ongoing malaise, weight loss, and anorexia. Both animals were immobilized and anesthetized for physical examinations and diagnostic testing. Complete blood counts revealed leukopenia and anemia in both tigers. Splenomegaly was identified on abdominal ultrasonography. Cytologic examination and immunohistochemical staining of splenic samples confirmed intermediate to large B-cell lymphoma; no evidence of lymphoma in surrounding organs was noted. The sire was treated with lomustine and prednisolone. This tiger was euthanized 21 months after initiation of treatment because of chronic progressive renal disease. The male offspring was treated with l-asparaginase but did not respond to the treatment. A splenectomy was performed, and malaise and anorexia resolved. No further chemotherapy was administered, and the male offspring was instead maintained on a low dose of prednisolone. Thirty-two months after diagnosis, the male offspring was still considered to be in remission. To our knowledge, this was the first known report of the diagnosis and management of a splenic B-cell lymphoma in a tiger. Both tigers achieved positive clinical responses and long-term survival by means of different treatment modalities. The finding of such an unusual neoplasm in a male tiger and its male offspring was noteworthy, raising the possibility of a genetic predisposition for this lymphoma type.


Novel superconducting structures of BH2 under high pressure.
The crystal structures of boron hydrides in a pressure range of 50-400 GPa were studied using the genetic algorithm (GA) method combined with first-principles density functional theory calculations. BH4 and BH5 are predicted to be thermodynamically unstable. Two new BH2 structures with Cmcm and C2/c space group symmetries, respectively, were predicted, in which the B atoms tend to form two-dimensional sheets. The calculated band structures showed that in the pressure range of 50-150 GPa, the Cmcm-BH2 phase has very small gaps, while the C2/c-BH2 phase at 200-400 GPa is metallic. The superconductivity of the C2/c-BH2 structure was also investigated, and electron-phonon coupling calculations revealed that the estimated Tc values of C2/c-BH2 are about 28.18-37.31 K at 250 GPa.


Evaluation of Vineyard Weeds as Potential Hosts of Black-Foot and Petri Disease Pathogens.
Weeds were sampled in grapevine rootstock mother fields, open-root field nurseries, and commercial vineyards of Albacete, Alicante, Castellón, Murcia, and Valencia provinces in Spain between June 2009 and June 2010 and evaluated as potential hosts of black-foot and Petri disease pathogens. Isolations were conducted in the root system and internal xylem tissues for black-foot and Petri disease pathogens, respectively. Cylindrocarpon macrodidymum was successfully isolated from the roots of 15 of 19 weed families evaluated and 26 of 52 weed species. Regarding Petri disease pathogens, one isolate of Phaeomoniella chlamydospora was obtained from Convolvulus arvensis, and three isolates of Cadophora luteo-olivacea were obtained from Bidens subalternans, Plantago coronopus, and Sonchus oleraceus. Pathogenicity tests showed that Cylindrocarpon macrodidymum isolates obtained from weeds were able to induce typical black-foot disease symptoms. When inoculated in grapevines, isolates of Cadophora luteo-olivacea and Phaeomoniella chlamydospora were also shown to be pathogenic on grapevine cuttings. Our ability to recover grapevine pathogens from vineyard weeds and to demonstrate pathogenicity of recovered strains on grape suggests that these weeds may serve as a source of inoculum for infection of grapevine.


Multimodal morphometry and functional magnetic resonance imaging in schizophrenia and auditory hallucinations.
To validate a multimodal [structural and functional magnetic resonance (MR)] approach as coincidence brain clusters are hypothesized to correlate with clinical severity of auditory hallucinations. Twenty-two patients meeting Diagnostic and Statistical Manual of Mental Disorders (fourth edition, DSM-IV) criteria for schizophrenia and experiencing persistent hallucinations together with 28 healthy controls were evaluated with structural and functional MR imaging with an auditory paradigm designed to replicate those emotions related to the patients' hallucinatory experiences. Coincidence maps were obtained by combining structural maps of gray matter reduction with emotional functional increased activation. Abnormal areas were correlated with the brief psychiatric rating scale (BPRS) and the psychotic symptom rating scale (PSYRATS) scales. The coincidence analysis showed areas with coexistence gray matter reductions and emotional activation in bilateral middle temporal and superior temporal gyri. Significant negative correlations between BPRS and PSYRATS scales were observed. BPRS scores were negatively correlated in the middle temporal gyrus (right) (t = 6.86, P = 0.001), while negative PSYRATS correlation affected regions in both the superior temporal gyrus (left) (t = 7.85, P = 0.001) and middle temporal gyrus (left) (t = 4.97, P = 0.002). Our data identify left superior and middle temporal gyri as relevant areas for the understanding of auditory hallucinations in schizophrenia. The use of multimodal approaches, sharing structural and functional information, may demonstrate areas specifically linked to the severity of auditory hallucinations.


Expanded treatment of hepatic tumors with radiofrequency ablation and cryoablation.
Three definitive treatment options are available for patients with hepatic tumors: hepatic resection, tumor ablation, and hepatic transplantation. Ablative techniques--including radiofrequency ablation (RFA) and cryoablation--have greatly improved physicians' ability to definitively treat patients with primary and secondary hepatic tumors. Both RFA and cryoablation are safe and well-tolerated, but the effectiveness for local tumor eradication depends on many factors, including tumor size, location, number, and type. The choice of ablation modality is based on user and institutional biases. Assessing outcome after ablation is difficult because few studies with good long-term follow-up have evaluated local recurrence, disease-free survival, and overall survival after ablation. This and other limitations make it difficult to draw meaningful conclusions.


Mg2+-dependent electrical control of flagellar activity in Euglena.
When a Euglena gracilis in a Ca2+-containing medium is impaled with a microelectrode, the flagellum is instantly ejected. In a Ca2+-free medium to which 1 mM EGTA has been added, the flagellum remains attached to the organism, but it loses activity upon impalement. Externally added ATP at a concentration of 10 mM will sustain normal flagellar activity (at approximately 20 Hz) of an impaled Euglena. If negative direct current of several tenths of a microamp is injected through the impaling microelectrode, the flagellar activity is stopped or much reduced. When the current injection is turned off the flagellum returns to its initial activity. This cycle can be repeated many times on the same animal, independent of whether Mg2+ is present in the external medium or not. If 1 micrometer of gramicidin is added to Ca2+-free medium containing 1 mM EGTA and 10 mM ATP, the flagellar activity becomes dependent on external Mg2+. Without external Mg2+ no flagellar activity is present after one or two current injection cycles as described above. With 1 mM Mg2+ present in the external medium many cycles (up to 10) can be produced. This Mg2+-dependent flagellar activity shows a smooth dependence on the amount of current injected. Observations taken by high speed cinemicrography show that in the third injection cycle the average frequency of the flagellar motion is 16-3 Hz at 0 muA, is 8 Hz at 0-2 muA, and is approximately 0 at 0-6 muA of negative current. The injection of positive current results in an increase in flagellar frequency dependent on the amount of current injected. The data indicate that the control of motility of Euglena flagella is dependent on an electrically activated Mg2+ pump.


Specific IgE responses in human strongyloidiasis.
IgE antibodies directed against Strongyloides stercoralis larval antigens were measured by a newly developed radioallergosorbant test (RAST). One hundred and fifty-two samples of sera from patients with parasitologically proven S. stercoralis infection were tested. One hundred and thirty-six of these (89.5%) were positive for parasite-specific IgE. Of 50 presumably non-infected North American adult control sera, 49 (98%) were negative. All sera from patients with other parasites were negative, except for two sera from subjects with Ascaris lumbricoides, who exhibited low positivity. Of eight sera from non-infected patients with allergies and high IgE levels, one was weakly positive, and the other seven were negative. Considerable individual variability was present in the levels of specific IgE as measured by the RAST in the infected patients. Significant differences were also found among the three major demographic groups which composed our study population, with Asians having higher values than Latin Americans and the latter having higher values than North American patients. We conclude that the majority of patients with strongyloidiasis develop IgE antibodies directed against antigens from filariform larvae, the invasive form of the parasite. While the functional significance of this response remains to be defined, the RAST for IgE may be a useful adjunct in the immunological evaluation of these patients.


Low contrast vision function predicts subsequent acuity loss in an aged population: the SKI study.
Can vision tests predict subsequent loss of acuity? The association between performance on several low contrast spatial vision measures, glare recovery, color discrimination, flicker sensitivity, stereopsis and ocular disease status at baseline and acuity loss 4.4 years later was examined in a large aged random sample with good initial acuity. In univariate analyses, several vision measures, retinal disease status and age were each significant predictors of subsequent acuity loss. In a multiple regression analysis, only low contrast spatial vision was a significant predictor, but the other vision measures, retinal disease status and age were not. For each doubling of low contrast spatial vision threshold at baseline, individuals were more than two times as likely to suffer subsequent significant visual acuity loss. Tests of low contrast spatial vision are strong predictors of significant subsequent visual acuity loss. These findings have implications for clinical trials, clinical management, and acceptance of these measures into clinical practice.


An aspartate residue in the extracellular loop of the N-methyl-D-aspartate receptor controls sensitivity to spermine and protons.
To study the role of acidic residues in modulation of NMDA receptors by spermine, we used site-directed mutagenesis of receptor subunits and voltage-clamp recording in Xenopus oocytes. Sixteen glutamate and aspartate residues, located in the first two thirds of the putative extracellular loop of the NR1A subunit, were individually mutated. This region of NR1A shows homology with bacterial amino acid binding proteins, a bacterial polyamine binding protein, and a bacterial spermidine acetyltransferase. Mutation of D669 to asparagine (D669N), alanine (D669A), or glutamate (D669E) abolished the "glycine-independent" form of spermine stimulation in heteromeric NR1A/NR2B receptors. These mutations also markedly reduced inhibition by ifenprodil and by protons at NR1A/NR2B receptors. Mutations at the equivalent position (D690) in NR1B, which contains the insert encoded by exon 5, reduced the pH sensitivity of NR1B/NR2B receptors. Thus, the effects of mutations at D669 are not prevented by the presence of exon 5, and the influence of exon 5 is not prevented by mutations at D669 (D690 in NR1B). Mutations at NR1A (D669) had little or no effect on the potencies of glutamate and glycine and did not alter voltage-dependent block by Mg2+ or the "glycine-dependent" form of spermine stimulation. Surprisingly, the D669N and D669A mutations, but not the D669E mutation, reduced voltage-dependent block by spermine at NR1A/NR2 receptors. Mutations in NR2B at a position (D668) equivalent to D669 did not alter spermine stimulation or sensitivity to pH and ifenprodil. However, mutations D668N and D668A but not D668E in NR2B reduced voltage-dependent block by spermine. Screening of the negative charges at NR1A(D669) and NR2B(D668) may be involved in voltage-dependent block by spermine. D669 in NR1A could form part of a binding site for polyamines and ifenprodil and/or part of the proton sensor of the NMDA receptor. Alternatively, this residue may be critical for coupling of modulators such as spermine, protons, and ifenprodil to channel gating.


LPIN2 is associated with type 2 diabetes, glucose metabolism, and body composition.
To identify the type 2 diabetes gene located at chromosome 18p11. We investigated the region in a young genetically isolated population by genotyping 34 single nucleotide polymorphisms (SNPs) in 78 case subjects and 101 control subjects. Two SNPs were selected and followed up in two cohorts. The first cohort came from a general Dutch population. In this cohort, association with type 2 diabetes was investigated using 616 type 2 diabetic case subjects and 2,890 control subjects; association with oral glucose tolerance test data was performed in 361 normoglycemic people. Association with fat distribution was studied in the second replication cohort, consisting of 836 people from the genetically isolated population. At the initial step, we found that the common C allele of SNP rs3745012 was associated with type 2 diabetes (odds ratio 2.01, P = 0.03). This SNP is located at the 3' untranslated region of the LPIN2 gene, which is a plausible candidate for type 2 diabetes and obesity. In the cohort from the general Dutch population, we demonstrated that rs3745012 interacts with BMI in determination of type 2 diabetes: whereas in subjects with high BMI, the common C allele is associated with type 2 diabetes, the same allele exhibits a neutral or protective effect in lean subjects (P = 0.05 overall effect, P = 0.02 interaction). Most remarkably, rs3745012 strongly affected composite insulin sensitivity index (P = 0.006 for overall effect, P = 0.004 for interaction). In the second replication cohort, we found that the allele C of rs3745012 increases trunk-to-legs fat mass ratio (P = 0.001) and may affect other fat-related measurements. rs3745012 SNP of the LPIN2 gene is associated with type 2 diabetes and fat distribution.


Characterization of commercial Sacha inchi oil according to its composition: tocopherols, fatty acids, sterols, triterpene and aliphatic alcohols.
Sacha inchi oil (SIO) is one of the largest vegetable oil exports in Peru, used for consumption, in the food industry, cosmetics, and pharmaceuticals; it represents a significant economic income for producers. This study addresses the characterization and quantification of fatty acids, tocopherols, sterols, and alcohols of commercial Sacha inchi oils from Peru. Some of the SIO samples received had a high substance consistency, while others differed in the compounds studied. The results showed that some of the commercialized oils present high levels of γ-tocopherol and δ-tocopherol, while other samples had variable fatty acid compositions; especially in α-linolenic, linoleic, oleic and palmitic acids. Fourteen sterols and eleven alcohols were identified (β-sitosterol, stigmasterol, campesterol, Δ5-avenasterol, triterpene alcohol, lanosterol isomer 1 and cycloartenol) being the major components. Some SIO samples presented the following ratios: The δ-tocopherol/γ-tocopherol ratio was 0.33-0.81, ω-6/ω-3 ratio was 0.77 and a stigmasterol/campesterol ratio of 3.13. The presence of brassicasterol in some commercial oils indicates the addition of rapeseed or canola oil. Tocopherols, fatty acids, sterols and alcohol data provided a classification of SIO samples, by an efficient k-means clustering algorithm analysis. The ANOVA found significant differences between clusters for palmitic acid, oleic acid, γ-tocopherol, δ-tocopherol, campesterol and stigmasterol; these compounds could be used as markers of authenticity in commercial Sacha inchi oils.


Self-reported use of complementary and alternative medicine (CAM) products in topical treatment of diabetic foot disorders by diabetic patients in Jeddah, Western Saudi Arabia.
There is little published on current Saudi diabetic patients' practices when they are exposed to foot disorders such as open wound, ulcer, and skin cracks. These factors are usually influenced by local culture and communities beliefs. The aim of the current study was to identify the pattern of patients' use of CAM products in dealing with diabetic foot disorders topically in a group of diabetic patients. A Cross-sectional descriptive study of a representative cohort of diabetic patients living in Jeddah, Saudi Arabia was designed. A pre-designed questionnaire to identify local diabetics' practices in dealing topically with foot disorders including open wound, chronic ulcer, and skin cracks was designed. Questionnaire was administered by a group of trained nutrition female students to diabetics face to face living in their neighborhood. A total of 1634 Saudi diabetics were interviewed. Foot disorders occurred in approximately two thirds of the respondents 1006 (61.6%). Out of the 1006 patients who had foot disorders, 653 reported trying some sort of treatment as 307 patients (47.1%) used conventional topical medical treatment alone, 142 (21.7%) used CAM products alone, and 204 (31.2%) used both treatments. The most commonly used CAM product by the patients was Honey (56.6%) followed by Commiphora Molmol (Myrrh) in (37.4%) and Nigellia Sativa (Black seed) in (35.1%). The least to be used was Lawsonia inermis (Henna) in (12.1%). Ten common natural preparations used topically to treat diabetic foot disorders were also identified. The use of CAM products in topical treatment of diabetic foot disorders is fairly common among Saudi diabetic patients. Honey headed the list as a solo topical preparation or in combination with other herbs namely black seeds and myrrh. The efficacy of the most common products needs further research.


[Differences between adipose-derived stem cells and mesenchymal stem cells in differentiation into cardiomyocytes].
Adipose-derived stem cells (ASCs) are similar to bone marrow mesenchymal stem cells (MSCs) in growth kinetics, antigen expression and multi-lineage differentiation capacity. The present study was designed to investigate the differences between ASCs and MSCs in in vitro culture and differentiation into cardiomyocytes. ASCs were isolated from the fat tissue of New Zealand white rabbits while MSCs were obtained from rat bone marrow. Both ASCs and MSCs were cultured in Iscove's modified Dulbecco's medium supplemented with 15% fetal bovine serum in the same incubator and treated with various concentrations of 5-azacytidine. A clonogenic assay was used to quantify ASCs in fat tissue and MSCs in bone marrow. The number of ASCs in the fat tissue was much higher than that of MSCs in the bone marrow quantified by clonogenic assay, and MSCs showed a remarkably slower proliferative rate compared with ASCs, especially at primary passage. ASCs began to attach to the bottom of the culture flask 12 h after seeding. The cells in culture assumed a short spindle shape under a phase-contrast microscope and did not form clusters. The phenotype was maintained through repeated subcultures under nonstimulating conditions. No other cell phenotype was observed. MSCs attached to the culture flask at 24-48 h after seeding and grew in clusters. The cells were fibroblast-like and prone to senescence or differentiation into adipose cells. Both ASCs and MSCs before treatment with 5-azacytidine were stained positively for CD29, CD44 and CD105 but negatively for CD34 and CD45, α-sarcromeric actin, cardiac troponin T and von Willebrand factor. ASCs differentiated into cardiomyocytes only after treatment with 6-9 μmol/L of 5-azacytidine, while MSCs differentiated into cardiomyocytes with 3-15 μmol/L of 5-azacytidine. After treatment with ideal dose of 5-azacytidine, ASCs began to change their morphology and showed multinucleation within the first week and formed a ball-like appearance thereafter, while MSCs showed multinucleation at the second week and formed a stick-like appearance at 3-4 weeks. The percentage of ASCs differentiated into cardiomyocytes after treatment with 5-azacytidine was significantly higher than that of MSCs. The age of animal had no significant influence on the tissue content, proliferation and differentiation rate of ASCs. However, the tissue content of MSCs in bone marrow decreased with increased age of animal and MSCs from old donor rats exhibited less myogenic cells than those from the young rats after exposure to 5-azacytidine. These results indicate that ASCs have advantages over MSCs in tissue content, homology, growth and differentiation rate, suggesting that ASCs are more suitable for cellular cardiomyoplasty than MSCs.


BMP9 Induces Cord Blood-Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1.
Modulating endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis, and thus various clinical trials involving EPCs are ongoing. However, the identification of environmental conditions and development of optimal methods are required to accelerate EPC-driven vasculogenesis. We evaluated gene expression profiles of cord blood-derived EPCs and endothelial cells to identify the key factors in EPC→endothelial cell differentiation and to show that transforming growth factor-β family members contribute to EPC differentiation. The expression levels of activin receptor-like kinase 1 (ALK1) and its high-affinity ligand, bone morphogenetic protein 9 (BMP9) were markedly changed in EPC→endothelial cell differentiation. Interestingly, BMP9 induced EPC→endothelial cell differentiation and EPC incorporation into vessel-like structures by acting on ALK1 expressed on EPCs in vitro. BMP9 also induced neovascularization in mice with hindlimb ischemia by increasing vessel formation and the incorporation of EPCs into vessels. Conversely, neovascularization was impaired when ALK1 signaling was blocked. Furthermore, EPCs exposed to either short- or long-term BMP9 stimulation demonstrated these functions in EPC-mediated neovascularization. Collectively, our results indicated that BMP9/ALK1 augmented vasculogenesis and angiogenesis, and thereby enhanced neovascularization. Thus, we suggest that BMP9/ALK1 may improve the efficacy of EPC-based therapies for treating ischemic diseases.


Ketone body transport in the human neonate and infant.
Using a continuous intravenous infusion of D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3 +/- 1.4 mumol kg-1 min-1 in the neonates, a value not different from that of 20.6 +/- 0.9 mumol kg-1 min-1 measured in the older infants. This rate was accelerated to 32.2 mumol kg-1 min-1 in the diabetic and slowed to 5.0 mumol kg-1 min-1 in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased. Compared with the adult, however, ketone body turnover rates of 12.8-21.9 mumol kg-1 min-1 in newborns fasted for less than 8 h, and rates of 17.9-26.0 mumol kg-1 min-1 in older infants fasted for less than 10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate's basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans.


Imidodiphosphonate Ligands for Enhanced Sensitization and Shielding of Visible and Near-Infrared Lanthanides.
The design of coordination sites around lanthanide ions has a strong impact on the sensitization of their luminescent signal. An imidodiphosphonate anionic binding site is attractive as it can be functionalized with "remote" sensitizer units, such as phenoxy moieties, namely, HtpOp, accompanied by an increased distance of the lanthanide from the ligand high-energy stretching vibrations which quench the luminescence signal, hence providing flexible shielding of the lanthanide. We report the formation and isolation of Ln(tpOp)3 complexes where Ln = Er, Gd, Tb, Dy, Eu, and Yb and the Y(tpOp)3 diamagnetic analogue. The complexes are formed from reaction of KtpOp and the corresponding LnCl3·6H2O salt either by titration and in situ formation or by mixing and isolation. All complexes are seven-coordinated by three tpOp ligand plus one ethanol molecule, except for Yb(tpOp)3 which has no solvent coordinated. Phosphorus NMR shows characteristic shifts to support the coordination of the lanthanide complexes. The complexes display visible and near-infrared luminescence with long lifetimes even for the near-infrared complexes which range from 3.3 μs for Nd(tpOp)3 to 20 μs for Yb(tpOp)3. The ligand shows more efficient sensitization than the imidodiphosphinate analogues for all lanthanide complexes with a notable quantum yield of the Tb(tpOp)3 complex at 45%. We attribute this to the properties of the remote sensitizer unit and its positioning further away from the lanthanide, eliminating quenching of high energy C-H vibrations from the ligand shell. Calculations of the ligand shielding support the photophysical properties of the complexes. These results suggest that these binding sites are promising in the further development of the lanthanide complexes in optoelectronic devices for telecommunications and new light emitting materials.


Effects of Acute Active Video Games on Endothelial Function Following a High-Fat Meal in Overweight Adolescents.
We tested the hypothesis that an active video game following a high-fat meal would partially prevent the unfavorable effect of a high-fat meal on vascular function in overweight adolescents. Twenty-four overweight adolescents were randomized to either a 60-minute active video game (AVG) group (n = 12) or seated rest (SR) as a control group (n = 12) after a high-fat meal. Blood parameters were measured, and vascular function was measured using brachial artery flow-mediated dilation (FMD) at baseline and 3 hours after a high-fat meal. No significant interaction was found in any blood parameter. A high-fat meal significantly increased blood triglyceride and glucose concentrations in both groups in a similar manner. Brachial artery FMD significantly decreased in the SR group (13.8 ± 3.2% to 11.8 ± 2.5), but increased in the AVG group (11.4 ± 4.0% to 13.3 ± 3.5), with a significant interaction (P = .034). These findings show that an active video game attenuated high-fat meal-induced endothelial dysfunction. This suggests that an active video game may have a cardioprotective effect on endothelial function in overweight adolescents when exposed to a high-fat meal.


Liver-brain proinflammatory signalling in acute liver failure: role in the pathogenesis of hepatic encephalopathy and brain edema.
A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood-brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.


Good test--retest reliability for standard and advanced false-belief tasks across a wide range of abilities.
Although tests of young children's understanding of mind have had a remarkable impact upon developmental and clinical psychological research over the past 20 years, very little is known about their reliability. Indeed, the only existing study of test-retest reliability suggests unacceptably poor results for first-order false-belief tasks (Mayes, Klin, Tercyak, Cicchetti, & Cohen, 1996), although this may in part reflect the nonstandard (video-based) procedures adopted by these authors. The present study had four major aims. The first was to re-examine the reliability of false-belief tasks, using more standard (puppet and storybook) procedures. The second was to assess whether the test-retest reliability of false-belief task performance is equivalent for children of contrasting ability levels. The third aim was to explore whether adopting an aggregate approach improves the reliability with which children's early mental-state awareness can be measured. The fourth aim was to examine for the first time the test-retest reliability of children's performances on more advanced theory-of-mind tasks. Our results suggest that most standard and advanced false-belief tasks do in fact show good test-retest reliability and internal consistency, with very strong test-retest correlations between aggregate scores for children of all levels of ability.


A PET study of visuospatial attention.
Positron emission tomography (PET) was used to identify the neural systems involved in shifting spatial attention to visual stimuli in the left or right visual field along foveofugal or foveocentric directions. Psychophysical evidence indicated that stimuli at validly cued locations were responded to faster than stimuli at invalidly cued locations. Reaction times to invalid probes were faster when they were presented in the same than in the opposite direction of an ongoing attention movement. PET evidence indicated that superior parietal and superior frontal cortex were more active when attention was shifted to peripheral locations than when maintained at the center of gaze. Both regions encoded the visual field and not the direction of an attention shift. In the right superior parietal lobe, two distinct responses were localized for attention to left and right visual field. Finally, the superior parietal region was active when peripheral locations were selected on the basis of cognitive or sensory cues independent of the execution of an overt response. The frontal region was active only when responses were made to stimuli at selected peripheral locations. These findings indicate that parietal and frontal regions control different aspects of spatial selection. The functional asymmetry in superior parietal cortex may be relevant for the pathophysiology of unilateral neglect.


Piloting a new model of crisis counseling: specialized crisis counseling services in Mississippi after Hurricane Katrina.
During January-April 2007, Project Recovery, a federally funded crisis counseling program implemented by Mississippi's Department of Mental Health, piloted a new model of Specialized Crisis Counseling Services (SCCS) on the Mississippi Gulf Coast. In this team-based approach, a masters-level counselor trained in a variety of intervention techniques and a resource coordinator worked together with persons whose needs were relatively intense. Compared to regular program (RCCS) participants over the same interval (n = 29,522), SCCS participants (n = 281) were more likely to be female, middle-aged, and at greater risk for severe distress. In a participant survey conducted in both programs over the same week, SCCS participants reported significantly greater benefit than did RCCS participants. A subset of 129 SCCS participants provided pre- and post-participation assessments and showed large improvements in disaster-related distress.


Heat shock protein 70 acts as a potential biomarker for early diagnosis of heart failure.
Early identification for heart failure (HF) may be useful for disease modifying treatment in order to reduce heart disease progression or even to reverse it. In our previous studies, we have revealed a group of heat shock proteins (HSPs) which might be related to neonatal rat cardiomyocyte hypertrophy by proteomic approach. Here, we confirm that HSPs, including HSP27 and HSP70, altered in the early stage of cardiac remodeling in vivo animal model. Furthermore, plasma concentrations of those HSPs and their potential screening value were evaluated at different stages in 222 patient subjects. Plasma HSP27, HSP70 and HSP90 were measured using enzyme-linked immunosorbent assay. Results indicate that HSP70 was positively correlated to the severity (progression) of HF (r = 0.456, p<0.001). The area under the rate of change (ROC) curve was 0.601 (p = 0.017) in patients with stage B HF and 0.835 (p<0.001) in those with stage C HF. However, HSP27 and HSP90 did not display significant changes in any stage of HF in this study. Taken together, plasma concentrations of HSP70 elevated with the progression of HF and might act as a potential screening biomarker for early diagnosis of HF.


Interaction of two optical beams at a symmetric random surface.

Recently it was shown that the incoherent part of light scattered from random surfaces with even profiles displays a well-defined peak in the specular direction. This effect has been termed specular enhancement.

Here we present an experimental and theoretical study of the scattering of two coherent optical beams from a symmetric random surface. It is found that, in addition to the two sharp peaks corresponding to the enhancements in the specular directions, there is a third peak that is due to the interaction of the two optical beams at the surface.


Heart rate variability spectral analysis in patients with panic disorder compared with healthy controls.
The aim of our study is to measure very low frequency band (VLF), low frequency band (LF) and high frequency band (HF) components of R-R interval during orthostatic test in patients with panic disorder and a comparison with healthy controls. We measured HRV in 31 patients with panic disorder and 20 healthy controls. Diagnosis was done according to the ICD-10 research diagnostic criteria confirmed with MINI (MINI international neuropsychiatric interview). Autonomic nervous system (ANS) has been evaluated during orthostatic change in three positions. Intensity of symptoms was assessed using psychiatric scales. There were highly statistically significant differences between panic patients and control group in all components of power spectral analysis in 2nd and 3rd VLF components and in HF components of 2nd. We have found highly statistically significant negative correlations between level of dissociation measured by DES and some parameters of ANS. We found negative correlations between the age of the patient and activity of ANS, and negative correlations between activity of ANS and duration and onset of disorder and dosage of antidepressants. These findings demonstrate a lower parasympathetic activity and higher sympathetic/parasympathetic ratio in panic disorder patients measured during the changes of postural position in comparison with healthy controls. Autonomic dysregulation is associated with panic disorder and has the relation with the level of dissociation, the age of patiens and age of onset of disorder.


Removal of Stratospheric O3 by Radicals: In Situ Measurements of OH, HO2, NO, NO2, ClO, and BrO.
Simultaneous in situ measurements of the concentrations of OH, HO(2), ClO, BrO, NO, and NO(2) demonstrate the predominance of odd-hydrogen and halogen free-radical catalysis in determining the rate of removal of ozone in the lower stratosphere during May 1993. A single catalytic cycle, in which the rate-limiting step is the reaction of HO(2) with ozone, accounted for nearly one-half of the total O(3) removal in this region of the atmosphere. Halogen-radical chemistry was responsible for approximately one-third of the photochemical removal of O(3); reactions involving BrO account for one-half of this loss. Catalytic destruction by NO(2), which for two decades was considered to be the predominant loss process, accounted for less than 20 percent of the O(3) removal. The measurements demonstrate quantitatively the coupling that exists between the radical families. The concentrations of HO(2) and ClO are inversely correlated with those of NO and NO(2). The direct determination of the relative importance of the catalytic loss processes, combined with a demonstration of the reactions linking the hydrogen, halogen, and nitrogen radical concentrations, shows that in the air sampled the rate of O(3) removal was inversely correlated with total NOx, loading.


Simple and robust speckle detection method for fire and heat detection in harsh environments.
Standard laser-based fire detection systems are often based on measuring the variation of optical signal amplitude. However, mechanical noise interference and loss from dust and steam can obscure the detection signal, resulting in faulty results or the inability to detect a potential fire. The presented fire detection technology will allow the detection of fire in harsh and dusty areas, which are prone to fires, where current systems show limited performance or are unable to operate. It is not the amount of light or its wavelength that is used for detecting fire, but how the refractive index randomly fluctuates due to heat convection from the fire. In practical terms, this means that light obstruction from ambient dust particles will not be a problem as long as a small fraction of the light is detected and that fires without visible flames can still be detected. The standalone laser system consists of a Linux-based Red Pitaya system, a cheap 650 nm laser diode, and a positive-intrinsic-negative photo-detector. Laser light propagates through the monitored area and reflects off a retroreflector generating a speckle pattern. Every 3 s, time traces and frequency noise spectra are measured, and eight descriptors are deduced to identify a potential fire. Both laboratory and factory acceptance tests have been performed with success.


The effect of chronic administration of methylphenidate on morphometric parameters of testes and fertility in male mice.
Due to common use of methylphenidate (MPH) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and the role of the reproductive system in the production of gametes, studying the effects of this medication on the morphometry of testes, serum testosterone concentration, leydig cells function, and fertility rate was the aim of this study. Twenty seven male mice (Balb/C), eight weeks old, were randomly divided into one control and two treated groups. After weighing the mice, the treated groups received MPH (produced in Novartis company) at the doses of 2 mg/kg and 10 mg/kg for 40 days. The control group received only normal saline. Subsequently, after weighing the animals, the weights of testes, dimensions of the testis, and the serum testosterone concentration were measured in six mice belonging to each group. After tissue processing, the samples were stained with hematoxylin and eosin, then the leydig cells were counted. In order to assess male fertility in each group, 3 male mice were chosen and each of them was kept with three female mice in a separate cage. After 10 days, the fertility rates of the male mice were determined by counting the number of embryos in uterus and the corpora lutea in their ovaries. The results of this study revealed that prescription of different doses of MPH can cause a significant decrease of the body weight. It reduces the number of leydig cells, too (p<0.01). Moreover, serum testosterone concentration (67.72±8.24 ng/ml in control group and 0.302±0.416 ng/ml after treatment with 2 mg/kg/day MPH) and fertility rate (95.42%±4.68% in control group and 64.96%±18.51% after treatment with 2 mg/kg/day MPH) of the male mice declined significantly in the treated groups compared with the control group (p<0.01), but it did not cause any changes in the weight or morphometric parameters of testes. The results of this study confirmed that MPH can negatively affect serum testosterone concentration and fertility rate of the male mice by decreasing the number of leydig cells and reducing the body weight.


Interunit Reliability and Effect of Data-Processing Methods of Global Positioning Systems.
To establish the interunit reliability of a range of global positioning system (GPS)-derived movement indicators, to determine the variation between manufacturers, and to investigate the difference between software-derived and raw data. A range of movement variables were obtained from 27 GPS units from 3 manufacturers (GPSports EVO, 10 Hz, n = 10; STATSports Apex, 10 Hz, n = 10; and Catapult S5, 10 Hz, n = 7) that measured the same team-sport simulation session while positioned on a sled. The interunit reliability was determined using the coefficient of variation (%) and 90% confidence limits, whereas between-manufacturers comparisons and comparisons of software versus raw processed data were established using standardized effect sizes and 90% confidence limits. The interunit reliability for both software and raw processed data ranged from good to poor (coefficient of variation = 0.2%; ±1.5% to 78.2%; ±1.5%), with distance, speed, and maximal speed exhibiting the best reliability. There were substantial differences between manufacturers, particularly for threshold-based acceleration and deceleration variables (effect sizes; ±90% confidence limits: -2.0; ±0.1 to 1.9; ±0.1), and there were substantial differences between data-processing methods for a range of movement indicators. The interunit reliability of most movement indicators was deemed as good regardless of processing method, suggesting that practitioners can have confidence within systems. Standardized data-processing methods are recommended, due to the large differences between data outputs from various manufacturer-derived software.


Biomechanical studies: science (f)or common sense?
It is our impression that many biomechanical studies invest substantial resources studying the obvious: that more and larger metal is stronger. The purpose of this study is to evaluate if a subset of biomechanical studies comparing fixation constructs just document common sense. Using a web-based survey, 274 orthopaedic surgeons and 81 medical students predicted the results of 11 biomechanical studies comparing fracture fixation constructs (selected based on the authors' sense that the answer was obvious prior to performing the study). Sensitivity, specificity, and accuracy were calculated according to standard formulas. The agreement among the observers was calculated by using a multirater kappa, described by Siegel and Castellan. The accuracy of predicting outcomes was 80% or greater for 10 of 11 studies. Accuracy was not influenced by level of experience (i.e., time in practice and medical students vs. surgeons). There were substantial differences in accuracy between observers from different regions. The overall categorical rating of inter-observer reliability according to Landis and Koch was moderate (κ=0.55; standard error (SE)=0.01). The results of a subset of biomechanical studies comparing fracture fixation constructs can be predicted prior to doing the study. As these studies are time and resource intensive, one criterion for proceeding with a biomechanical study should be that the answer is not simply a matter of common sense.


Tumor-associated Apc mutations in Mlh1-/- Apc1638N mice reveal a mutational signature of Mlh1 deficiency.
Apc1638N mice, which are heterozygous for a germline mutation in Apc, typically develop three to five spontaneous intestinal tumors per animal. In most cases this is associated with allelic loss of wildtype Apc. We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc1638N with an Mlh1-deficient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC). The increased tumor multiplicity in these mice was associated with somatic mutations in the Apc tumor suppressor gene. Here, we have examined the nature and distribution of 91 Apc mutations implicated in the development of intestinal tumors in Mlh1-/- Apc1638N animals. Protein truncation mutations were detected in a majority of tumor samples, indicating that the prevailing mechanism of Apc mutation in tumors is altered from allelic loss to intragenic mutation as a result of Mlh1 deficiency. The observed mutations were a mixture of base substitutions (27%) and frameshifts (73%). Most frameshifts were detected within dinucleotide repeats and there were prominent mutational hotspots within sequences of this sort at codons 927-929, 1209-1211 and 1461-1464. The observed Apc mutations caused protein truncation upstream of the third 20 amino acid beta-catenin binding domain and the first Axin-binding SAMP repeat, yielding Apc proteins that are predicted to be deficient in destabilizing beta-catenin. Our results reveal a characteristic mutational signature in Apc that is attributable to Mlh1 deficiency. This demonstrates a direct effect of Mlh1 deficiency in the mutation of Apc in these tumors, and provides data that clarify the role of Mlh1 in mammalian DNA mismatch repair.


Positive genetic correlation between parasite resistance and body size in a free-living ungulate population.
Parasite resistance and body size are subject to directional natural selection in a population of feral Soay sheep (Ovis aries) on the island of St. Kilda, Scotland. Classical evolutionary theory predicts that directional selection should erode additive genetic variation and favor the maintenance of alleles that have negative pleiotropic effects on other traits associated with fitness. Contrary to these predictions, in this study we show that there is considerable additive genetic variation for both parasite resistance, measured as fecal egg count (FEC), and body size, measured as weight and hindleg length, and that there are positive genetic correlations between parasite resistance and body size in both sexes. Body size traits had higher heritabilities than parasite resistance. This was not due to low levels of additive genetic variation for parasite resistance, but was a consequence of high levels of residual variance in FEC. Measured as coefficients of variation, levels of additive genetic variation for FEC were actually higher than for weight or hindleg length. High levels of additive genetic variation for parasite resistance may be maintained by a number of mechanisms including high mutational input, balancing selection, antagonistic pleiotropy, and host-parasite coevolution. The positive genetic correlation between parasite resistance and body size, a trait also subject to sexual selection in males, suggests that parasite resistance and growth are not traded off in Soay sheep, but rather that genetically resistant individuals also experience superior growth.


A prospective randomised controlled study of the use of ranitidine in patients with gastric cancer. Yorkshire GI Tumour Group.
Does the use of the histamine H2 receptor antagonist ranitidine improve the outcome of patients with gastric cancer? A total of 222 patients with gastric cancer who had received radical or palliative resection or who were deemed inoperable at presentation. Hospitals within Yorkshire, the participating clinicians being members of the Yorkshire GI Tumour Group. A multicentre prospective randomised double blind trial comparing ranitidine 150 mg twice daily with placebo twice daily was undertaken. The principal outcome measures were survival and survival excluding those who died within 30 days of operation. The median survival (95% confidence intervals) was 331 (232 to 393) days for patients in the ranitidine group compared with 187 (143 to 269) for those in the placebo group. The difference in survival was not statistically significant (p = 0.225). When patients who died within 30 days of operation were excluded (21 in the placebo group, 15 in the ranitidine group), the difference in survival remained not significant (p = 0.358). No subgroup could be identified who significantly benefited from treatment, but for patients with stage VIa cancer the median survival was 134 days with placebo compared with 313 days with ranitidine (p = 0.073). This study does not show significant benefit from the use of ranitidine for gastric cancer but further larger studies may be indicated.


Presence of Genetic Variants Among Young Men With Severe COVID-19.
Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19. Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments. Severe COVID-19. Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects. The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.


High sodium chloride concentrations inhibit staphylococcal enterotoxin C gene (sec) expression at the level of sec mRNA.
Expression of the staphylococcal enterotoxin type C gene (sec) is regulated in response to both high NaCl concentrations (osmolarity) and the accessory gene regulator (agr). agr is a global regulator that alters the expression of many genes in Staphylococcus aureus. In this report, we have demonstrated that osmoregulation of sec occurs at the level of mRNA independently of an intact agr allele. Northern (RNA) and Western blot (immunoblot) analyses of samples from cultures grown in low- (0 M NaCl) and high-osmotic-strength (1.2 M NaCl) media revealed that the low-osmotic-strength culture contained approximately 16-fold more SEC and sec mRNA than the high-osmotic-strength culture. sec expression in high-osmotic-strength medium was enhanced when osmoprotective compounds were added. Osmoregulation of sec expression in Agr- strains was also examined; SEC and sec mRNA levels decreased in response to high osmolarity in a manner similar to that seen in the Agr+ strains.


Such stuff as dreams are made on? Elaborative encoding, the ancient art of memory, and the hippocampus.
This article argues that rapid eye movement (REM) dreaming is elaborative encoding for episodic memories. Elaborative encoding in REM can, at least partially, be understood through ancient art of memory (AAOM) principles: visualization, bizarre association, organization, narration, embodiment, and location. These principles render recent memories more distinctive through novel and meaningful association with emotionally salient, remote memories. The AAOM optimizes memory performance, suggesting that its principles may predict aspects of how episodic memory is configured in the brain. Integration and segregation are fundamental organizing principles in the cerebral cortex. Episodic memory networks interconnect profusely within the cortex, creating omnidirectional "landmark" junctions. Memories may be integrated at junctions but segregated along connecting network paths that meet at junctions. Episodic junctions may be instantiated during non-rapid eye movement (NREM) sleep after hippocampal associational function during REM dreams. Hippocampal association involves relating, binding, and integrating episodic memories into a mnemonic compositional whole. This often bizarre, composite image has not been present to the senses; it is not "real" because it hyperassociates several memories. During REM sleep, on the phenomenological level, this composite image is experienced as a dream scene. A dream scene may be instantiated as omnidirectional neocortical junction and retained by the hippocampus as an index. On episodic memory retrieval, an external stimulus (or an internal representation) is matched by the hippocampus against its indices. One or more indices then reference the relevant neocortical junctions from which episodic memories can be retrieved. Episodic junctions reach a processing (rather than conscious) level during normal wake to enable retrieval. If this hypothesis is correct, the stuff of dreams is the stuff of memory.


DNA methylome and transcriptome landscapes of cancer-associated fibroblasts reveal a smoking-associated malignancy index.
Unlike the better-studied aberrant epigenome in the tumor, the clinicopathologic impact of DNA methylation in the tumor microenvironment (TME), especially the contribution from cancer-associated fibroblasts (CAFs), remains elusive. CAFs exhibit profound patient-to-patient tumorigenic heterogeneity. We asked whether such heterogeneity may be exploited to quantify the level of TME malignancy. We developed a robust and efficient methylome/transcriptome co-analytical system for CAFs and paired normal fibroblasts (NFs) from non-small-cell lung cancer patients. We found 14,781 CpG sites of CAF/NF differential methylation, of which 3,707 sites showed higher methylation changes in ever-smokers than in nonsmokers. Concomitant CAF/NF differential gene expression analysis pointed to a subset of 54 smoking-associated CpG sites with strong methylation-regulated gene expression. A methylation index that summarizes the β values of these CpGs was built for NF/CAF discrimination (MIND) with high sensitivity and specificity. The potential of MIND in detecting premalignancy across individual patients was shown. MIND succeeded in predicting tumor recurrence in multiple lung cancer cohorts without reliance on patient survival data, suggesting that the malignancy level of TME may be effectively graded by this index. Precision TME grading may provide additional pathological information to guide cancer prognosis and open up more options in personalized medicine.


2-Carboxyquinoxalines kill mycobacterium tuberculosis through noncovalent inhibition of DprE1.
Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 μM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC50's and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.


Better sexual acceptability of agomelatine (25 and 50 mg) compared to escitalopram (20 mg) in healthy volunteers. A 9-week, placebo-controlled study using the PRSexDQ scale.
The present double-blind, placebo-controlled study evaluates the effects of agomelatine and the selective serotonin reuptake inhibitor escitalopram on sexual dysfunction in healthy men and women. A total of 133 healthy volunteers (67 men, 66 women) were randomly assigned to agomelatine (25 or 50 mg) or escitalopram (20 mg) or placebo for nine weeks. Sexual acceptability was evaluated by using the psychotropic-related sexual dysfunction questionnaire 5-items total score and sexual dysfunction relative to each sub-score (in 110 volunteers with sexual activity). Sexual dysfunction was evaluated at baseline and after two, five and eight weeks of treatment and one week after drug discontinuation. The psychotropic-related sexual dysfunction questionnaire 5-items total score was significantly lower in both agomelatine groups versus escitalopram at all visits (p < 0.01 to p < 0.0001) with no difference between agomelatine and placebo nor between both agomelatine doses. Similar results were observed after drug discontinuation. The total score was significantly higher in the escitalopram group than in the placebo group at each post-baseline visit (p < 0.01 to p < 0.001). Similar results were observed regardless of volunteers' gender. Compared to placebo, only escitalopram significantly impaired dysfunction relative to "delayed orgasm or ejaculation" (p < 0.01) and "absence of orgasm or ejaculation" (p < 0.05 to p < 0.01). The percentage of participants with a sexual dysfunction was higher in the escitalopram group than in agomelatine groups (p < 0.01 to p < 0.05) and placebo (p < 0.01). The study confirms the better sexual acceptability profile of agomelatine (25 or 50 mg) in healthy men and women, compared to escitalopram. Evaluation of the effect of agomelatine and escitalopram on emotions and motivation in healthy male and female volunteers. ISRCTN75872983.


Genetic dissection of rice blast resistance by QTL mapping approach using an F3 population.
Rice blast is one of the major fungal diseases that badly reduce rice production in Asia including Malaysia. There is not much information on identification of QTLs as well as linked markers and their association with blast resistance within local rice cultivars. In order to understanding of the genetic control of blast in the F3 families from indica rice cross Pongsu seribu2/Mahsuri, an analysis of quantitative trait loci against one of the highly virulent Malaysian rice blast isolate Magnaporthe oryzae, P5.0 was carried out. Result indicated that partial resistance to this pathotype observed in the present study was controlled by multiple loci or different QTLs. In QTL analysis in F3 progeny fifteen QTLs on chromosomes 1, 2, 3, 5, 6, 11 and 12 for resistance to blast nursery tests was identified. Three of detected QTLs (qRBr-6.1, qRBr-11.4, and qRBr-12.1) had significant threshold (LOD >3) and approved by both IM and CIM methods. Twelve suggestive QTLs, qRBr-1.2, qRBr-2.1, qRBr-4.1, qRBr-5.1, qRBr-6.2, qRBr-6.3, qRBr-8.1, qRBr-10.1, qRBr-10.2, qRBr-11.1, qRBr-11.2 and qRBr-11.3) with Logarithmic of Odds (LOD) <3.0 or LRS <15) were distributed on chromosomes 1, 2, 4, 5, 6, 8, 10, and 11. Most of the QTLs detected using single isolate had the resistant alleles from Pongsu seribu 2 which involved in the resistance in the greenhouse. We found that QTLs detected for deferent traits for the using isolate were frequently located in similar genomic regions. Inheritance study showed among F3 lines resistance segregated in the expected ratio of 15: 1 for resistant to susceptible. The average score for blast resistance measured in the green house was 3.15, 1.98 and 29.95 % for three traits, BLD, BLT and % DLA, respectively.


Functional responses in the human spinal cord during willed motor actions: evidence for side- and rate-dependent activity.
Although the spinal cord is the output station of the central motor system, little is known about the relationships between its functional activity and willed movement parameters in humans. We investigated here blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) signal changes in the cervical spinal cord during a simple finger-to-thumb opposition task in 13 right-handed volunteers, using a dedicated array of 16 receive-only surface coils on a 3 Tesla MRI system. In a first experiment, we found significant fMRI signal increases on both sides of the lower cervical spinal cord while subjects performed the motor task at a comfortable pace (approximately 0.5 Hz) using either hand. Both the spatial extent of movement-related clusters and peak signal increases were significantly higher on the side of the cord ipsilateral to the moving hand than on the contralateral side. Movement-related activity was consistently larger than signal fluctuations during rest. In a second experiment, we recorded spinal cord responses while the same motor sequence was performed using the dominant hand at two different rates (approximately 0.5 or 1 Hz). The intensity but not the spatial extent of the response was larger during higher rates, and it was higher on the ipsilateral side of the cord. Notwithstanding the limited spatial resolving power of the adopted technique, the present results clearly indicate that the finger movement-related fMRI signals recorded from the spinal cord have a neural origin and that as a result of recent technological advances, fMRI can be used to obtain novel and quantitative physiological information on the activity of spinal circuits.