Control of mitotic and meiotic centriole duplication by the Plk4-related kinase ZYG-1.
Centriole duplication is of crucial importance during both mitotic and male meiotic divisions, but it is currently not known whether this process is regulated differently during the two modes of division. In Caenorhabditis elegans, the kinase ZYG-1 plays an essential role in both mitotic and meiotic centriole duplication. We have found that the C-terminus of ZYG-1 is necessary and sufficient for targeting to centrosomes and is important for differentiating mitotic and meiotic centriole duplication. Small truncations of the C-terminus dramatically lower the level of ZYG-1 at mitotic centrosomes but have little effect on the level of ZYG-1 at meiotic centrosomes. Interestingly, truncation of ZYG-1 blocks centrosome duplication in the mitotic cycle but leads to centrosome amplification in the meiotic cycle. Meiotic centriole amplification appears to result from the overduplication of centrioles during meiosis I and leads to the formation of multipolar meiosis II spindles. The extra centrioles also disrupt spermatogenesis by inducing the formation of supernumerary fertilization-competent spermatids that contain abnormal numbers of chromosomes and centrioles. Our data reveal differences in the regulation of mitotic and meiotic centrosome duplication, particularly with regard to ZYG-1 activity, and reveal an important role for centrosomes in spermatid formation.


Detection of advected, reacting redox fronts from self-potential measurements.
We report on an experiment aimed at testing the use of self-potential measurements to monitor the motion and mixing of redox reactants advected through a well-controlled, laboratory-scale, artificial aquifer system. A rectangular, plastic tank was filled up with water-saturated sand and an array of unpolarizable electrodes was installed in the sand body. A nearly uniform, steady-state flow was established by tilting the tank and controlling the water level in reservoirs at both ends. Then, we simultaneously injected a known quantity of KMnO(4) and FeCl(2), respectively, into two separate compartments forming the upstream reservoir. We thus generated two abrupt fronts, one oxidizing and the other reducing, which subsequently travelled in parallel by advection through the sand body. The KMnO(4) and FeCl(2) solutions were in contact and reacted with each other in a region located along the median vertical plane parallel to the flow direction. During flow, the electrical potential differences between each electrode and a reference located in the downstream reservoir were recorded. In the unreacted FeCl(2) region the electric potential showed sudden variations successively occurring at increasing distances in the flow direction, associated with the passage of the FeCl(2) front. These signals essentially corresponded to the junction potential produced by the difference in ionic mobility of Fe(2+) and Cl(-). In the unreacted KMnO(4) region sharp signals, but with much smaller amplitudes, were also observed. Near the vertical median plane on the FeCl(2) side, we observed a second front associated with the spreading of the reaction zone. The shape and evolution of the reaction zone was largely controlled by the precipitation of Fe(OH)(3).


FoxO1 regulates myocardial glucose oxidation rates via transcriptional control of pyruvate dehydrogenase kinase 4 expression.
Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation and a critical regulator of metabolic flexibility during the fasting to feeding transition. PDH is regulated via both PDH kinases (PDHK) and PDH phosphatases, which phosphorylate/inactivate and dephosphorylate/activate PDH, respectively. Our goal was to determine whether the transcription factor forkhead box O1 (FoxO1) regulates PDH activity and glucose oxidation in the heart via increasing the expression of Pdk4, the gene encoding PDHK4. To address this question, we differentiated H9c2 myoblasts into cardiac myocytes and modulated FoxO1 activity, after which Pdk4/PDHK4 expression and PDH phosphorylation/activity were assessed. We assessed binding of FoxO1 to the Pdk4 promoter in cardiac myocytes in conjunction with measuring the role of FoxO1 on glucose oxidation in the isolated working heart. Both pharmacological (1 µM AS1842856) and genetic (siRNA mediated) inhibition of FoxO1 decreased Pdk4/PDHK4 expression and subsequent PDH phosphorylation in H9c2 cardiac myocytes, whereas 10 µM dexamethasone-induced Pdk4/PDHK4 expression was abolished via pretreatment with 1 µM AS1842856. Furthermore, transfection of H9c2 cardiac myocytes with a vector expressing FoxO1 increased luciferase activity driven by a Pdk4 promoter construct containing the FoxO1 DNA-binding element region, but not in a Pdk4 promoter construct lacking this region. Finally, AS1842856 treatment in fasted mice enhanced glucose oxidation rates during aerobic isolated working heart perfusions. Taken together, FoxO1 directly regulates Pdk4 transcription in the heart, thereby controlling PDH activity and subsequent glucose oxidation rates.NEW & NOTEWORTHY Although studies have shown an association between FoxO1 activity and pyruvate dehydrogenase kinase 4 expression, our study demonstrated that pyruvate dehydrogenase kinase 4 is a direct transcriptional target of FoxO1 (but not FoxO3/FoxO4) in the heart. Furthermore, we report here, for the first time, that FoxO1 inhibition increases glucose oxidation in the isolated working mouse heart.


Optical multichannel room temperature magnetic field imaging system for clinical application.
Optically pumped magnetometers (OPM) are a very promising alternative to the superconducting quantum interference devices (SQUIDs) used nowadays for Magnetic Field Imaging (MFI), a new method of diagnosis based on the measurement of the magnetic field of the human heart. We present a first measurement combining a multichannel OPM-sensor with an existing MFI-system resulting in a fully functional room temperature MFI-system.


Long-term outcome of healthy participants with atrial premature complex: a 15-year follow-up of the NIPPON DATA 90 cohort.
Atrial premature complexes (APC) are among the most frequently encountered electrocardiographic abnormalities. However, their prognostic value among healthy individuals is unclear. This study aimed to clarify the role of APC in predicting cardiovascular events in a large Japanese community cohort using long-term follow-up data. National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1990-2005, (NIPPON DATA 90) was a large cohort study of cardiovascular disease (CVD) in Japan. A total of 7692 otherwise healthy participants with no history of myocardial infarction, stroke, atrial fibrillation, or atrial flutter were enrolled (men, 41.5%; mean age, 52.5 ± 13.7 years). A total of 64 (0.8%) participants had at least one beat of APC on screening 12-lead electrocardiogram. During the follow-up of 14.0 ± 2.9 years (total, 107,474 patient-years), 338 deaths occurred due to CVD. The association between APC and CVD outcome was assessed using Cox proportional hazard models. Cox regression analysis revealed that the presence of APC was an independent predictor for CVD deaths (HR: 2.03, 95% CI: 1.12-3.66, P = 0.019). The association of APC on CVD death was more evident in participants with hypertension (P-value for interaction, 0.03). APC recorded during the screening electrocardiogram are significantly associated with an increased risk of CVD deaths in a Japanese community-dwelling population and are a strong prognostic factor for hypertensive participants.


Patchy interspecific sequence similarities efficiently identify positive cis-regulatory elements in the sea urchin.
We demonstrate that interspecific sequence conservation can provide a systematic guide to the identification of functional cis-regulatory elements within a large expanse of genomic DNA. The test was carried out on the otx gene of Strongylocentrotus purpuratus. This gene plays a major role in the gene regulatory network that underlies endomesoderm specification in the embryo. The cis-regulatory organization of the otx gene is expected to be complex, because the gene has three different start sites (X. Li, C.-K. Chuang, C.-A. Mao, L. M. Angerer, and W. H. Klein, 1997, Dev. Biol. 187, 253-266), and it is expressed in many different spatial domains of the embryo. BAC recombinants containing the otx gene were isolated from Strongylocentrotus purpuratus and Lytechinus variegatus libraries, and the ordered sequence of these BACs was obtained and annotated. Sixty kilobases of DNA flanking the gene, and included in the BAC sequence from both species, were scanned computationally for short conserved sequence elements. For this purpose, we used a newly constructed software package assembled in our laboratory, "FamilyRelations." This tool allows detection of sequence similarities above a chosen criterion within sliding windows set at 20-50 bp. Seventeen partially conserved regions, most a few hundred base pairs long, were amplified from the S. purpuratus BAC DNA by PCR, inserted in an expression vector driving a CAT reporter, and tested for cis-regulatory activity by injection into fertilized S. purpuratus eggs. The regulatory activity of these constructs was assessed by whole-mount in situ hybridization (WMISH) using a probe against CAT mRNA. Of the 17 constructs, 11 constructs displayed spatially restricted regulatory activity, and 6 were inactive in this test. The domains within which the cis-regulatory constructs were expressed are approximately consistent with results from a WMISH study on otx expression in the embryo, in which we used probes specific for the mRNAs generated from each of the three transcription start sites. Four separate cis-regulatory elements that specifically produce endomesodermal expression were identified, as well as ubiquitously active elements, and ectoderm-specific elements. We confirm predictions from other work with respect to target sites for specific transcription factors within the elements that express in the endoderm.


Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate.
Deactivation of voltage-gated potassium (K(+)) channels can slow or prevent the recovery from block by charged organic compounds, a phenomenon attributed to trapping of the compound within the inner vestibule by closure of the activation gate. Unbinding and exit from the channel vestibule of a positively charged organic compound should be favored by membrane hyperpolarization if not impeded by the closed gate. MK-499, a methanesulfonanilide compound, is a potent blocker (IC(50) = 32 nM) of HERG K(+) channels. This bulky compound (7 x 20 A) is positively charged at physiological pH. Recovery from block of HERG channels by MK-499 and other methanesulfonanilides is extremely slow (Carmeliet 1992; Ficker et al. 1998), suggesting a trapping mechanism. We used a mutant HERG (D540K) channel expressed in Xenopus oocytes to test the trapping hypothesis. D540K HERG has the unusual property of opening in response to hyperpolarization, in addition to relatively normal gating and channel opening in response to depolarization (Sanguinetti and Xu 1999). The hyperpolarization-activated state of HERG was characterized by long bursts of single channel reopening. Channel reopening allowed recovery from block by 2 microM MK-499 to occur with time constants of 10.5 and 52.7 s at -160 mV. In contrast, wild-type HERG channels opened only briefly after membrane hyperpolarization, and thus did not permit recovery from block by MK-499. These findings provide direct evidence that the mechanism of slow recovery from HERG channel block by methanesulfonanilides is due to trapping of the compound in the inner vestibule by closure of the activation gate. The ability of HERG channels to trap MK-499, despite its large size, suggests that the vestibule of this channel is larger than the well studied Shaker K(+) channel.


New Clox Systems for rapid and efficient gene disruption in Candida albicans.
Precise genome modification is essential for the molecular dissection of Candida albicans, and is yielding invaluable information about the roles of specific gene functions in this major fungal pathogen of humans. C. albicans is naturally diploid, unable to undergo meiosis, and utilizes a non-canonical genetic code. Hence, specialized tools have had to be developed for gene disruption in C. albicans that permit the deletion of both target alleles, and in some cases, the recycling of the Candida-specific selectable markers. Previously, we developed a tool based on the Cre recombinase, which recycles markers in C. albicans with 90-100% efficiency via site-specific recombination between loxP sites. Ironically, the utility of this system was hampered by the extreme efficiency of Cre, which prevented the construction in Escherichia coli of stable disruption cassettes carrying a methionine-regulatable CaMET3p-cre gene flanked by loxP sites. Therefore, we have significantly enhanced this system by engineering new Clox cassettes that carry a synthetic, intron-containing cre gene. The Clox kit facilitates efficient transformation and marker recycling, thereby simplifying and accelerating the process of gene disruption in C. albicans. Indeed, homozygous mutants can be generated and their markers resolved within two weeks. The Clox kit facilitates strategies involving single marker recycling or multi-marker gene disruption. Furthermore, it includes the dominant NAT1 marker, as well as URA3, HIS1 and ARG4 cassettes, thereby permitting the manipulation of clinical isolates as well as genetically marked strains of C. albicans. The accelerated gene disruption strategies afforded by this new Clox system are likely to have a profound impact on the speed with which C. albicans pathobiology can be dissected.


Microbiological features distinguishing Lyme disease and relapsing fever spirochetes.
The recent proposal of splitting the genus Borrelia into two genera in the newly formed family of Borreliaceae, i. e. Borrelia and Borreliella has motivated us to reflect upon how these organisms has been characterized and differentiated. This article therefore aims to take a closer look on the biology and virulence attributes of the two suggested genera, i. e. those causing Lyme borreliosis and relapsing fever borreliosis. Both genera have much in common with similar infection biological features. They are both characterized as bacterial zoonoses, transmitted by hematophagous arthropods with almost identical microbiological appearance. Nevertheless, a closer look at the genotypic and phenotypic characteristics clearly reveals several differences that might motivate the suggested split. On the other hand, a change of this well-established classification within the genus Borrelia might impose an economical burden as well as a great confusion in society, including medical and scientific societies as well as the general population.


Epidemiology of pediatric hospitalizations at general hospitals and freestanding children's hospitals in the United States.
Children may be hospitalized at general hospitals or freestanding children's hospitals. Knowledge about how inpatient care differs at these hospitals is important to inform national research and quality efforts. To describe the volume and characteristics of pediatric hospitalizations at acute care general and freestanding children's hospitals in the United States. Cross-sectional study of hospitalizations in the United States among children <18 years, excluding in-hospital births, using the Healthcare Cost and Utilization Project's 2012 Kids' Inpatient Database. We examined differences between hospitalizations at general and freestanding children's hospitals, applying weights to generate national estimates. Reasons for hospitalization were categorized using a pediatric grouper, and differences in hospital volumes were assessed for common diagnoses. A total of 1,407,822 (standard deviation 50,456) hospitalizations occurred at general hospitals, representing 71.7% of pediatric hospitalizations. Hospitalizations at general hospitals accounted for 63.6% of hospital days and 50.0% of pediatric inpatient healthcare costs. Median volumes of pediatric hospitalizations, per hospital, were significantly lower at general hospitals than freestanding children's hospitals for common medical and surgical diagnoses. Although the most common reasons for hospitalization were similar, the most costly conditions differed. In 2012, more than 70% of pediatric hospitalizations occurred at general hospitals in the United States. Differences in patterns of care at general hospitals and freestanding children's hospitals may inform clinical programs, research, and quality improvement efforts. Journal of Hospital Medicine 2016;11:743-749. © 2016 Society of Hospital Medicine.


COBRA: a sensitive and quantitative DNA methylation assay.
We report here on a quantitative technique called COBRA to determine DNA methylation levels at specific gene loci in small amounts of genomic DNA. Restriction enzyme digestion is used to reveal methylation-dependent sequence differences in PCR products of sodium bisulfite-treated DNA as described previously. We show that methylation levels in the original DNA sample are represented by the relative amounts of digested and undigested PCR product in a linearly quantitative fashion across a wide spectrum of DNA methylation levels. In addition, we show that this technique can be reliably applied to DNA obtained from microdissected paraffin-embedded tissue samples. COBRA thus combines the powerful features of ease of use, quantitative accuracy, and compatibility with paraffin sections.


Intraobserver and Interobserver Reliability of the Oberg-Manske-Tonkin (OMT) Classification: Establishing a Registry on Congenital Upper Limb Differences.
The purpose of this investigation was to determine the reliability of the Oberg-Manske-Tonkin (OMT) classification system applied to patients enrolled in a prospective, multicenter cohort study of congenital upper limb differences. Our hypothesis was that the OMT classification would exhibit high intraobserver and interobserver reliability and thus would be an appropriate tool for the new Congenital Upper Limb Differences registry. Four pediatric hand surgeons independently reviewed the medical records, clinical photographs, and radiographs of 60 randomly selected patients previously enrolled in the Congenital Upper Limb Differences registry. Patient's information was summarized and shared electronically (PowerPoint). Each rater classified each congenital anomaly according to the OMT classification system. Responses were recorded using a web-based data capture tool (REDCap). Three weeks later, the surgeons repeated the process. Intraobserver reliability for each rater was assessed using Fleiss' κ. Interobserver reliability was assessed using percent exact agreement (when all 4 raters were in agreement) as well as Fleiss' κ. Using the OMT classification, intraobserver reliability for the 4 pediatric hand surgeons showed almost perfect agreement, with κ values in the range of 0.89 to 0.93. Interobserver reliability demonstrated substantial agreement, with κ value of 0.79 (95% confidence interval, 0.77-0.82) in the first reading and 0.80 (95% confidence interval, 0.77-0.83) in the second reading. The highest possible agreement (κ=1) was seen for the following diagnoses: congenital dislocation of radial head (OMT I.A.2.v), Madelung deformity (I.A.2.vii), radial polydactyly (I.B.2.iii), triphalangeal thumb (I.B.2.iv), Kirner deformity (I.B.4.vi), and osteochondromatosis (3.B.4.i). The OMT classification of congenital upper limb differences exhibits substantial to almost perfect intraobserver and interobserver reliability among pediatric hand surgeons at different institutions. The OMT is therefore well-suited for classification of congenital upper limb anomalies in patients enrolled in a multicenter registry. Level II-diagnostic.


Erring on the side of caution: pregnant women's perceptions of consuming fish in a risk averse society.
Fish and seafood are good sources of several nutrients that are important for foetal growth and development. Despite guidelines encouraging the eating of fish during pregnancy, research indicates that pregnant women may be limiting or avoiding these foods. Possible factors contributing to this include concerns regarding levels of mercury and other contaminants and pregnant women's purported heightened risk consciousness. The present study aimed to explore pregnant women's perceptions of consuming fish and seafood during pregnancy. Semi-structured telephone interviews were conducted with 15 pregnant women across all three trimesters in New South Wales, Australia. Questions focussed on exploring nutrition information received during pregnancy, dietary changes made during pregnancy and, more specifically, perceptions of fish and seafood, as well as views on information of fish and seafood commonly provided to pregnant women. Data were collected, then transcribed and analysed using an inductive coding process, guided by the qualitative theory grounded approach. Multiple inter-related themes were found to shape pregnant women's perceptions related to fish and seafood consumption during pregnancy; namely, the understanding of fish and seafood as part of a healthy diet, external factors such as cost, individual preferences such as taste, and confidence in choosing and preparing fish. The context of a risk adverse society permeated these themes. The present study provides insight into the inter-related factors that influence pregnant women's consumption or avoidance of fish and seafood.


Intravesical instillation of onabotulinum toxin A embedded in inert hydrogel in the treatment of idiopathic overactive bladder: A double-blind randomized pilot study.
It was hypothesized that increasing the time for which onabotulinum toxin A (OnabotA) is exposed to the urothelium following intravesical instillation will augment its effect. TC-3 is an inert heat-sensitive hydrogel, which creates an intravesical bulk providing a slow release of the embedded drug after instillation. The aim of this study was to evaluate the effect of OnabotA, embedded in inert TC-3 hydrogel, in patients with idiopathic overactive bladder (OAB). In total, 39 female patients (age 30-65, average 53.8 years) with OAB symptoms were randomized for the study into four groups, each receiving 50 ml of the following intravesical instillations: Group A, 0.9% NaCl (placebo, n = 11); Group B, TC-3 gel + 200 U OnabotA (n = 9); Group C, TC-3 gel + 200 U OnabotA + dimethyl sulfoxide (DMSO) (n = 10); and Group D, DMSO (n = 9). The parameters were compared before and 1 month after treatment. When comparing parameters using conventional statistical methods (Kruskal-Wallis test), no statistically significant changes were observed within the groups. Comparison of the medians using an analysis based on the mathematical gnostics showed the superiority of the method used in Group B over the other groups in the following parameters: number of urgency grade 3 + 4 episodes/72 h, number of leakage episodes/72 h, Overactive Bladder Questionnaire total score and Patient Perception of Bladder Condition total score. Group D showed its superiority over the other groups in respect to the number of nocturia episodes/72 h. The results indicate that intravesical instillation of OnabotA, embedded in TC-3 gel, could become an alternative to intramural injection for a well-selected subgroup of patients.


[Endemic corridors: a useful tool for the epidemiological surveillance of influenza].
Epidemiological surveillance provides updated information about health problems which allows for the establishment of health policy guidelines. The methods for detecting the epidemic frequency of disease require the systematic collection of data on the occurrence of specific diseases. Influenza has cyclic seasonal peaks and its endemic baseline rates are useful for identifying outbreaks: the comparison between baseline and current data supplies epidemiological evidence related to an ongoing outbreak. The upper and lower incidence curves were traced for the data referring to IA detection in the nasopharyngeal aspirates from children hospitalized for acute lower respiratory tract infection from 1996 to 2002. The arithmetic mean and the 95% confidence interval for upper and lower limits of weekly incidence were calculated. The highest incidence was observed between weeks 25 and 32. When analyzing the prepared endemic corridor, it was observed that the highest detection in 2003 occurred between weeks 19 and 25, whereas two peaks occurred in 2004, the first starting at week 20, at a lower level than the normal epidemic peak, and the second at week 26.


Practice nurses experiences of mentoring undergraduate nursing students in Australian general practice.
Internationally, the delivery of health services has shifted from secondary to primary care, necessitating an exponential growth of the nursing workforce and expansion of the nursing role in general practice. This growth, and the subsequent need to develop this workforce, has created a need to expose undergraduate nurses to general practice nursing as a viable career option. Concurrently, universities are struggling to find sufficient clinical places for their undergraduate students to gain clinical experience. It is logical, therefore, to increase the number of undergraduate nursing student placements in general practice. Through qualitative research methods, this paper seeks to explore the experiences of practice nurses mentoring undergraduate students on clinical placements within the general practice setting. Findings are presented in the following three themes: (1) Promoting Practice Nursing: We really need to get students in, (2) Mentoring future co-workers: Patience and reassurance, and (3) Reciprocity in learning: It's a bit of a two way street, which show the benefits of such placements. Clinical placements in general practice settings can be mutually beneficial in terms of providing quality teaching and learning experiences for students. Conversely, the experience provides an impetus for practice nurses to maintain currency of their clinical skills and knowledge through mentoring student nurses.


A 35Cl(-)-NMR study of the singular anion-binding properties of dromedary hemoglobin.
35Cl(-)-NMR measurements of chloride binding to carbonmonoxy- and deoxy-dromedary hemoglobin reveal the existence of two classes of chloride-binding sites, one of high and the other of low affinity. Although this situation resembles that described for human hemoglobin, it was found that the number of binding sites as well as the association equilibrium constant for chloride binding are significantly higher in the dromedary protein. This difference may be due to the greater number of basic residues exposed to solvent and to the higher flexibility of dromedary hemoglobin. The two oxygen-linked polyanion-binding sites characteristic of this hemoglobin show competition for some of the high-affinity chloride-binding sites in keeping with their location in the cleft enclosed by the beta chains and between the alpha chains termini. It is suggested that the observed anion-binding properties of dromedary hemoglobin may contribute to the control of the physiological osmotic shock after rehydration.


Interstitial cells of Cajal and adaptive relaxation in the mouse stomach.
Interstitial cells of Cajal (ICC) are proposed to play a role in stretch activation of nerves and are under intense investigation for potential roles in enteric innervation. Most data to support such roles come from in vitro studies with muscle strips whereas data at the whole organ level are scarce. To obtain insight into the role of ICC in distention-induced motor patterns developing at the organ level, we studied distension-induced adaptive relaxation in the isolated whole stomach of wild-type and W/W(v) mice. A method was developed to assess gastric adaptive relaxation that gave quantitative information on rates of pressure development and maximal adaptive relaxation. Pressure development was monitored throughout infusion of 1 ml of solution over a 10-min period. The final intraluminal pressure was sensitive to blockade of nitric oxide synthase, in wild-type and W/W(v) mice to a similar extent, indicating NO-mediated relaxation in W/W(v) mice. Adaptive relaxation occurred between 0.2 and 0.5 ml of solution infusion; this reflex was abolished by TTX, was not sensitive to blockade of nitric oxide synthase, but was abolished by apamin, suggesting that ATP and not nitric oxide is the neurotransmitter responsible for this intrinsic reflex. Despite the absence of intramuscular ICC (ICC-IM), normal gastric adaptive relaxation occurred in the W/W(v) stomach. Because pressure development was significantly lower in W/W(v) mice compared with wild type in all the conditions studied, including in the presence of TTX, ICC-IM may play a role in development of myogenic tone. In conclusion, a mouse model was developed to assess the intrinsic component of gastric accommodation. This showed that ICC-IM are not essential for activation of intrinsic sensory nerves nor ATP-driven adaptive relaxation nor NO-mediated relaxation in the present model. ICC-IM may be involved in regulation of (distention-induced) myogenic tone.


Heat freezes niche evolution.
Climate change is altering phenology and distributions of many species and further changes are projected. Can species physiologically adapt to climate warming? We analyse thermal tolerances of a large number of terrestrial ectotherm (n = 697), endotherm (n = 227) and plant (n = 1816) species worldwide, and show that tolerance to heat is largely conserved across lineages, while tolerance to cold varies between and within species. This pattern, previously documented for ectotherms, is apparent for this group and for endotherms and plants, challenging the longstanding view that physiological tolerances of species change continuously across climatic gradients. An alternative view is proposed in which the thermal component of climatic niches would overlap across species more than expected. We argue that hard physiological boundaries exist that constrain evolution of tolerances of terrestrial organisms to high temperatures. In contrast, evolution of tolerances to cold should be more frequent. One consequence of conservatism of upper thermal tolerances is that estimated niches for cold-adapted species will tend to underestimate their upper thermal limits, thereby potentially inflating assessments of risk from climate change. In contrast, species whose climatic preferences are close to their upper thermal limits will unlikely evolve physiological tolerances to increased heat, thereby being predictably more affected by warming.


(-)-Epigallocathechin-3-gallate, an AMPK activator, decreases ovariectomy-induced bone loss by suppression of bone resorption.
Previously, we showed that AMP-activated protein kinase (AMPK) negatively regulates receptor activator of nuclear factor-κB ligand-induced osteoclast formation in vitro. The present study investigated the effect of (-)-epigallocathechin-3-gallate (EGCG), an AMPK activator, on ovariectomy (OVX)-induced bone loss in mice. Female mice subjected to OVX were administered EGCG for 8 weeks. We measured total-body bone mineral density (BMD) before and after the operation at an interval of 4 weeks. We performed micro-computed tomography (micro-CT) of the tibia and bone histomorphometric examination of the femur. Western blot analysis was additionally performed, to detect levels of the phosphorylated and total forms of AMPK-α in calvarial extracts. EGCG prevented OVX-induced body weight gain. The OVX control did not show a significant increase in BMD values at baseline and after treatment, unlike the sham control. EGCG attenuated OVX-induced bone loss. Micro-CT experiments revealed that EGCG induced a significant increase in trabecular bone volume and trabecular number and a decrease in trabecular spacing compared to the OVX control. Histomorphometric analyses further showed that EGCG suppressed osteoclast surface and number. Phosphorylated AMPK expression was significantly elevated in bone following EGCG treatment. Our findings collectively indicate that EGCG decreases OVX-induced bone loss via inhibition of osteoclasts.


Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study.
Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.


Preoperative stereotactic radiosurgery before planned resection of brain metastases: updated analysis of efficacy and toxicity of a novel treatment paradigm.
OBJECTIVEPreoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS and may lower the risk of radiation necrosis (RN) and leptomeningeal disease (LMD) recurrence. The study goal was to report the efficacy and toxicity of preoperative SRS in an expanded patient cohort with longer follow-up period relative to prior reports.METHODSThe records for patients with brain metastases treated with preoperative SRS and planned resection were reviewed. Patients with classically radiosensitive tumors, planned adjuvant whole brain radiotherapy, or no cranial imaging at least 1 month after surgery were excluded. Preoperative SRS dose was based on lesion size and was reduced approximately 10-20% from standard dosing. Surgery generally followed within 48 hours.RESULTSThe study cohort consisted of 117 patients with 125 lesions treated with single-fraction preoperative SRS and planned resection. Of the 117 patients, 24 patients were enrolled in an initial prospective trial; the remaining 93 cases were consecutively treated patients who were retrospectively reviewed. Most patients had a single brain metastasis (70.1%); 42.7% had non-small cell lung cancer, 18.8% had breast cancer, 15.4% had melanoma, and 11.1% had renal cell carcinoma. Gross total resection was performed in 95.2% of lesions. The median time from SRS to surgery was 2 days, the median SRS dose was 15 Gy, and the median gross tumor volume was 8.3 cm3. Event cumulative incidence at 2 years was as follows: cavity local recurrence (LR), 25.1%; distant brain failure, 60.2%; LMD, 4.3%; and symptomatic RN, 4.8%. The median overall survival (OS) and 2-year OS rate were 17.2 months and 36.7%, respectively. Subtotal resection (STR, n = 6) was significantly associated with increased risk of cavity LR (hazard ratio [HR] 6.67, p = 0.008) and worsened OS (HR 2.63, p = 0.05) in multivariable analyses.CONCLUSIONSThis expanded and updated analysis confirms that single-fraction preoperative SRS confers excellent cavity local control with very low risk of RN or LMD. Preoperative SRS has several potential advantages compared to postoperative SRS, including reduced risk of RN due to smaller irradiated volume without need for cavity margin expansion and reduced risk of LMD due to sterilization of tumor cells prior to spillage at the time of surgery. Subtotal resection, though infrequent, is associated with significantly worse cavity LR and OS. Based on these results, a randomized trial of preoperative versus postoperative SRS is being designed.


Fishing for contaminants: identification of three mechanism specific transcriptome signatures using Danio rerio embryos.
In ecotoxicology, transcriptomics is an effective way to detect gene expression changes in response to environmental pollutants. Such changes can be used to identify contaminants or contaminant classes and can be applied as early warning signals for pollution. To do so, it is important to distinguish contaminant-specific transcriptomic changes from genetic alterations due to general stress. Here we present a first step in the identification of contaminant class-specific transcriptome signatures. Embryos of zebrafish (Danio rerio) were exposed to three substances (methylmercury, chlorpyrifos and Aroclor 1254, each from 24 to 48 hpf exposed) representing sediment typical contaminant classes. We analyzed the altered transcriptome to detect discriminative genes significantly regulated in reaction to the three applied contaminants. By comparison of the results of the three contaminants, we identified transcriptome signatures and biologically important pathways (using Cytoscape/ClueGO software) that react significantly to the contaminant classes. This approach increases the chance of finding genes that play an important role in contaminant class-specific pathways rather than more general processes.


Biogeography of Burkholderia pseudomallei in the Torres Strait Islands of Northern Australia.
It has been hypothesized that biogeographical boundaries are a feature of Burkholderia pseudomallei ecology, and they impact the epidemiology of melioidosis on a global scale. This study examined the relatedness of B. pseudomallei sourced from islands in the Torres Strait of Northern Australia to determine if the geography of isolated island communities is a determinant of the organisms' dispersal. Environmental sampling on Badu Island in the Near Western Island cluster recovered a single clone. An additional 32 clinical isolates from the region were sourced. Isolates were characterized using multilocus sequence typing and a multiplex PCR targeting the flagellum gene cluster. Gene cluster analysis determined that 69% of the isolates from the region encoded the ancestral Burkholderia thailandensis-like flagellum and chemotaxis gene cluster, a proportion significantly lower than that reported from mainland Australia and consistent with observations of isolates from southern Papua New Guinea. A goodness-of-fit test indicated that there was geographic localization of sequence types throughout the archipelago, with the exception of Thursday Island, the economic and cultural hub of the region. Sequence types common to mainland Australia and Papua New Guinea were identified. These findings demonstrate for the first time an environmental reservoir for B. pseudomallei in the Torres Strait, and multilocus sequence typing suggests that the organism is not randomly distributed throughout this region and that seawater may provide a barrier to dispersal of the organism. Moreover, these findings support an anthropogenic dispersal hypothesis for the spread of B. pseudomallei throughout this region.


Efficacy of a Spatial Repellent for Control of Malaria in Indonesia: A Cluster-Randomized Controlled Trial.
A cluster-randomized, double-blinded, placebo-controlled trial was conducted to estimate the protective efficacy (PE) of a spatial repellent (SR) against malaria infection in Sumba, Indonesia. Following radical cure in 1,341 children aged ≥ 6 months to ≤ 5 years in 24 clusters, households were given transfluthrin or placebo passive emanators (devices designed to release vaporized chemical). Monthly blood screening and biweekly human-landing mosquito catches were performed during a 10-month baseline (June 2015-March 2016) and a 24-month intervention period (April 2016-April 2018). Screening detected 164 first-time infections and an accumulative total of 459 infections in 667 subjects in placebo-control households, and 134 first-time and 253 accumulative total infections among 665 subjects in active intervention households. The 24-cluster protective effect of 27.7% and 31.3%, for time to first-event and overall (total new) infections, respectively, was not statistically significant. Purportedly, this was due in part to zero to low incidence in some clusters, undermining the ability to detect a protective effect. Subgroup analysis of 19 clusters where at least one infection occurred during baseline showed 33.3% (P-value = 0.083) and 40.9% (P-value = 0.0236, statistically significant at the one-sided 5% significance level) protective effect to first infection and overall infections, respectively. Among 12 moderate- to high-risk clusters, a statistically significant decrease in infection by intervention was detected (60% PE). Primary entomological analysis of impact was inconclusive. Although this study suggests SRs prevent malaria, additional evidence is required to demonstrate the product class provides an operationally feasible and effective means of reducing malaria transmission.


Vaccines against non-communicable diseases.
Chronic non-communicable diseases (NCDs) are increasingly recognized as the major cause of morbidity and mortality worldwide. Effective, affordable and broadly accessible medicines for their treatment are much sought after. Therapeutic B-cell vaccines aim at inducing neutralizing auto-reactive antibodies against important mediators of such diseases. Numerous animal models have demonstrated that active immunotherapy can induce disease-modifying levels of auto-antibodies. Recent findings from clinical trials have indicated that self-reactive antibodies can also be readily induced in humans; therapeutic efficacy, however, has not always been achieved. To date, clinical experience with vaccines against self-molecules is limited. Choice of the right target, proper vaccine design, optimal vaccine dose and regimen remain the major challenges to achieve clinical efficacy and safety for this novel class of biotherapeutics.


Clinical features of and risk factors for rhabdomyolysis among adult patients with dengue virus infection.
Among 1,076 dengue patients, 9 patients with rhabdomyolysis and 1,067 patients without rhabdomyolysis (controls) were retrospectively analyzed. Of nine patients with rhabdomyolysis, the most commonly reported symptom other than fever was myalgia; dengue hemorrhagic fever (DHF) was found in seven cases, and acute kidney injury was found in six cases. Furthermore, one (11.1%) patient died. The median duration from hospital admission to rhabdomyolysis diagnosis was 3 days. Patients with rhabdomyolysis had higher age, proportion of men, prevalence of hypertension, frequency of myalgia, and incidences of DHF, pleural effusion, and acute kidney injury than controls. Multivariate analysis showed that hypertension (odds ratio [OR] = 14.270), myalgia (OR = 20.377), and acute kidney injury (OR = 65.547) were independent risk factors for rhabdomyolysis. Comparison of cytokine/chemokine concentrations in 101 DHF patients, including those with (N = 4) and without (N = 97) rhabdomyolysis, showed that interleukin-6 and tumor necrosis factor-α levels were significantly increased in the former.


Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.


Adaptive immunity does not strongly suppress spontaneous tumors in a Sleeping Beauty model of cancer.
The tumor immunosurveillance hypothesis describes a process by which the immune system recognizes and suppresses the growth of transformed cancer cells. A variety of epidemiological and experimental evidence supports this hypothesis. Nevertheless, there are a number of conflicting reports regarding the degree of immune protection conferred, the immune cell types responsible for protection, and the potential contributions of immunosuppressive therapies to tumor induction. The purpose of this study was to determine whether the adaptive immune system actively suppresses tumorigenesis in a Sleeping Beauty (SB) mouse model of cancer. SB transposon mutagenesis was performed in either a wild-type or immunocompromised (Rag2-null) background. Tumor latency and multiplicity were remarkably similar in both immune cohorts, suggesting that the adaptive immune system is not efficiently suppressing tumor formation in our model. Exceptions included skin tumors, which displayed increased multiplicity in wild-type animals, and leukemias, which developed with shorter latency in immune-deficient mice. Overall tumor distribution was also altered such that tumors affecting the gastrointestinal tract were more frequent and hemangiosarcomas were less frequent in immune-deficient mice compared with wild-type mice. Finally, genetic profiling of transposon-induced mutations identified significant differences in mutation prevalence for a number of genes, including Uba1. Taken together, these results indicate that B and T cells function to shape the genetic profile of tumors in various tumor types, despite being ineffective at clearing SB-induced tumors. To our knowledge, this study represents the first forward genetic screen designed to examine tumor immunosurveillance mechanisms.


Satisfaction With the Quality Nursing Work Environment Among Psychiatric Nurses Working in Acute Care General Hospitals.
The objective of this study was to investigate the impact on patient care quality of a positive, high-quality environment that is tailored to the practice of nursing. This study enabled nurses to show their professional skills and knowledge, which may help enhance job satisfaction. To date, little research has been done to assess the relationship between the nursing work environment and the job satisfaction of psychiatric nurses employed in acute wards of general hospitals. This study was designed to explain the relationship between job satisfaction and the perceived indicators of a quality nursing work environment (QNWE) after adjusting for demographic characteristics and work characteristics. A cross-sectional correlational design was employed, and a stratified random sample of 185 psychiatric nurses (99% response rate) working in acute wards in Taiwan was surveyed in 2013. Nurses were asked to complete a self-administered questionnaire that included measures of perceived QNWE and job satisfaction and demographic variables. A statistically significant, positive relationship was found between perceived indicators of QNWE and job satisfaction (r = .813, p < .001). In the hierarchical multiple linear regression model, for the subdimensions of QNWE, the variables "perceived indicators of professional specialization and teamwork" and "support and caring" showed a significant and positive association with job satisfaction, after adjusting for personal demographic characteristics. Job satisfaction is related to the perception of nurses regarding their work environment. Therefore, nursing managers should improve workplace satisfaction by supporting and caring for nurses and creating better career development and teamwork opportunities for nurses through job training and planning.


OKT3 prophylaxis in renal grafts with prolonged cold ischemia times: association with improvement in long-term survival.
The data on patients participating in two randomized, prospective studies with similar immunosuppressive regimens were updated and combined to evaluate the long-term effects of OKT3 according to cold ischemia time (< or = or > 24 hr). Among 159 patients in the OKT3 and 153 in the cyclosporine A (CsA) group, 8 and 12 deaths occurred, respectively (P = NS). In patients with cold ischemia > 24 hours, OKT3 prophylaxis resulted in a lower mean number of rejection episodes per patient than did CsA prophylaxis within one year (mean +/- SEM: 0.87 +/- 0.11 vs. 1.35 +/- 0.14, respectively; P = 0.008) and within five years (1.07 +/- 0.12 vs. 1.49 +/- 0.15, respectively; P = 0.032). In contrast, rejection incidences in patients with cold ischemia < or = 24 hours was not significantly different in the two groups. In all study patients, there was a trend towards higher graft survival rates in the OKT3 group versus the CsA group (at 5 years, 73% vs. 66%, respectively; P = 0.182). Among recipients of kidneys with cold ischemia times > 24 hours, OKT3 patients had significantly higher graft survival than CsA patients at two years (84% vs. 64%, respectively) and at five years (71% vs. 56%, respectively; P = 0.045). Significant differences were not observed in recipients of kidneys with cold ischemia times < or = 24 hours. In conclusion, patients receiving renal grafts with long cold ischemia times strongly benefit from OKT3 prophylaxis.


Pulmonary marginal zone lymphoma: a single centre experience and review of the SEER database.
Pulmonary marginal zone lymphoma is a rare disease arising from bronchial-associated lymphoid tissue (BALT). There is limited information on clinical presentation, natural history and treatment of this type of lymphoma. We conducted a retrospective review of patients with biopsy-proven BALT lymphoma treated at our institution and patients from the surveillance epidemiology and end results (SEER) database. Twenty-one patients (median age 57) with disease stage IE (n = 10) and IV (n = 11), were treated at our institution. Initial management included observation (n = 4), surgery (n = 5), combination chemotherapy (n = 7), single-agent rituximab (n = 3) and radioimmunotherapy (n = 2). Complete remission was observed in 10, partial remission in 3, stable disease in 7, and disease progression in 1 patient. With a median follow-up of 20 months, Kaplan-Meier estimates for progression-free and overall survival (OS) at 80 months were 90% and 95%, respectively. We identified 326 patients (59% females and 41% males; median age 68 [30 to 85) with BALT lymphoma in the SEER database. Fifty-five per cent had stage IE, 10% stage IIE, 3% stage IIIE, and 22% stage IV disease. After a median follow-up of 35 months, median OS was 112 months, and disease-specific median survival was not reached. At 90 months, disease-specific survival was 85% (CI 77-92) with no significant differences in outcome between patients presenting with different stages. Our single institution experience and review of the SEER database, confirm the indolent features and favourable outcome of this rare disease.


Tumors of the nail unit. A review. Part II: acquired localized longitudinal pachyonychia and masked nail tumors.
This second part of the review categorizes the site-specific nail tumors, as proposed in the first part, according to their clinical presentations. Acquired localized longitudinal pachyonychia allows for the specific recognition of onychogenic nail tumor, which can be classified into 2 groups according to the predominant compartment of origin within the nail unit as follows: epithelial tumors encompassing onychocytic matricoma and onychocytic carcinoma, and fibroepithelial tumors: the so-called onychomatricoma. As onychomatricoma is neither an epithelial matrical tumor nor a tumor with a limited differentiation toward the matrix, the author proposes instead the descriptive term of panonychoma fibropapilliferum (POP). The designation of POP does convey to the surgical pathologist or the dermatopathologist the key morphological pattern of this tumor. It should be noted that the proposed term of panonychoma is analogous to the nomenclature that is well established for follicular neoplasms with differentiation toward all elements of the normal hair follicle, that is panfolliculoma. The second term fibropapilliferum is used to highlight the mixed fibroepithelial nature of this neoplasm, which forms multiple rudimentary nail units. These nail units construct multiple nail plates that join together and form a single thick nail plate. According to nail anatomy, 2 types of POP are described: POP of the apical matrix/eponychium, with a pseudo-condylomatous pattern, and POP of the ventral matrix with a foliated pattern in transverse sections and a fibrokeratoma-like pattern in the longitudinal sections. Suggestions for the evaluation and clinical management of localized longitudinal pachyonychia are proposed. On histology of a nail clipping, 2 patterns with clinical significance can be individualized. A horizontal alignment of large cavities indicates POP of the ventral matrix. A haphazard arrangement of smaller cavities in the nail plate, including an arrangement in the inferior two-thirds of the nail clipping, should prompt a biopsy of the distal ventral matrix to rule out a malignant lesion. In the setting of the "masked "nail tumor, a clinical subtype with some significance can be individualized, the subungual keratotic nodule growing rapidly. Three nail bed tumors are discussed within this latter group. Two new clinicopathological variants of subungual keratoacanthoma are described, and a new nail bed tumor is discussed: the infundibulocystic nail bed squamous cell carcinoma. The absence of striking nuclear atypia and the giant cystic to multicystic pattern distinguishes infundibulocystic nail bed squamous cell carcinoma from follicular infundibulocystic squamous cell carcinoma. The last section proposes a classification of folliculogenic nail bed tumors. The follicular microcysts of the nail bed have previously been called subungual epidermoid inclusions or onycholemmal cysts, but the term follicular microcysts of the nail bed is more pertinent, because of the multiple lines of follicular differentiation (infundibular, tricholemmal, apocrine, and sebaceous) seen in their benign and malignant counterparts. Absent in a large portion of the normal nail bed, the follicular microcysts seem to have a peculiar propensity for the formation of tumors that vary in maturity from simple follicular microcystic hyperplasia associated with acquired longitudinal melanonychia to microcystic nail bed hamartoma and microcystic nail bed carcinoma (the so-called onycholemmal carcinoma). The concluding tables emphasize the key and essential histological features required to make the diagnosis of site-specific nail tumors and guide appropriate therapy. The author proposes to categorize subungual tumors into 2 types: subungual skin tumors (including subungual skin metastasis from internal malignancies) and nail tumors. Nail tumors can be accurately classified using a combined clinical and histogenetic approach. This new and expanding group of appendageal tumors is important for both dermatologists and dermatopathologists for the potential early detection of a malignant lesion or for the avoidance of overtreatment of a benign lesion.


Prevention of tuberculosis in macaques after intravenous BCG immunization.
Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide1. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission1,2. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta). Compared with intradermal or aerosol delivery, intravenous immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage and lung lymph nodes. Moreover, intravenous immunization induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues. Six months after BCG vaccination, macaques were challenged with virulent Mtb. Notably, nine out of ten macaques that received intravenous BCG vaccination were highly protected, with six macaques showing no detectable levels of infection, as determined by positron emission tomography-computed tomography imaging, mycobacterial growth, pathology and granuloma formation. The finding that intravenous BCG prevents or substantially limits Mtb infection in highly susceptible rhesus macaques has important implications for vaccine delivery and clinical development, and provides a model for defining immune correlates and mechanisms of vaccine-elicited protection against tuberculosis.


Functional importance of regions in Escherichia coli elongation factor NusA that interact with RNA polymerase, the bacteriophage lambda N protein and RNA.
The association of the essential Escherichia coli protein NusA with RNA polymerase increases pausing and the efficiency of termination at intrinsic terminators. NusA is also part of the phage lambda N protein-modified antitermination complex that functions to prevent transcriptional termination. We have investigated the structure of NusA using various deletion fragments of NusA in a variety of in vitro assays. Sequence and structural alignments have suggested that NusA has both S1 and KH homology regions that are thought to bind RNA. We show here that the portion of NusA containing the S1 and KH homology regions is important for NusA to enhance both termination and antitermination. There are two RNA polymerase-binding regions in NusA, one in the amino-terminal 137 amino acids and the other in the carboxy-terminal 264 amino acids; only the amino-terminal RNA polymerase-binding region provides a functional contact that enhances termination at an intrinsic terminator or antitermination by N. The carboxy-terminal region of NusA is also required for interaction with N and is important for the formation of an N-NusA-nut site or N-NusA-RNA polymerase-nut site complex; the instability of complexes lacking this carboxy-terminal region of NusA that binds N and RNA polymerase can be compensated for by the presence of the additional E. coli elongation factors, NusB, NusG and ribosomal protein S10.


Targeting eukaryotic protein translation in mesothelioma.
The default mechanism for protein translation in eukaryotes involves activation of the eIF4 complex at the 5' end of mRNA. This activity is upregulated in cancers, resulting in the expression of a variety of proteins necessary for the development and maintenance of the neoplastic state. Not surprisingly, mesothelioma demonstrates this same reliance on activation of 5' cap mediated translation. Efforts are ongoing to target and exploit our knowledge of this key molecular switch for cancer therapy. Agents targeting the critical eIF4E cap binding protein, disruption of the eIF4 complex, and exploitation for oncolytic virotherapy are some of the important areas of current research in mesothelioma protein translational research.


Decoupling electron and phonon transport in single-nanowire hybrid materials for high-performance thermoelectrics.
Organic-inorganic hybrids have recently emerged as a class of high-performing thermoelectric materials that are lightweight and mechanically flexible. However, the fundamental electrical and thermal transport in these materials has remained elusive due to the heterogeneity of bulk, polycrystalline, thin films reported thus far. Here, we systematically investigate a model hybrid comprising a single core/shell nanowire of Te-PEDOT:PSS. We show that as the nanowire diameter is reduced, the electrical conductivity increases and the thermal conductivity decreases, while the Seebeck coefficient remains nearly constant-this collectively results in a figure of merit, ZT, of 0.54 at 400 K. The origin of the decoupling of charge and heat transport lies in the fact that electrical transport occurs through the organic shell, while thermal transport is driven by the inorganic core. This study establishes design principles for high-performing thermoelectrics that leverage the unique interactions occurring at the interfaces of hybrid nanowires.


Contextual factors related to implementation of classroom physical activity breaks.
Brief structured physical activity in the classroom is effective for increasing student physical activity. The present study investigated the association between implementation-related contextual factors and intervention implementation after adoption of a structured classroom physical activity intervention. Six elementary-school districts adopted structured classroom physical activity programs in 2013-2014. Implementation contextual factors and intervention implementation (structured physical activity provided in past week or month, yes/no) were assessed using surveys of 337 classroom teachers from 24 schools. Mixed-effects models accounted for the nested design. Availability of resources (yes/no, ORs = 1.91-2.93) and implementation climate z-scores (ORs = 1.36-1.47) were consistently associated with implementation. Teacher-perceived classroom behavior benefits (OR = 1.29) but not student enjoyment or health benefits, and time (OR = 2.32) and academic (OR = 1.63) barriers but not student cooperation barriers were associated with implementation (all z-scores). Four implementation contextual factor composites had an additive association with implementation (OR = 1.64 for each additional favorable composite). Training and technical assistance alone may not support a large proportion of teachers to implement structured classroom physical activity. In addition to lack of time and interference with academic lessons, school climate related to whether administrators and other teachers were supportive of the intervention were key factors explaining whether teachers implemented the intervention. Evidence-based implementation strategies are needed for effectively communicating the benefits of classroom physical activity on student behavior and improving teacher and administrator climate/attitudes around classroom physical activity.


Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire.
Human immunodeficiency virus 1 (HIV-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using freshly isolated peripheral blood mononuclear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-1-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCR) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-1-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using V alpha and V beta family-specific primers was performed on each clone, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized V alpha 14 and V beta 4 genes. Sequence analysis of the TCR revealed the first nine clones isolated to also be identical at the nucleotide level. The TCR-alpha junctional region sequence of the tenth clone was identical to the junctional region sequences of the other nine, but this clone utilized distinct D beta and J beta gene segments. This study provides evidence that the observed high degree of HIV-1-specific CTL activity may be due to monoclonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.


Early and phasic cortical metabolic changes in vestibular neuritis onset.
Functional brain activation studies described the presence of separate cortical areas responsible for central processing of peripheral vestibular information and reported their activation and interactions with other sensory modalities and the changes of this network associated to strategic peripheral or central vestibular lesions. It is already known that cortical changes induced by acute unilateral vestibular failure (UVF) are various and undergo variations over time, revealing different cortical involved areas at the onset and recovery from symptoms. The present study aimed at reporting the earliest change in cortical metabolic activity during a paradigmatic form of UVF such as vestibular neuritis (VN), that is, a purely peripheral lesion of the vestibular system, that offers the opportunity to study the cortical response to altered vestibular processing. This research reports [(18)F]fluorodeoxyglucose positron emission tomography brain scan data concerning the early cortical metabolic activity associated to symptoms onset in a group of eight patients suffering from VN. VN patients' cortical metabolic activity during the first two days from symptoms onset was compared to that recorded one month later and to a control healthy group. Beside the known cortical response in the sensorimotor network associated to vestibular deafferentation, we show for the first time the involvement of Entorhinal (BAs 28, 34) and Temporal (BA 38) cortices in early phases of symptomatology onset. We interpret these findings as the cortical counterparts of the attempt to reorient oneself in space counteracting the vertigo symptom (Bas 28, 34) and of the emotional response to the new pathologic condition (BA 38) respectively. These interpretations were further supported by changes in patients' subjective ratings in balance, anxiety, and depersonalization/derealization scores when tested at illness onset and one month later. The present findings contribute in expanding knowledge about early, fast-changing, and complex cortical responses to pathological vestibular unbalanced processing.


Interstitial spinal-cord oedema in syringomyelia associated with Chiari type 1 malformations.
The pathophysiology of syringomyelia in Chiari type 1 malformations has not been clarified. Oedema-like spinal-cord swelling was recently reported in several pathological conditions, including Chiari type 1 malformations as a pre-syrinx state. However, the role of the pre-syrinx state in the development of syringomyelia is unknown. The purpose of this study is to investigate the parenchymal changes of the spinal cord in syringomyelia associated with Chiari type 1 malformations. Pre- and postoperative MRI findings in 14 patients who underwent foramen magnum decompression in our institute were reviewed. The analysis was focused on differences in visualisation of the syrinx between T1- and T2-weighted images and abnormal parenchymal signal changes. There were 6 men and 8 women, aged from 6 to 79 years. No patients showed hydrocephalus. Twelve patients had large and expansive syrinx, whereas 2 patients showed small syrinx confined to the centre of the spinal cord. T2-weighted images displayed significantly larger intramedullary abnormal signal areas. Nine patients showed parenchymal hyperintensity areas around the enlarged central canal or base of the posterior white columns adjacent to the syringomyelic cavity. Such parenchymal hyperintensity areas markedly diminished with reduction of the syrinx after surgery and were considered to be interstitial oedema. From this study, the interstitial oedema of the spinal cord commonly accompanies syringomyelia with Chiari type 1 malformations. Accumulation of the extracellular fluid due to disturbed absorption mechanisms may play an important role in the pathophysiology of syringomyelia associated with Chiari type 1 malformations.


A Systemic Review of Adult Mesenchymal Stem Cell Sources and their Multilineage Differentiation Potential Relevant to Musculoskeletal Tissue Repair and Regeneration.
Adult mesenchymal stem cells (MSCs) were first isolated from bone marrow by Friedenstein in 1976. These cells were clonogenic, non-haematopoietic, and able to replicate extensively in vitro. The fields of regenerative medicine and tissue engineering have grown dramatically since their inception. In the decades since, MSCs have been identified from mesoderm-, endoderm- and ectoderm-derived tissues. In light of our ageing population, the need for effective cell-based therapies for tissue repair and regeneration is ever-expanding. The purpose of this systematic review was to summarise evidence from the most recent studies outlining different sources of adult MSCs and their suitability in musculoskeletal applications. Online published articles were searched for using the PubMed/MEDLINE and Ovid databases, and relevant articles fulfilling the pre-defined eligibility criteria were analysed. To date, MSCs have been isolated from a number of adult tissues, including trabecular bone, adipose tissue, bone marrow, synovium, dermis, periodontal ligament, dental pulp, bursa and the umbilical cord. Bone marrow MSCs are currently considered the gold standard, with which newly discovered sources are compared on the basis of their renewal capabilities and multipotency. Furthermore, MSCs have been successful in the regeneration of osteonecrosis, osteoarthritis, bony defects, fracture remodeling and so on. Unfortunately, significant hurdles remain and will need to be overcome before tissue engineering using MSCs becomes routine in clinical practice. Thus, further research and understanding are required into the safe and effective sourcing and application of mesenchymal stem cells in musculoskeletal applications.


Buoyancy and solar spin-down.
The transition of a cylinder of water with a vertical density gradient between convective and viscous spindown occurs near the point at which the maximum buoyancy force equals the radial pressure gradient that is driving the convection. A similar analysis applied to the sun shows the maximum buoyancy force to be 1500 times the convective force. A rapidly rotating solar interior would not be damped by largescale convection.


Evidence of accelerated aging among African Americans and its implications for mortality.
Blacks experience morbidity and mortality earlier in the life course compared to whites. Such premature declines in health may be indicative of an acceleration of the aging process. The current study uses data on 7644 black and white participants, ages 30 and above, from the third National Health and Nutrition Examination Survey, to compare the biological ages of blacks and whites as indicated from a combination of ten biomarkers and to determine if such differences in biological age relative to chronological age account for racial disparities in mortality. At a specified chronological age, blacks are approximately 3 years older biologically than whites. Differences in biological age between blacks and whites appear to increase up until ages 60-65 and then decline, presumably due to mortality selection. Finally, differences in biological age were found to completely account for higher levels of all-cause, cardiovascular and cancer mortality among blacks. Overall, these results suggest that being black is associated with significantly higher biological age at a given chronological age and that this is a pathway to early death both overall and from the major age-related diseases.


Psychobiotics and the gut-brain axis: in the pursuit of happiness.
The human intestine houses an astounding number and species of microorganisms, estimated at more than 10(14) gut microbiota and composed of over a thousand species. An individual's profile of microbiota is continually influenced by a variety of factors including but not limited to genetics, age, sex, diet, and lifestyle. Although each person's microbial profile is distinct, the relative abundance and distribution of bacterial species is similar among healthy individuals, aiding in the maintenance of one's overall health. Consequently, the ability of gut microbiota to bidirectionally communicate with the brain, known as the gut-brain axis, in the modulation of human health is at the forefront of current research. At a basic level, the gut microbiota interacts with the human host in a mutualistic relationship - the host intestine provides the bacteria with an environment to grow and the bacterium aids in governing homeostasis within the host. Therefore, it is reasonable to think that the lack of healthy gut microbiota may also lead to a deterioration of these relationships and ultimately disease. Indeed, a dysfunction in the gut-brain axis has been elucidated by a multitude of studies linked to neuropsychological, metabolic, and gastrointestinal disorders. For instance, altered microbiota has been linked to neuropsychological disorders including depression and autism spectrum disorder, metabolic disorders such as obesity, and gastrointestinal disorders including inflammatory bowel disease and irritable bowel syndrome. Fortunately, studies have also indicated that gut microbiota may be modulated with the use of probiotics, antibiotics, and fecal microbiota transplants as a prospect for therapy in microbiota-associated diseases. This modulation of gut microbiota is currently a growing area of research as it just might hold the key to treatment.


Novel insights into mechanisms for Pak1-mediated regulation of cardiac Ca(2+) homeostasis.
A series of recent studies report novel roles for Pak1, a key member of the highly conserved family of serine-threonine protein kinases regulated by Ras-related small G-proteins, Cdc42/Rac1, in cardiac physiology and cardioprotection. Previous studies had identified Pak1 in the regulation of hypertrophic remodeling that could potentially lead to heart failure. This article provides a review of more recent findings on the roles of Pak1 in cardiac Ca(2+) homeostasis. These findings identified crucial roles for Pak1 in cardiomyocyte Ca(2+) handling and demonstrated that it functions through unique mechanisms involving regulation of the post-transcriptional activity of key Ca(2+)-handling proteins, including the expression of Ca(2+)-ATPase SERCA2a, along with the speculative possibility of an involvement in the maintenance of transverse (T)-tubular structure. They highlight important regulatory functions of Pak1 in Ca(2+) homeostasis in cardiac cells, and identify novel potential therapeutic strategies directed at manipulation of Pak1 signaling for the management of cardiac disease, particularly heart failure.


Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial.
Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections. The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection. The MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).


Efficacy of fusion peptide homologs in blocking cell lysis and HIV-induced fusion.
Contrary to earlier reports, we have found that tri- and hexapeptides analogous or homologous with segments of the 23-residue N-terminal fusion sequence (FS) of the viral transmembrane glycoprotein gp41 (residues 517-539) did not significantly inhibit HIV-1-induced syncytium formation, using an uninfected cell-infected cell fusion assay. In contrast, we found that the high molecular weight apolipoprotein A-1 and a 23-residue analog of the FS, with the phenylalanine residues at positions 524 and 527 replaced with alanine residues, were effective inhibitors. Although the tripeptides were ineffective as inhibitors of syncytium formation, we found a number of them inhibited red cell lysis induced by the synthetic peptide AVGIGALFLGFLGAAGSTMGARS (based on the HIV-1 gp41 FS). This effect was also seen with apolipoprotein A-1. The Ala524,527 analog of the fusion sequence could not be tested in this system because it was hemolytic. We concluded that the smaller peptides were effective inhibitors of hemolysis because they interfered with pore formation by the fusion sequence peptide, either by disrupting the pores or by preventing the peptide from adopting the alpha-helical conformation found in the pores. On the other hand, membrane fusion, which is a prelude to syncytium formation, has been shown to require the fusion sequence in the beta-strand conformation. We argue that small peptides would be unable to block interaction between such strands, although larger molecules, such as apolipoprotein A-1 and the Ala524,527 analog, would be able to do so and thus inhibit fusion. It seems, therefore, that a successful drug directed against the FS-cell membrane interaction stage of syncytium formation would need to be of relatively high molecular weight and complexity.


MarrowCellDLD: a microfluidic method for label-free retrieval of fragile bone marrow-derived cells.
Functional bone marrow studies have focused primarily on hematopoietic progenitors, leaving limited knowledge about other fragile populations, such as bone marrow adipocytes (BMAds) and megakaryocytes. The isolation of these cells is challenging due to rupture susceptibility and large size. We introduce here a label-free cytometry microsystem, MarrowCellDLD, based on deterministic lateral displacement. MarrowCellDLD enables the isolation of large, fragile BM-derived cells based on intrinsic size properties while preserving their viability and functionality. Bone marrow adipocytes, obtained from mouse and human stromal line differentiation, as well as megakaryocytes, from primary human CD34+ hematopoietic stem and progenitor cells, were used for validation. Precise micrometer-range separation cutoffs were adapted for each cell type. Cells were sorted directly in culture media, without pre-labeling steps, and with real-time imaging for quality control. At least 106 cells were retrieved intact per sorting round. Our method outperformed two FACS instruments in purity and yield, particularly for large cell size fractions. MarrowCellDLD represents a non-destructive sorting tool for large, fragile BM-derived cells, facilitating the separation of pure populations of BMAds and megakaryocytes to further investigate their physiological and pathological roles.


Error rates for unvalidated medical age assessment procedures.
During 2014-2015, Sweden received asylum applications from more than 240,000 people, of which more than 40,000 were termed unaccompanied minors. In a large number of cases, claims by asylum seekers of being below 18 years were not trusted by Swedish authorities. To handle the situation, the Swedish national board of forensic medicine (Rättsmedicinalverket, RMV) was assigned by the government to create a centralized system for medical age assessments. RMV introduced a procedure including two biological age indicators; x-ray of the third molars and magnetic resonance imaging of the distal femoral epiphysis. In 2017, a total of 9617 males and 337 females were subjected to this procedure. No validation study for the procedure was however published, and the observed number of cases with different maturity combinations in teeth and femur were unexpected given the claims originally made by RMV. We present a general stochastic model enabling us to study which combinations of age indicator model parameters and age population profiles are consistent with the observed 2017 data for males. We find that, contrary to some RMV claims, maturity of the femur, as observed by RMV, appears on average well before maturity of teeth. According to our estimates, approximately 15% of the tested males were children. These children had an approximate 33% risk of being classified as adults. The corresponding risk for an adult to be misclassified as a child was approximately 7%. We determine uncertainties and ranges of estimates under reasonable perturbations of the prior.


Confined wave packets in the domain of Rayleigh-Wood anomalies.
It is known that near grating anomalies of the resonance type a beam may undergo a lateral shift of the order of the beam width, and a pulse may be delayed by a time of the order of the pulse duration. These numerical investigations are extended to Rayleigh anomalies that occur when, upon variation of the wavelength or the angle of incidence, an additional propagating diffraction order emerges. It is shown that delays and displacements are 1 order of magnitude smaller than in the resonance case. However, with increasing beam width (or pulse duration), the lateral displacement (or the temporal delay) can become large.


Photocatalytic TiO2 Micromotors for Removal of Microplastics and Suspended Matter.
Environmental contamination is a major global challenge, and the effects of contamination are found in most habitats. In recent times, the pollution by microplastics has come to the global attention and their removal displays an extraordinary challenge with no reasonable solutions presented so far. One of the new technologies holding many promises for environmental remediation on the microscale are self-propelled micromotors. They present several properties that are of academic and technical interest, such as the ability to overcome the diffusion limitation in catalytic processes, as well as their phoretic interaction with their environment. Here, we present two novel strategies for the elimination of microplastics using photocatalytic Au@Ni@TiO2-based micromotors. We show that individual catalytic particles as well as assembled chains show excellent collection and removal of suspended matter and microplastics from environmental water samples.


Resveratrol for Weight Loss in Obesity: An Assessment of Randomized Control Trial Designs in ClinicalTrials.gov.
Resveratrol is a polyphenol that may improve weight loss outcomes in obese individuals. However, assessing the effectiveness of resveratrol supplementations as an appropriate intervention for weight loss in obesity across randomized control trials (RCTs) has been complicated by variability in their design. This study aims to evaluate design elements across RCTs of resveratrol interventions in obesity with weight loss as an end-point outcome, as recorded in ClinicalTrials.gov. We found discrepancies in participant inclusion criteria (sample size, age ranges, sex, BMI, medical conditions), interventional design (delivery modalities, dosages, duration) and primary outcomes measured (anthropomorphic, blood biomarkers). We identified a near three-fold variation in study sample size, two-fold variation in minimum inclusion age, five modalities of therapeutic resveratrol delivery with interventional durations ranging from two weeks to six months. Weight loss was only identified as a primary outcome in three of the seven studies evaluated. In conclusion, heterogeneity in trial design using resveratrol suggests that weight-loss-related outcomes are difficult to interpret and cross-validate. Indeed, conclusions drawn from human studies have been inconsistent, which may be attributed to study design heterogeneity including major differences in sample population, age, sex, BMI, underlying health conditions and end-point measures.


Detection of the p53 regulator murine double-minute protein 2 in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by hyperplasia of synovial lining tissue, which is involved directly in the damage of cartilage and bone. One of the factors thought to contribute to this synovial lining hyperplasia is dysregulation of, or functional abnormality in, the tumor suppressor protein p53. The protein known as murine double-minute protein 2 (MDM2) is the major negative regulator of p53, and in tumors contributes to increased cell proliferation. The detection of MDM2 in rheumatoid synovium has not previously been described. We investigated whether this protein is detectable in cells and tissues derived from patients with RA. Expression of MDM2 protein was examined in fibroblast-like synoviocytes (FLS) by methods including permeabilization flow cytometry, immunofluorescence, and Western blotting, and in synovial tissues using immunohistochemistry. The proliferative capacity of these cells was also examined using 3H/thymidine incorporation. Cell cycle analysis was performed by propidium iodide incorporation. MDM2 was detected in RA FLS and synovial tissues. MDM2 protein was identified in CD14-positive and CD14-negative synovial lining cells and CD14-positive sublining cells. RA FLS exhibited faster proliferative rates and higher levels of MDM2 expression than FLS derived from patients with osteoarthritis (OA). Both OA and RA FLS were found to be in similar phases of the cell cycle at the time of MDM2 protein analysis. The abundant expression of MDM2 in RA may be a contributing factor to the hypoapoptotic phenotype of lining tissue through its capacity to downregulate p53 levels and effects. Further studies are required to determine the relationship between this cell-cycle protein profile, tissue hyperplasia, and the functional abnormality of p53 in RA.


Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation.
Several adult stem cell populations exhibit myogenic regenerative potential, thus representing attractive candidates for therapeutic approaches of neuromuscular diseases such as Duchenne Muscular Dystrophy (DMD). We have recently shown that systemic delivery of MuStem cells, skeletal muscle-resident stem cells isolated in healthy dog, generates the remodelling of muscle tissue and gives rise to striking clinical benefits in Golden Retriever Muscular Dystrophy (GRMD) dog. This global effect, which is observed in the clinically relevant DMD animal model, leads us to question here the molecular pathways that are impacted by MuStem cell transplantation. To address this issue, we compare the global gene expression profile between healthy, GRMD and MuStem cell treated GRMD dog muscle, four months after allogenic MuStem cell transplantation. In the dystrophic context of the GRMD dog, disease-related deregulation is observed in the case of 282 genes related to various processes such as inflammatory response, regeneration, calcium ion binding, extracellular matrix organization, metabolism and apoptosis regulation. Importantly, we reveal the impact of MuStem cell transplantation on several molecular and cellular pathways based on a selection of 31 genes displaying signals specifically modulated by the treatment. Concomitant with a diffuse dystrophin expression, a histological remodelling and a stabilization of GRMD dog clinical status, we show that cell delivery is associated with an up-regulation of genes reflecting a sustained enhancement of muscle regeneration. We also identify a decreased mRNA expression of a set of genes having metabolic functions associated with lipid homeostasis and energy. Interestingly, ubiquitin-mediated protein degradation is highly enhanced in GRMD dog muscle after systemic delivery of MuStem cells. Overall, our results provide the first high-throughput characterization of GRMD dog muscle and throw new light on the complex molecular/cellular effects associated with muscle repair and the clinical efficacy of MuStem cell-based therapy.


Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci.
Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC (P < 1 × 10(-7); Bonferroni), including probes in the recently reported HIF3A, CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP, KDM2B, PBX1 and BBS2, among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.


Highly Confined and Switchable Mid-Infrared Surface Phonon Polariton Resonances of Planar Circular Cavities with a Phase Change Material.
Mid-infrared (MIR) photonics demands highly confined optical fields to obtain efficient interaction between long-wavelength light and nanomaterials. Surface polaritons excited on polar semiconductor and metallic material interfaces exhibit near-fields localized on subwavelength scales. However, realizing a stronger field concentration in a cavity with a high quality ( Q) factor and a small mode volume is still challenging in the MIR region. This study reports MIR field concentration of surface phonon polaritons (SPhPs) using planar circular cavities with a high Q factor of ∼150. The cavities are fabricated on a thin film of the phase change material Ge3Sb2Te6 (GST) deposited on a silicon carbide (SiC) substrate. Scattering-type scanning near-field optical microscopy visualizes the near-field distribution on the samples and confirms directly that the SPhP field is strongly concentrated at the center of the centrosymmetric cavities. The smallest concentrated field size is 220 nm in diameter which corresponds to 1/50 of the wavelength of the incident light that is far below the diffraction limit. The thin GST film enhances the SPhP confinement, and it is used to switch the confinement off by tuning the cavity resonance induced by the phase change from the amorphous to the crystalline phase. This subwavelength and switchable field concentration within a high- Q polariton cavity has the potential to greatly enhance the light-matter interaction for molecular sensing and emission enhancement in MIR systems.


IgA receptors in health and disease.
The varied interaction of the Fc region of IgA with receptors confers this antibody class with many of its unique properties. The epithelial polymeric Ig receptor on mucosal epithelial cells transports polymeric immunoglobulin A (pIgA) produced by mucosal B cells to the mucosal surface where, in complex with the secretory component (SC), this secretory immunoglobulin A (SIgA) excludes the multitude of dietary, environmental, and microbial antigens that continuously bombard the mucosae. In health, this IgA-mediated exclusion not only forms the initial defence against infection, it also spares the systemic immune system from potentially deleterious responses to innocuous antigens which can otherwise culminate in inflammatory bowel disease or asthma. Beyond antigen exclusion, in closer encounters with antigens, IgA receptors play roles in protective immunity and disease. FcaRI is the principal myeloid IgA receptor and is responsible for differing IgA-mediated effector responses such as respiratory burst, degranulation, and phagocytosis variously by granulyoctes, monocytes, and macrophages. Furthermore an unknown IgA receptor specific for the secretory component (SC) elicits powerful effector responses from eosinophils. On dendritic cells, FcaRI participates in antigen presentation while on microfold cells, key cells in mucosal antigen presentation, another unknown IgA receptor functions in the transport of antigens across the mucosal epithelial barrier. The activity of another uncharacterized IgA1/IgD receptor on T cells may affect autoimmune disorders. The interplay of different IgA receptors affects immune complex deposition in the common renal disease immunoglobulin A nephropathy (IgAN). Finally, the therapeutic application of various IgA receptors has been sought in the areas of infectious disease, vaccines, and cancer.


Evolutionary Rescue over a Fitness Landscape.
Evolutionary rescue describes a situation where adaptive evolution prevents the extinction of a population facing a stressing environment. Models of evolutionary rescue could in principle be used to predict the level of stress beyond which extinction becomes likely for species of conservation concern, or, conversely, the treatment levels most likely to limit the emergence of resistant pests or pathogens. Stress levels are known to affect both the rate of population decline (demographic effect) and the speed of adaptation (evolutionary effect), but the latter aspect has received less attention. Here, we address this issue using Fisher's geometric model of adaptation. In this model, the fitness effects of mutations depend both on the genotype and the environment in which they arise. In particular, the model introduces a dependence between the level of stress, the proportion of rescue mutants, and their costs before the onset of stress. We obtain analytic results under a strong-selection-weak-mutation regime, which we compare to simulations. We show that the effect of the environment on evolutionary rescue can be summarized into a single composite parameter quantifying the effective stress level, which is amenable to empirical measurement. We describe a narrow characteristic stress window over which the rescue probability drops from very likely to very unlikely as the level of stress increases. This drop is sharper than in previous models, as a result of the decreasing proportion of stress-resistant mutations as stress increases. We discuss how to test these predictions with rescue experiments across gradients of stress.