Kinetic manifestation of processivity during multiple methylations catalyzed by SET domain protein methyltransferases.
Processive versus distributive methyl group transfer was assessed for pea Rubisco large subunit methyltransferase, a SET domain protein lysine methyltransferase catalyzing the formation of trimethyllysine-14 in the large subunit of Rubisco. Catalytically competent complexes between an immobilized form of des(methyl) Rubisco and Rubisco large subunit methyltransferase were used to demonstrate enzyme release that was co-incident with and dependent on formation of trimethyllysine. Catalytic rate constants determined for formation of trimethyllysine were considerably lower ( approximately 10-fold) than rate constants determined for total radiolabel incorporation from [3H-methyl]-S-adenosylmethionine. Double-reciprocal velocity plots under catalytic conditions favoring monomethyllysine indicated a random or ordered reaction mechanism, while conditions favoring trimethyllysine suggested a hybrid ping-pong mechanism. These results were compared with double-reciprocal velocity plots and product analyses obtained for HsSET7/9 (a monomethyltransferase) and SpCLR4 (a dimethyltransferase) and suggest a predictive ability of double-reciprocal velocity plots for single versus multiple methyl group transfers by SET domain protein lysine methyltransferases. A model is proposed for SET domain protein lysine methyltransferases in which initial binding of polypeptide substrate and S-adenosylmethionine is random, with polypeptide binding followed by deprotonation of the epsilon-amine of the target lysyl residue and subsequent methylation. Following methyl group transfer, S-adenosylhomocysteine and monomethylated polypeptide dissociate from monomethyltransferases, but di- and trimethyltransferases begin a successive and catalytically obligatory deprotonation of enzyme-bound methylated lysyl intermediates, which along with binding and release of S-adenosylmethionine and S-adenosylhomocysteine is manifested as a hybrid ping-pong-like reaction mechanism.


Infantile-onset Pompe disease complicated by sickle cell anemia: Case report and management considerations.
Infantile-onset Pompe disease (IOPD) is a rare, severe disorder of lysosomal storage of glycogen that leads to progressive cardiac and skeletal myopathy. IOPD is a fatal disease in childhood unless treated with enzyme replacement therapy (ERT) from an early age. Sickle cell anemia (SCA) is a relatively common hemoglobinopathy caused by a specific variant in the hemoglobin beta-chain. Here we report a case of a male newborn of African ancestry diagnosed and treated for IOPD and SCA. Molecular testing confirmed two GAA variants, NM_000152.5: c.842G>C, p.(Arg281Pro) and NM_000152.5: c.2560C>T, p.(Arg854*) in trans, and homozygosity for the HBB variant causative of SCA, consistent with his diagnosis. An acute neonatal presentation of hypotonia and cardiomyopathy required ERT with alglucosidase alfa infusions preceded by immune tolerance induction (ITI), as well as chronic red blood cell transfusions and penicillin V potassium prophylaxis for treatment of IOPD and SCA. Clinical course was further complicated by multiple respiratory infections. We review the current guidelines and interventions taken to optimize his care and the pitfalls of those guidelines when treating patients with concomitant conditions. To the best of our knowledge, no other case reports of the concomitance of these two disorders was found. This report emphasizes the importance of newborn screening, early intervention, and treatment considerations for this complex patient presentation of IOPD and SCA.


Systematic cytokine receptor profiling reveals GM-CSF as a novel TLR-independent activator of human plasmacytoid predendritic cells.
Human plasmacytoid predendritic cells (pDCs) can be activated during microbial infection through Toll-like receptor engagement. They are also involved in nonmicrobial inflammatory diseases, but their activation pathways in this context remain elusive. To identify Toll-like receptor-independent pDC activators, we performed a systematic analysis of cytokine receptors on primary human pDCs. Six receptors were expressed both at mRNA and protein levels: interleukin-3 receptor (IL-3R), IL-6R, IL-10R, IL-18R, interferon-gamma receptor, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Only GM-CSF and IL-3 were able to efficiently promote pDC survival and induce their differentiation into dendritic cells. Allogeneic naive CD4 T cells primed with GM-CSF-activated pDCs produced more interferon-gamma and less IL-4 and IL-10 compared with IL-3-activated pDCs, indicating a shift in the Th1/Th2 balance. Our data point at a novel function of GM-CSF, which may serve as a link between a pathologic inflammatory environment, pDC activation, and the modulation of CD4 T-cell responses.


Western-style diet induces insulin insensitivity and hyperactivity in adolescent male rats.
The prevalence of obesity in children and adolescents has increased rapidly over the past 30 years, as has the incidence of attention deficit hyperactivity disorder (ADHD). In 2012, it was found that overweight children have a twofold higher chance of developing ADHD than their normal weight counterparts. Previous work has documented learning and memory impairments linked to consumption of an energy-dense diet in rats, but the relationship between diet and ADHD-like behaviors has yet to be explored using animal models. Therefore, the purpose of this study was to explore the role of diet in the etiology of attention and hyperactivity disorders using a rat model of diet-induced obesity. Male Sprague-Dawley rats were fed either a control diet or a Western-style diet (WSD) for ten weeks, and specific physiological and behavioral effects were examined. Tail blood samples were collected to measure fasting blood glucose and insulin levels in order to assess insulin insensitivity. Rats also performed several behavioral tasks, including the open field task, novel object recognition test, and attentional set-shifting task. Rats exposed to a WSD had significantly higher fasting insulin levels than controls, but both groups had similar glucose levels. The quantitative insulin sensitivity check index (QUICKI) indicated the development of insulin resistance in WSD rats. Performance in the open field test indicated that WSD induced pronounced hyperactivity and impulsivity. Further, control diet animals were able to discriminate between old and novel objects, but the WSD animals were significantly impaired in object recognition. However, regardless of dietary condition, rats were able to perform the attentional set-shifting paradigm. While WSD impaired episodic memory and induced hyperactivity, attentional set-shifting capabilities are unaffected. With the increasing prevalence of both obesity and ADHD, understanding the potential links between the two conditions is of clinical relevance.


Presynaptic Regulation of Leptin in a Defined Lateral Hypothalamus-Ventral Tegmental Area Neurocircuitry Depends on Energy State.
Synaptic transmission controls brain activity and behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamic area (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types, and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole-cell patch-clamp recordings and post hoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone- and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding. A presynaptic mechanism mediated by distinct intracellular signaling mechanisms may account for this regulation by leptin. The regulatory effects of leptin depend on intact leptin receptor signaling. Interestingly, the synaptic regulatory function of leptin in the LHA-to-VTA neuronal pathway is highly sensitive to energy states: both energy deficiency (acute fasting) and excessive energy storage (high-fat diet-induced obesity) blunt the effect of leptin. These data revealed that leptin may regulate synaptic transmission in the LHA-to-VTA neurocircuitry in an inverted "U-shape" fashion dependent on plasma glucose levels and related to metabolic states.SIGNIFICANCE STATEMENT The lateral hypothalamic area (LHA) to ventral tegmental area (VTA) projection is an important neural pathway involved in balancing whole-body energy states and reward. We found that the excitatory synaptic inputs to both orexin- and melanin-concentrating hormone expressing LHA neurons projecting to the VTA were suppressed by leptin, a peptide hormone derived from adipocytes that signals peripheral energy status to the brain. Interestingly, energy states seem to affect how leptin regulates synaptic transmission since both the depletion of energy induced by acute food deprivation and excessive storage of energy by high-fat diet feeding dampen the suppressive effect of leptin on synaptic transmission. Together, these data show that leptin regulates synaptic transmission and might be important for maintaining energy homeostasis.


L337H mutant of rat neuronal nitric oxide synthase resembles human neuronal nitric oxide synthase toward inhibitors.
A common dichotomy exists in inhibitor design: should the compounds be designed to block the enzymes of animals in the preclinical studies or to inhibit the human enzyme? We report that a single mutation of Leu-337 in rat neuronal nitric oxide synthase (nNOS) to His makes the enzyme resemble human nNOS more than rat nNOS. We expect that the approach used in this study can unite the dichotomy and speed up the process of inhibitor design and development.


A concise self-report scale can identify high expressed emotions and predict higher relapse risk in schizophrenia.
Although high expressed emotions (EE) is one of the most significant predictors for schizophrenic relapse, the assessment of EE is often impeded by the demanding Camberwell Family Interview (CFI) that is required to be conducted by specifically trained staff. To enable a more efficient assessment of EE, we developed the 12-item Concise Chinese Level of Expressed Emotion Scale (CCLEES) and reported its predictive and concurrent validity in this study. A one-year prospective study design was adopted. Totally 101 participants diagnosed with schizophrenia were recruited from the department of psychiatry of a major acute hospital in Hong Kong. CCLEES was administered and subsequent relapse information was collected from all participants. At baseline, 10 family members of the participants were also administered CFI. Participants who scored above the optimal cut-off point (Score 13 on Criticism, and/or 13 on Hostility, and/or 15 on Emotional Over-involvement) showed a 6.3 times elevated 12-month schizophrenic relapse rate compared to those who scored below cut-off. The CCLEES also demonstrated excellent correspondence with CFI, the widely-recognized golden benchmark of EE assessment. The results support the CCLEES as a brief and psychometrically sound self-report measurement for EE in Chinese people with schizophrenia.


Intestinal Microbiota in Postmenopausal Breast Cancer Patients and Controls.
Previous preclinical and clinical research has investigated the role of intestinal microbiota in carcinogenesis. Growing evidence exists that intestinal microbiota can influence breast cancer carcinogenesis. However, the role of intestinal microbiota in breast cancer needs to be further investigated. This study aimed to identify the microbiota differences between postmenopausal breast cancer patients and controls. This prospective cohort study compared the intestinal microbiota richness, diversity, and composition in postmenopausal histologically proven ER+/HER2- breast cancer patients and postmenopausal controls. Patients scheduled for (neo)adjuvant adriamycin, cyclophosphamide (AC), and docetaxel (D), or endocrine therapy (tamoxifen) were prospectively enrolled in a multicentre cohort study in the Netherlands. Patients collected a faecal sample and completed a questionnaire before starting systemic cancer treatment. Controls, enrolled from the National Dutch Breast Cancer Screening Programme, also collected a faecal sample and completed a questionnaire. Intestinal microbiota was analysed by amplicon sequencing of the 16S rRNA V4 gene region. In total, 81 postmenopausal ER+/HER2- breast cancer patients and 67 postmenopausal controls were included, resulting in 148 faecal samples. Observed species richness, Shannon index, and overall microbial community structure were not significantly different between breast cancer patients and controls. There was a significant difference in overall microbial community structure between breast cancer patients scheduled for adjuvant treatment, neoadjuvant treatment, and controls at the phylum (p = 0.042) and genus levels (p = 0.015). Dialister (p = 0.001) and its corresponding family Veillonellaceae (p = 0.001) were higher in patients scheduled for adjuvant treatment, compared to patients scheduled for neoadjuvant treatment. Additional sensitivity analysis to correct for the potential confounding effect of prophylactic antibiotic use, indicated no differences in microbial community structure between patients scheduled for neoadjuvant systemic treatment, adjuvant systemic treatment, and controls at the phylum (p = 0.471) and genus levels (p = 0.124). Intestinal microbiota richness, diversity, and composition are not different between postmenopausal breast cancer patients and controls. The increased relative abundance of Dialister and Veillonellaceae was observed in breast cancer patients scheduled for adjuvant treatment, which might be caused by a relative decrease in other bacteria due to prophylactic antibiotic administration rather than an absolute increase.


The evolution of juvenile susceptibility to infectious disease.
Infection prior to reproduction usually carries greater fitness costs for hosts than infection later in life, suggesting selection should tend to favour juvenile resistance. Yet, juveniles are generally more susceptible than adults across a wide spectrum of host taxa. While physiological constraints and a lack of prior exposure can explain some of this pattern, studies in plants and insects suggest that hosts may trade off juvenile susceptibility against other life-history traits. However, it is unclear precisely how trade-offs shape the evolution of juvenile susceptibility. Here, we theoretically explore the evolution of juvenile susceptibility subject to trade-offs with maturation or reproduction, which could realistically occur due to resource allocation during development (e.g. prioritizing growth over immune defence). We show how host lifespan, the probability of maturation (i.e. of reaching the adult stage) and transmission mode affect the results. Our key finding is that elevated juvenile susceptibility is expected to evolve over a wide range of conditions, but should be lowest when hosts have moderate lifespans and an intermediate probability of reaching the adult stage. Our results elucidate how interactions between trade-offs and the epidemiological-demographic structure of the population can lead to the evolution of elevated juvenile susceptibility.


Audiological and Demographic Factors that Impact the Precision of Speech Categorization in Cochlear Implant Users.
The ability to adapt to subtle variations in acoustic input is a necessary skill for successful speech perception. Cochlear implant (CI) users tend to show speech perception benefits from the maintenance of their residual acoustic hearing. However, previous studies often compare CI users in different listening conditions within-subjects (i.e., in their typical Acoustic + Electric configuration compared with Acoustic-only or Electric-only configurations) and comparisons among different groups of CI users do not always reflect an Acoustic + Electric benefit. Existing work suggests that CI users with residual acoustic hearing perform similarly to Electric-only listeners on phonetic voicing contrasts and unexpectedly poorer with fricative contrasts which have little energy in the range of the Acoustic + Electric listeners' acoustic hearing. To further investigate how residual acoustic hearing impacts sensitivity to phonetic ambiguity, we examined whether device configuration, age, and device experience influenced phonetic categorization in a large individual differences study. CI users with various device configurations (Electric-only N = 41; Acoustic + Electric N = 95) categorized tokens from five /b-p/ and five /s-ʃ/ minimal pair continua (e.g., bet-pet; sock-shock). We investigated age, device experience, and when applicable, residual acoustic hearing (pure tone hearing thresholds) as predictors of categorization. We also examined the relationship between phonetic categorization and clinical outcomes (CNC, AzBio) in a subset of our sample. Acoustic + Electric CI users were better able to categorize along the voicing contrast (steeper categorization slope) compared with Electric-only users, but there was no group-level difference for fricatives. There were differences within the subgroups for fricatives: bilateral users showed better categorization than unilateral users and bimodal users had better categorization than hybrid users. Age was a significant factor for voicing, while device experience was significant for fricatives. Critically, within the Acoustic + Electric group, hybrid CI users had shallower slopes than bimodal CI users. Our findings suggest residual acoustic hearing is beneficial for categorizing stop voicing, but not frication. Age impacts the categorization of voicing, while device experience matters for fricatives. For CI users with ipsilateral residual acoustic hearing, those with better hearing thresholds may be over-relying on their acoustic hearing rather than extracting as much information as possible from their CI, and thus have shallower fricative categorization.


[A Case of Intra-abdominal Tuberculosis Due to Mycobacterium bovis Mimicking Ovarian Cancer: Importance of Microbiological Diagnosis].
Mycobacterium bovis causes gastrointestinal tuberculosis by being transmitted through consumption of infected milk and dairy products, mostly in developing countries, and can spread to the other neighbourhood intra-abdominal tissues and organs. In addition to the symptoms such as weight loss, weakness, abdominal pain, and chronic diarrhea in female patients with abdominal tuberculosis, findings such as pelvic mass, ascites and CA-125 elevation may be encountered. Patients with these symptoms usually preliminary diagnosed as having ovarian cancer. It is very important to distinguish between these two diseases quickly, which have different treatment protocols. In this case report, a case of intra-abdominal tuberculosis caused by M.bovis, whose diagnosis was confirmed by microbiological methods with the findings mimicking ovarian cancer such as weight loss, ascites, pelvic mass and increased CA-125 was presented. Tuberculosis was considered in the differential diagnosis of a 23-yearold female patient with abdominal pain, weight loss, ascites, pelvic mass, and elevated CA-125 (643.9 U/ml) findings and a mass in the left tubaovarian region on abdominal CT. The ileum biopsy sample taken during colonoscopy and ascitic fluid sample taken with paracentesis were sent to our laboratory for acid-fast bacilli (AFB) staining and tuberculosis culture. In our laboratory, samples were incubated in both liquid culture system [BACTEC MGIT 320 Mycobacteria Culture System (Becton Dickinson,USA)] and solid culture medium [Lowenstein-Jensen Medium (Becton Dickinson,USA)] and AFB smears were performed. While AFB smears were negative, ileum biopsy material showed growth on day 14 and ascitic fluid sample on day 11 in liquid culture medium. AFB smear was prepared from broth and red bacilli were seen on a blue background that formed cord factor. The bacillus was identified as Mycobacterium tuberculosis complex by the immunochromatographic rapid test [BD MGIT TBc Identification Test (BD,USA)]. The anti-tuberculosis drug treatment was initiated with the diagnosis of intra-abdominal tuberculosis. The isolated bacillus was found to be sensitive to isoniazid, rifampicin, ethambutol and resistant to streptomycin, according the drug susceptibility test results. Subspecies identification of M.tuberculosis complex was investigated by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) but could not be determined by this method. Genotyping was performed with the GenoType MTBC VER 1.X (Hain Lifescience, HardwiesenstraBe, Germany) kit. The isolate was identified as M.bovis. In the follow-up of the patient three months later, it was determined that tumor markers, ascitic fluid and intra-abdominal lymph nodes regressed significantly and the mass in the left ovary completely disappeared. In this report, we presented a case with intra-abdominal tuberculosis whose clinical, radiological and laboratory findings mimic ovarian cancer to imply the importance of microbiological diagnosis.


MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression.
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH-IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.


Model for Protein Concentration Gradients in the Cytoplasm.
Intracellular protein concentration gradients are generally thought to be unsustainable at steady-state due to diffusion. Here we show how protein concentration gradients can theoretically be sustained indefinitely through a relatively simple mechanism that couples diffusion to a spatially segregated kinase-phosphatase system. Although it is appreciated that such systems can theoretically give rise to phosphostate gradients, it has been assumed that they do not give rise to gradients in the total protein concentration. Here we show that this assumption does not hold if the two forms of protein have different diffusion coefficients. If, for example, the phosphorylated state binds selectively to a second larger protein or protein complex then a steady state gradient in total protein concentration will be created. We illustrate the principle with an analytical solution to the diffusion-reaction problem and by stochastic individual-based simulations using the Smoldyn program. We argue that protein gradients created in this way need to be considered in experiments using fluorescent probes and could in principle encode spatial information in the cytoplasm.


Friendship as protection from peer victimization for girls with and without ADHD.
The goal of this study was to examine the ability of friendship to moderate the association between behavioral risk and peer victimization for girls with attention-deficit/hyperactivity disorder (ADHD; n = 140) and comparison girls (n = 88) in a 5-week naturalistic summer camp setting. Participants were an ethnically and socioeconomically diverse group of girls ages 6-12. Parents and teachers reported on pre-summer internalizing behavior, externalizing behavior, and social competence. Participants reported on friendships and peer victimization through a peer report measure at the summer camps; friendship was scored via mutual nominations. Pre-summer externalizing behavior, internalizing behavior, and low social competence predicted peer victimization at the summer camps. Friendship moderated the association between behavioral risk and victimization for the entire sample, such that the presence of at least one friend reduced the risk of victimization. Additional analyses suggested that girls with ADHD were no more or less protected by the presence of a friendship than were comparison girls. Finally, preliminary analyses suggested that girls having only friends with ADHD were not significantly less protected than girls with at least one comparison friend. Future directions and implications for intervention are discussed.


Roles of hCG in Advancing Follicular Growth to Ovulation after Concurrent Injections of PGF(2α) and GnRH in Postpubertal Holstein Heifers Bearing a CL.
A study was conducted to test the hypothesis that injecting Gonadotropin-releasing hormone (GnRH) concurrently with Prostaglandin F2 alpha (PGF(2α)) followed by an injection of human Chorionic Gonadotropin (hCG), would advance follicular growth to ovulation in Holstein heifers bearing a corpus luteum (CL). After manual examination of the CL, group 1 (PGF; n = 12) received an injection of PGF(2α) (25 mg, im). Group 2 (PGF + GnRH; n = 13) received an injection of GnRH (100 μg, im) immediately after an injection of PGF(2α). Group 3 (PGF + GnRH + hCG; n = 12) received concurrent injections of PGF(2α) and GnRH followed with hCG (1500 IU, im) two days later. Follicular size and day of ovulation were monitored by daily ultrasonographic examination from days 1 to 10. Blood was collected on days-7, 0 (PGF(2α) administration), 2, and 7. Progesterone was not different (P > .05) on days-7, 0, and 2 between the experimental groups. However, it was higher (P < .005) in the PGF + GnRH + hCG group on day 7 compared to PGF + GnRH heifers, but not significantly higher than the PGF. Additionally, heifers in the PGF + GnRH + hCG group ovulated earlier (P < .05) than heifers in the PGF + GnRH and the PGF group. This data indicates that hCG advances follicular growth to ovulation in spite of high levels of progesterone when injected 48 h after concurrent treatments of GnRH and PGF(2α) on heifers bearing a CL.


Complete genome sequence of a novel bacteriophage, PBKP05, infecting Klebsiella pneumoniae.
An increasing number of Klebsiella pneumoniae isolates have been found to be multi-drug resistant. A novel bacteriophage, PBKP05, which infects K. pneumoniae, was isolated and characterized. It has a linear double-stranded DNA genome of 30,240 base pairs in length. Its G+C content is 53%, and 47 putative open reading frames are functionally annotated. This phage can be a candidate material for phage therapy.


Delayed antimicrobial therapy increases mortality and organ dysfunction duration in pediatric sepsis.
Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We sought to determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock. Retrospective observational study. PICU at an academic medical center. One hundred thirty patients treated for severe sepsis or septic shock. None. We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure-free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74-277 min) and to first appropriate antimicrobial was 177 minutes (90-550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27-12.06) and 3.59 (95% CI, 1.09-11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45-16.2) and 4.92 (95% CI, 1.30-18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure-free days (16 [interquartile range, 1-23] vs 20 [interquartile range, 6-26]; p = 0.04). Delayed antimicrobial therapy was an independent risk factor for mortality and prolonged organ dysfunction in pediatric sepsis.


Efficacy and safety of Shumian capsules in treating insomnia: A systematic review and meta-analysis.
It is known to all that the incidence of insomnia is becoming higher and higher with the increase of people's life stress. To some extent, it has brought about bad effects on people's life, work, study, and health, such as mental exhaustion, low work efficiency, and mood irritability. Now there are medications and non-medications methods for insomnia. As one of the treatments for insomnia, western medicine is to prolong the sleeping time and improve the anxious mood. However, taking western medicine to treat insomnia can also be accompanied by some adverse reactions at the same time, such as drug dependence, an allergic reaction, and so on. Traditional Chinese medicine therapy is based on syndrome differentiation and holistic concept. Shumian capsules (SM) are a kind of proprietary Chinese medicine for insomnia, which have the effect of relieving depression and calming the mind. But there are no studies on the efficacy and safety of SM in the treatment of insomnia. Therefore, I will provide a systematic review and meta-analysis to evaluate the efficacy and safety of SM for insomnia. All the studies searched were from PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and WanFang databases, and the studies types included in the analysis were all randomized controlled trials. All the retrieval contents were completed independently by 2 researchers, and a third reviewer would be involved when there existed any disagreement. The eligible studies were screened out according to the inclusion criteria and exclusion criteria, and some useful information was extracted and made into a feature table, including the year of the included studies, the age, and disease course of the participants in the studies and intervention methods, etc. Cochrane risk-of-bias tool was used to evaluate the quality of literature and meta-analysis was conducted by RevMan 5.4 software. A total of 9 articles including 709 participants were included in the study after screening out. The primary outcomes of statistical analysis were cure rate and total effective rate, while the secondary outcomes included Pittsburgh sleep quality index score and incidence of adverse reactions. The results showed that Pittsburgh sleep quality index score of the SM group and Western medicine group were statistically significant (MD = -0.50, 95% confidence interval [CI] = [-0.78, -0.22], P = .0005). The total effective rate of the SM group was slightly higher than that of the Western medicine group, but there was no statistical significance (relative risk [RR] = 1.03, 95% CI = [0.95,1.13], P = .43). This meta-analysis provides evidence for the efficacy and safety of SM in the treatment of insomnia, and provides a new idea for the clinical treatment of insomnia. But more research is needed to support further evidence.


A 24-Week Treatment of Pediatric Hemangioma with Oral Propranolol.
Hemangioma is a benign vascular tumor that shouldbe treated in problematic situations.Propranolol efficacy, target dose, range of age, duration of treatment and complications arenot conclusive for treatment of pediatric hemangioma. Our goal was to study efficacy and safety of propranolol for hemangioma treating in children. A randomized, open label crossover trial with two twenty four-week treatment phases separated by a one-week washout period, was conducted in Amir-Kabir Hospital, Arak, Iran. Thirty two patients with age of 1 month to 15 years were randomized to receive either oral propranolol 2 mg/Kg/day or receivedno treatment. The primary outcome measure changed in hemangioma size assessed at baseline, day 3, day 7, and every month. At baseline, the mean surface area was 36.9 ± 36.3 cm2. After 1 week of treatment, a decrease was seen in size of hemangiomas. After one month, a significant reduction was seen in size of lesionsin treatment group compared to observation group (30 cm2vs 16 cm2, P < 0.01). Significant reductions were present at other intervals (P < 0.05). In the second phase of the study, a significant reduction was observed only after one month of treatment (P < 0.05). The trial suggested that 24 week treatment with oral propranolol was effective for treatment of pediatric hemangiomas with acceptable safety profile.


[Efficiency of computed tomography in diagnosis of silicotuberculosis].
The routine methods X-ray study and computed tomography (CT) were compared in a group of patients engaged in fireproof industry. CT yields valuable additional data in early silicotuberculosis, which makes it possible to follow the extent of a silicotuberculous process more completely, to make a better diagnosis of nodal and focal shadows, to identify small decay cavities in the foci and infiltrates. CT is the method of choice in following up patients with silicotuberculosis.


Covalent attachment of soluble proteins by nonenzymatically glycosylated collagen. Role in the in situ formation of immune complexes.
The chronic tissue damage associated with long-term diabetes mellitus may arise in part from in situ immune complex formation by accumulated immunoglobulins and/or antigens bound to long-lived structural proteins that have undergone excessive nonenzymatic glycosylation. In this report, we have tested this hypothesis using nonenzymatically glycosylated collagen. Binding of both albumin and IgG averaged four times the amount bound to unmodified collagen. Both albumin and IgG (anti-BSA) bound to nonenzymatically glycosylated collagen retained their ability to form immune complexes in situ with free antibody and antigen.


Prospective Longitudinal Substance Use Patterns in Patients Preparing for Hepatitis C Treatment.
This study prospectively examined the independent courses of alcohol, drugs, and smoking over 18 months in 154 patients preparing for hepatitis C virus (HCV) treatment in relation to functioning, negative coping, and satisfaction with quality of life in data collected from a randomized controlled trial of multiple-family group psychoeducation for patients preparing for HCV treatment. Patients with HCV who had consistent abstinence, consistent use, or achievement of abstinence after study entry were examined for outcomes pertaining to functioning in the context of HCV, negative coping, and satisfaction with quality of life. Of 309 patients considering treatment for HCV recruited from outpatient clinics at two major university medical centers and a Veterans Affairs medical center for a randomized controlled trial of a psychoeducation intervention, 154 completed baseline, 6-month, and 18-month assessments. The assessments included structured diagnostic interviews; questionnaires examining functioning, coping, and satisfaction with quality of life; medical record review; and urine testing for substances of abuse. For these analyses, substance use patterns were determined as consistent abstinence, consistent use, and achieving abstinence after study entry for alcohol and drug use and smoking. The entire sample generally improved in all of these three outcomes over the course of the study. The course of alcohol, drugs, and smoking predicted HCV-related functioning, negative coping, and satisfaction with quality-of-life outcomes over 18 months. Three specific patterns of use (consistent abstinence, consistent use, and achievement of abstinence after study entry) of these substances diverged in association with outcomes related to functioning, negative coping, and satisfaction with quality of life, not only across trajectories over time within substance types but also among types of substances. This study's finding that different substances were associated with distinct clinical outcomes suggests the need to conceptually unbundle different types of substances in managing HCV. Future research is needed to examine the clinical utility of further unbundling these substances and also to further investigate effects of various amounts of use of these substances.


A qualitative phenomenological exploration of prolonged grief in New Delhi, India.
Prolonged grief disorder (PGD) is a condition characterized by difficulty in coping effectively with the loss of loved ones. The proposed diagnostic criteria for PGD have been based predominantly on research from developed Western nations. The cultural variations associated with experience and expression of grief and associated mourning rituals have not been considered comprehensively. The current study aimed to understand the experience of prolonged grief in India through a qualitative enquiry with mental health professionals (focus group discussions) and affected individuals (key informant interviews). Several novel findings diverging from the current understanding of manifestation and narratives of PGD emerged from the study, including differences in the social contexts of bereavement and culture-specific magico-religious beliefs and idioms of distress. The findings point to limitations of existing diagnostic systems for PGD. The results of this study suggest that the assumption of content equivalence for psychiatric disorders across cultures may not be justified and that there is a need to develop culturally sensitive diagnostic criteria and assessment scales for PGD.


peri-Acenoacenes.
We report the challenging synthesis and electronic properties of a new class of rhombic peri-fused acene dimers, the so-called peri-acenoacenes. Compared to rectangular peri-fused peri-acenes, peri-acenoacenes show less diradical character and higher stability. Two soluble and stable aryl-substituted peri-acenoacenes, peri-tetracenotetracene (TT-Ar) and peri-pentacenopentacene (PP-Ar), are synthesized and their structures are confirmed by X-ray crystallographic analysis. Their optical properties and electronic properties are different from those of peri-acene derivatives. Unexpectedly, both the neutral compounds and dications are aromatic.


Cancer stem cells: the emerging challenge of drug targeting.
Stem cells are defined by their unique property to self-renew and starting from one single cell to generate all the different progenies required for tissue regeneration. In adults, stem cells are still present in the majority of tissues and organs where they are responsible for continuous organs and tissues homeostasis. Adult stem cells have been isolated in various tissues and all share common specific characteristics (localization in stem cell niches, drug transporter expression, adhesion, levels of apoptosis inhibitors, DNA methylation, -) involved in high levels of drug resistance of this specific cell subtype. Several studies have identified different populations of cancer cells, within the same tumor, some of them which present properties closely related to normal stem cells and raised the concept of cancer stem cells. Interestingly, the cell surface markers expressed by these particular cancer cells are the same as those expressed by normal stem cells, suggesting that cancer can arise in some cases from the malignant transformation of stem cells. The cancer stem cell (CaSC) model predicts that, even if "conventional" cancer cells can be killed by chemotherapy or radiotherapy, only the destruction of CaSC, considered responsible for relapse, will allow full recovery, thus demonstrating the importance of CaSC-targeting for patient outcome. Therapeutic innovations will emerge from a better understanding of the biology and environment of cancer stem cells. The tumor environment can create a niche favoring the survival and proliferation of CaSC. It also protects CaSC from chemotherapy-induced apoptosis. Clinically, it is crucial to get rid of quiescent and resistant cells and to adapt the therapeutic strategy to cancer stem cells sheltered in niches. Here, we review the major characteristics of cancer stem cells and their behavior in response to chemotherapy; we also highlight the main issues to be considered for efficient and specific cancer stem cell targeting.


Age and Ketogenic Diet Have Dissociable Effects on Synapse-Related Gene Expression Between Hippocampal Subregions.
As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication. In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus. Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregion-specific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals.


Uptake and metabolism of propionate in the liver isolated from sheep treated with glucagon.
The uptake and metabolism of propionate in the isolated perfused caudal lobe of the liver and in isolated hepatocytes were examined following treatment of sheep with glucagon or saline. Glucagon or sterile saline was infused at 9.8 micrograms/min for 3 h into the jugular vein and then the caudal lobe of the liver was removed surgically under anaesthesia. The caudal lobe was used either to prepare hepatocytes or in a non-recirculating perfusion experiment. Uptake and metabolism of propionate were studied using [2-14C]propionate. In studies using the non-recirculation perfusion of the caudal lobe of the sheep liver it was shown that the treatment of sheep with glucagon resulted in an increased rate of gluconeogenesis from propionate and in an increased net uptake of propionate by the caudal lobe. The uptake of propionate into the hepatocytes was saturable, concentrative and exhibited a K(m) for propionate of 0.24 (SE 0.07) mM and a maximal rate of uptake (Vmax) of 6.7 (SE 0.6) nmol/mg dry cells per min and was unaffected by glucagon treatment of sheep. After incubation of cells in medium containing 0.5 mM-[2-14C]propionate for 10 min, the rate of gluconeogenesis from propionate was 22% higher in the hepatocytes isolated from glucagon-treated sheep. Concentrations in the medium of 1.35 mM butyrate and 1 mM-caproate inhibited propionate uptake by about 50% and abolished the glucagon-induced stimulation of gluconeogenesis from propionate. The results are consistent with a regulatory role for glucagon in the gluconeogenesis from propionate in the sheep liver.


Increasing adult neurogenesis protects mice from epilepsy.
Neurogenesis occurs in the adult brain in the hippocampal dentate gyrus, an area that contains neurons which are vulnerable to insults and injury, such as severe seizures. Previous studies showed that increasing adult neurogenesis reduced neuronal damage after these seizures. Because the damage typically is followed by chronic lifelong seizures (epilepsy), we asked if increasing adult neurogenesis would prevent epilepsy. Adult neurogenesis was selectively increased by deleting the pro-apoptotic gene Bax from Nestin-expressing progenitors. Tamoxifen was administered at 6 weeks of age to conditionally delete Bax in Nestin-CreERT2Baxfl/fl mice. Six weeks after tamoxifen administration, severe seizures (status epilepticus; SE) were induced by injection of the convulsant pilocarpine. Mice with increased adult neurogenesis exhibited fewer chronic seizures. Postictal depression was reduced also. These results were primarily female mice, possibly because they were the more affected by Bax deletion than males, consistent with sex differences in Bax in development. The female mice with enhanced adult neurogenesis also showed less neuronal loss of hilar mossy cells and hilar somatostatin-expressing neurons than wild type females or males, which is notable because these two cell types are implicated in epileptogenesis. The results suggest that increasing adult neurogenesis in the normal adult brain can reduce experimental epilepsy, and the effect shows a striking sex difference. The results are surprising in light of past studies showing that suppressing adult-born neurons can also reduce chronic seizures.


Utilizing a Biology-Driven Approach to Map the Exposome in Health and Disease: An Essential Investment to Drive the Next Generation of Environmental Discovery.
Recent developments in technologies have offered opportunities to measure the exposome with unprecedented accuracy and scale. However, because most investigations have targeted only a few exposures at a time, it is hypothesized that the majority of the environmental determinants of chronic diseases remain unknown. We describe a functional exposome concept and explain how it can leverage existing bioassays and high-resolution mass spectrometry for exploratory study. We discuss how such an approach can address well-known barriers to interpret exposures and present a vision of next-generation exposomics. The exposome is vast. Instead of trying to capture all exposures, we can reduce the complexity by measuring the functional exposome-the totality of the biologically active exposures relevant to disease development-through coupling biochemical receptor-binding assays with affinity purification-mass spectrometry. We claim the idea of capturing exposures with functional biomolecules opens new opportunities to solve critical problems in exposomics, including low-dose detection, unknown annotations, and complex mixtures of exposures. Although novel, biology-based measurement can make use of the existing data processing and bioinformatics pipelines. The functional exposome concept also complements conventional targeted and untargeted approaches for understanding exposure-disease relationships. Although measurement technology has advanced, critical technological, analytical, and inferential barriers impede the detection of many environmental exposures relevant to chronic-disease etiology. Through biology-driven exposomics, it is possible to simultaneously scale up discovery of these causal environmental factors. https://doi.org/10.1289/EHP8327.


High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity.
Diet and exercise underpin the risk of obesity-related metabolic disease. Diet alters the gut microbiota, which contributes to aspects of metabolic disease during obesity. Repeated exercise provides metabolic benefits during obesity. We assessed whether exercise could oppose changes in the taxonomic and predicted metagenomic characteristics of the gut microbiota during diet-induced obesity. We hypothesized that high-intensity interval training (HIIT) would counteract high-fat diet (HFD)-induced changes in the microbiota without altering obesity in mice. Compared with chow-fed mice, an obesity-causing HFD decreased the Bacteroidetes-to-Firmicutes ratio and decreased the genetic capacity in the fecal microbiota for metabolic pathways such as the tricarboxylic acid (TCA) cycle. After HFD-induced obesity was established, a subset of mice were HIIT for 6 wk, which increased host aerobic capacity but did not alter body or adipose tissue mass. The effects of exercise training on the microbiota were gut segment dependent and more extensive in the distal gut. HIIT increased the alpha diversity and Bacteroidetes/Firmicutes ratio of the distal gut and fecal microbiota during diet-induced obesity. Exercise training increased the predicted genetic capacity related to the TCA cycle among other aspects of metabolism. Strikingly, the same microbial metabolism indexes that were increased by exercise were all decreased in HFD-fed vs. chow diet-fed mice. Therefore, exercise training directly opposed some of the obesity-related changes in gut microbiota, including lower metagenomic indexes of metabolism. Some host and microbial pathways appeared similarly affected by exercise. These exercise- and diet-induced microbiota interactions can be captured in feces.


Unusual Survival of Anomalous Left Coronary Artery From the Pulmonary Artery With Severe Rheumatic Mitral Stenosis in Septuagenarian Women: Foes Becoming Friends?
ALCAPA syndrome (anomalous origin of the left coronary artery from the pulmonary artery) is a rare disease but lethal with clinical expression from myocardial infarction, congestive heart failure to death during early infancy and unusual survival to adulthood. We report a 73-year-old woman with ALCAPA who presented with exertional dyspnea (NYHA functional class II) over past 2 years. Physical examination revealed soft S, long mid diastolic rumbling murmur and apical pan-systolic murmur. Electrocardiography displayed biatrial enlargement and poor R progression and normal sinus rhythm. Echocardiography established calcified severe mitral stenosis (MS), presence of continuous flow entering the pulmonary trunk, turbulent continuous flow in inter-ventricular septum with left to right shunt in contrast echocardiography and normal systolic function. Coronary angiogram showed absence of left coronary artery (LCA) originating from aorta, dilated and tortuous right coronary artery (RCA) and abundant Rentrop grade 3 intercoronary collateral communicating with LCA originating from pulmonary trunk which was also confirmed on coronary CT angiogram thus establishing diagnosis of ALCAPA. It is exceedingly rare to be associated with severe MS. However, such a long survival in our patient can be explained by the severe pulmonary arterial hypertension which may be contributing to lesser coronary steal.


Efficient iron-catalyzed N-arylation of aryl halides with amines.
A practical and promising protocol was developed for N-arylations of various amines with differently substituted aryl halides. The processes are efficiently promoted by the catalyst system involving the environmentally benign Fe2O3 and the universal ligand L-proline. The versatility, convenient operation, low cost, and environmental friendliness, in combination with the high yields, render this method viable for use in both laboratory research and larger industrial scales.


Termination of resuscitation in the prehospital setting for adult patients suffering nontraumatic cardiac arrest. National Association of EMS Physicians Standards and Clinical Practice Committee.
The National Association of EMS Physicians (NAEMSP) supports out-of-hospital termination of resuscitation for adult, nontraumatic cardiac arrest patients who have not responded to full resuscitative efforts. The following factors should be considered in establishing termination of resuscitation protocols: 1) Termination of resuscitation may be considered for any adult patient who suffers sudden cardiac death that is likely to be medical. 2) Unwitnessed cardiac arrest with delayed initiation of cardiopulmonary resuscitation (CPR) beyond 6 minutes and delayed defibrillation beyond 8 minutes has a poor prognosis. 3) In the absence of "do not resuscitate" or advanced directives, a full resuscitative effort including CPR, definitive airway management, medication administration, defibrillation if necessary, and at least 20 minutes of treatment following Advanced Cardiac Life Support (ACLS) guidelines should be performed prior to declaring the patient dead. 4) A patient whose rhythm changes to, or remains in, ventricular fibrillation or ventricular tachycardia should have continued resuscitative efforts. Patients in asystole or pulseless electrical activity should be strongly considered for out-of-hospital termination of resuscitation. 5) Logistic factors should be considered, such as collapse in a public place, family wishes, and safety of the crew and public. 6) Online medical direction should be established prior to termination of resuscitation. The decision to terminate efforts should be a consensus between the on-scene paramedic and the online physician. 7) The on-scene providers and family should have access to resources, such as clergy, crisis workers, and social workers. 8) Quality review is necessary to ensure appropriate application of the termination protocol, law enforcement notification, medical examiner or coroner involvement, and family counseling.


Offline adaptive radiotherapy for bladder cancer using cone beam computed tomography.
We investigated if an adaptive radiotherapy approach based on cone beam CT (CBCT) acquired during radical treatment was feasible and resulted in improved dosimetric outcomes for bladder cancer patients compared to conventional planning and treatment protocol. A secondary aim was to compare a conventional plan with a theoretical online process where positioning is based on soft tissue position on a daily basis and treatment plan choice is based on bladder size. A conventional treatment plan was derived from a planning CT scan in the radical radiotherapy of five patients with muscle invasive bladder cancer. In this offline adaptive protocol using CBCT, the patients had 10 CBCT: daily CBCT for the first five fractions and then CBCT scan on a weekly basis. The first five daily CBCT in each patient were used to create a single adaptive plan for treatment from fraction eight onwards. A different process using the planning CT and the first five daily CBCT was used to create small, average and large bladder volumes, giving rise to small, average and large adaptive bladder treatment plans, respectively. In a retrospective analysis using the CBCT scans, we compared the clinical target volume (CTV) coverage using three protocols: (i) conventional; (ii) offline adaptive; and (iii) online adaptive with choice of 'plan of the day'. Daily CBCT prolonged treatment time by an average of 7 min. Two of the five patients demonstrated such variation in CTV that an offline adaptive plan was used for treatment after the first five CBCT. Comparing the offline adaptive plan with the conventional plan, the CTV coverage improved from a minimum of 60.1 to 94.7% in subsequent weekly CBCT. Using the CBCT data, modelling an online adaptive protocol showed that coverage of the CTV by the 95% prescribed dose line by small, medium and large adaptive plans were 34.9, 67.4 and 90.7% of occasions, respectively. More normal tissue was irradiated using a conventional CTV to planning target volume margin (1.5 cm) compared to an online adaptive process (0.5 cm). An offline adaptive strategy improves dose coverage in certain patients to the CTV and results in a higher conformity index compared to conventional planning. Further research in online adaptive radiation therapy for bladder cancer is indicated.


Reading as Statistical Learning.
The purpose of this tutorial is to explain how learning to read can be thought of as learning statistical regularities and to demonstrate why this is relevant for theory, modeling, and practice. This tutorial also shows how triangulation of methods and cross-linguistic research can be used to gain insight. The impossibility of conveying explicitly all of the regularities that children need to acquire in a deep orthography, such as English, can be demonstrated by examining lesser-known probabilistic orthographic cues to lexical stress. Detection of these kinds of cues likely occurs via a type of implicit learning known as statistical learning (SL). The first part of the tutorial focuses on these points. Next, studies exploring how individual differences in the capacity for SL relate to variability in word reading accuracy in the general population are discussed. A brief overview of research linking impaired SL and dyslexia is also provided. The final part of the tutorial focuses on how we might supplement explicit literacy instruction with implicit learning methods and emphasizes the value of testing the efficacy of new techniques in the classroom. The basic and applied research reviewed here includes corpus analyses, behavioral testing, computational modeling, and classroom-based research. Although some of these methods are not commonly used in clinical research, the depth and breadth of this body of work provide a compelling case for why reading can be thought of as SL and how this view can inform practice. Implicit methods that draw on the principles of SL can supplement the much-needed explicit instruction that helps children learn to read. This synergy of methods has the potential to spark innovative practices in literacy instruction and remediation provided by educators and clinicians to support typical learners and those with developmental disabilities.


Novel biomimetic fiber incorporated scaffolds for tissue engineering.
From a structural perspective, an ideal scaffold ought to possess interconnected macro pores with sizes from 10 to 100 μm to facilitate cell infiltration and tissue formation, as well as similar topography to the natural extracellular matrix (ECM) which would have an impact on cell behavior such as cell adhesion and gene expression. For that purpose, here we developed a fabrication process to incorporate electrospun short fibers within freeze-dried scaffolds for tissue engineering applications. Briefly, PCL short fibers were first produced from electrospun fibers with ultrasonication method. They were then evenly dispersed in gelatin solution and freeze-dried to obtain fiber incorporated scaffolds. The resulting scaffolds exhibited hierarchical structure including major pores with sizes ranging from 50 to 150 μm and the short fibers dispersed in the thin walls of major pores, mimicking the fibrous feature of natural ECM. The short fibers were proven to modify the mechanical properties of scaffold and to facilitate cell adhesion and proliferation on the scaffold. As a promising scaffold for tissue engineering and regenerative medicine, the fiber incorporated scaffold may have further biomedical applications, in which the short fibers can act as drug release vehicles for growth factors or other biomolecules to promote vascularization.


The Effects of a Parent-Focused Social Media Intervention on Child Sun Safety: Pilot and Feasibility Study.
Middle childhood (ages 8-12 years) is a critical period for forming behavioral habits and reducing the risk for the development of skin cancer later in life. During this time, children develop more autonomy and spend more unsupervised time away from their parents. Professional agencies recommend that all children engage in regular sun protection behaviors and avoid the sun during peak daytime hours. Unfortunately, in middle childhood, child sun protection often declines and UV radiation exposure increases. Effective parenting involves balancing ways to encourage the child's increasing independence while providing practical assistance to ensure sun protection is implemented. The goal was to evaluate the feasibility, acceptability, and preliminary effects of Sun Safe Families, a Facebook group intervention for parents of children between 8 and 12 years of age. The team developed Facebook messages targeting parent knowledge, normative influences, sun safety barriers, planning and goal setting, confidence in implementing sun safety, communication, forming habits, and managing sun safety in risky situations. A total of 92 parents were enrolled, and the groups ran for 6 weeks. Feasibility was measured by enrollment and retention rates. Acceptability was measured by engagement in the Facebook groups. Satisfaction was assessed by a treatment evaluation. At pre- and post-intervention, parents completed measures of child sun protection, UV radiation exposure, sunburn, sun safety knowledge, child risk, barriers, sun protection self-efficacy, planning, sun safe habits, norms for child sun safety, and communication about sun safety. Enrollment (64.3%, 92/143) and retention (94.6%, 87/92) were good. On average, participants viewed 67.6% (56.8/84) of posts, "liked" 16.4% (13.77/84) of posts, commented on 14.8% (12.43/84) of posts, and voted on 46% (6.4/14) of polls. Satisfaction was excellent. From pre- to post-intervention, there were significant increases in child sun protection, sun exposure, and sunburn (P<.01; moderate effect sizes), as well as statistically significant increases in planning and self-efficacy (P<.05) and family norms and parent communication (P<.01). This study demonstrated high survey retention, acceptability, and satisfaction with the intervention. There were promising preliminary effects on child sun protection behaviors and parent sun protection attitudes and communication with their child. Replication with a larger sample size and a comparison condition is warranted.


Overwhelming leukoencephalopathy as the only sign of neuropsychiatric lupus.
We describe a patient with diffuse leukoencephalopathy, a rare central nervous system complication of systemic lupus erythematosus, who died of brain herniation despite aggressive management. Brain magnetic resonance imaging revealed diffuse white matter hyperintensities consistent with vasogenic edema. Autopsy revealed only widespread cerebral edema. Early recognition and persistent, aggressive treatment will be required to avoid this fatal and rare manifestation of neuropsychiatric lupus.


Mutations that render the promoter of the histidine operon of Salmonella typhimurium insensitive to nutrient-rich medium repression and amino acid downshift.
The effects of mutations in the promoter of the histidine operon of Salmonella typhimurium were examined in vivo. The wild-type chromosomal copy of the his promoter was replaced with mutations in the -10 hexamer sequence and in the region between the -10 hexamer and the transcriptional start point-termed the discriminator sequence. The substitutions were performed with a phage M13 allele replacement system. Expression of the his operon is known to correlate with levels of guanosine 5',3'-bispyrophosphate (ppGpp) in vivo. Strains containing either the wild-type his promoter or his promoter mutations were grown in both nutrient-rich and minimal media under steady-state conditions known to alter intracellular levels of ppGpp in a predictable way. The effect of the presence or absence of the his attenuator was assessed under these conditions as well. Expression of the his operon was studied by measuring the differential rate of beta-galactosidase synthesis with a his-lac transcriptional fusion. Regulation of the his operon in the promoter mutants was also studied under conditions of a transient amino acid downshift induced by the addition of serine hydroxamate to cultures growing in nutrient-rich medium. These growth conditions cause elevated levels of ppGpp. The results provide physiological confirmation of previous evidence obtained with a coupled transcription-translation system in vitro which indicated that ppGpp regulates interaction of RNA polymerase at the his promoter. More specifically, the in vivo evidence shows that the region of the his promoter that includes the -10 hexamer and discriminator sequences is the target at which ppGpp stimulates transcription.


The Caltech Tomography Database and Automatic Processing Pipeline.
Here we describe the Caltech Tomography Database and automatic image processing pipeline, designed to process, store, display, and distribute electron tomographic data including tilt-series, sample information, data collection parameters, 3D reconstructions, correlated light microscope images, snapshots, segmentations, movies, and other associated files. Tilt-series are typically uploaded automatically during collection to a user's "Inbox" and processed automatically, but can also be entered and processed in batches via scripts or file-by-file through an internet interface. As with the video website YouTube, each tilt-series is represented on the browsing page with a link to the full record, a thumbnail image and a video icon that delivers a movie of the tomogram in a pop-out window. Annotation tools allow users to add notes and snapshots. The database is fully searchable, and sets of tilt-series can be selected and re-processed, edited, or downloaded to a personal workstation. The results of further processing and snapshots of key results can be recorded in the database, automatically linked to the appropriate tilt-series. While the database is password-protected for local browsing and searching, datasets can be made public and individual files can be shared with collaborators over the Internet. Together these tools facilitate high-throughput tomography work by both individuals and groups.


Altered cardiac polyamine biosynthesis in spontaneously hypertensive rats.
To evaluate the role of polyamine biosynthesis in myocardial growth, the activity of ornithine decarboxylase (ODC) and the levels of the polyamines, spermidine, spermine, and putrescine, were measured in the hearts of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats between birth and 30 wk of age and in 30-wk-old rats after 6 wk treatment with either minoxidil (0.08 mg/ml) or methyldopa (5 mg/ml drinking water). ODC activity was initially high in the developing heart (150 pmol X mg protein-1 X 30 min-1) and decreased with age. In the SHR after 4 wk of age, spermidine content was consistently raised in both ventricles compared with the WKY rats. Spermine was reduced in the left ventricle of the SHR, resulting in high spermidine-to-spermine ratios characteristic of rapidly growing systems. Ventricular ODC activity and putrescine levels were also slightly but less consistently elevated in the ventricles of the SHR compared with respective WKY rats. Minoxidil treatment increased heart weight and left ventricular spermidine and spermine content in both SHR and WKY rats. Methyldopa also caused a significant increase in left ventricular spermidine content despite a marked reduction in ventricular mass. Thus ventricular hypertrophy in SHR is accompanied by an enhanced synthesis and accumulation of spermidine. The fact that myocardial spermidine content increased during methyldopa treatment, which reduced the myocardial mass, suggests that regression of ventricular hypertrophy can occur independently of changes in polyamine content.


Titration of African swine fever (ASF) virus.
A haemadsorption microtest for African swine fever (ASF) virus is described. This assay is as sensitive and its response is faster than the conventional assay which uses buffy coat cultures in Leighton tubes. The method can also process a larger number of samples by using smaller amounts of swine blood and laboratory space. A plaque assay for ASF virus adapted to grow in VERO cells gives a titre similar to that obtained using the haemadsorption microtest. In both the micromethod and the plaque assay infection may be produced by a single infective particle.


Technical note: Impact of beamline-specific particle energy spectra on clinical plans in carbon ion beam therapy.
The Local Effect Model version one (LEM I) is applied clinically across Europe to quantify the relative biological effectiveness (RBE) of carbon ion beams. It requires the full particle fluence spectrum differential in energy in each voxel as input parameter. Treatment planning systems (TPSs) use beamline-specific look-up tables generated with Monte Carlo (MC) codes. In this study, the changes in RBE weighted dose were quantified using different levels of details in the simulation or different MC codes. The particle fluence differential in energy was simulated with FLUKA and Geant4 at 500 depths in water in 1-mm steps for 58 initial carbon ion energies (between 120.0 and 402.8 MeV/u). A dedicated beam model was applied, including the full description of the Nozzle using GATE-RTionV1.0 (Geant4.10.03p03). In addition, two tables generated with FLUKA were compared. The starting points of the FLUKA simulations were phase space (PhS) files from, firstly, the Geant4 nozzle simulations, and secondly, a clinical beam model where an analytic approach was used to mimic the beamline. Treatment plans (TPs) were generated with RayStation 8B (RaySearch Laboratories AB, Sweden) for cubic targets in water and 10 clinical patient cases using the clinical beam model. Subsequently, the RBE weighted dose was re-computed using the two other fluence tables (FLUKA PhS or Geant4). The fluence spectra of the primary and secondary particles simulated with Geant4 and FLUKA generally agreed well for the primary particles. Differences were mainly observed for the secondary particles. Interchanging the two energy spectra (FLUKA vs. GEANT4) to calculate the RBE weighted dose distributions resulted in average deviations of less than 1% in the entrance up to the end of the target region, with a maximum local deviation at the distal edge of the target. In the fragment tail, larger discrepancies of up to 5% on average were found for deep-seated targets. The patient and water phantom cases demonstrated similar results. RBE weighted doses agreed well within all tested setups, confirming the clinical beam model provided by the TPS vendor. Furthermore, the results showed that the open source and generally available MC code Geant4 (in particular using GATE or GATE-RTion) can also be used to generate basic beam data required for RBE calculation in carbon ion therapy.


The chemistry of planet-forming regions is not interstellar.
Advances in infrared and submillimeter technology have allowed for detailed observations of the molecular content of the planet-forming regions of protoplanetary disks. In particular, disks around solar-type stars now have growing molecular inventories that can be directly compared with both prestellar chemistry and that inferred for the early solar nebula. The data directly address the old question of whether the chemistry of planet-forming matter is similar or different and unique relative to the chemistry of dense clouds and protostellar envelopes. The answer to this question may have profound consequences for the structure and composition of planetary systems. The practical challenge is that observations of emission lines from disks do not easily translate into chemical concentrations. Here, we present a two-dimensional radiative transfer model of RNO 90, a classical protoplanetary disk around a solar-mass star, and retrieve the concentrations of dominant molecular carriers of carbon, oxygen and nitrogen in the terrestrial region around 1 AU. We compare our results to the chemical inventory of dense clouds and protostellar envelopes, and argue that inner disk chemistry is, as expected, fundamentally different from prestellar chemistry. We find that the clearest discriminant may be the concentration of CO2, which is extremely low in disks, but one of the most abundant constituents of dense clouds and protostellar envelopes.


Protein-RNA interaction prediction with deep learning: structure matters.
Protein-RNA interactions are of vital importance to a variety of cellular activities. Both experimental and computational techniques have been developed to study the interactions. Because of the limitation of the previous database, especially the lack of protein structure data, most of the existing computational methods rely heavily on the sequence data, with only a small portion of the methods utilizing the structural information. Recently, AlphaFold has revolutionized the entire protein and biology field. Foreseeably, the protein-RNA interaction prediction will also be promoted significantly in the upcoming years. In this work, we give a thorough review of this field, surveying both the binding site and binding preference prediction problems and covering the commonly used datasets, features and models. We also point out the potential challenges and opportunities in this field. This survey summarizes the development of the RNA-binding protein-RNA interaction field in the past and foresees its future development in the post-AlphaFold era.


POLG1 mutations associated with progressive encephalopathy in childhood.
We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.


Fulminant myocarditis associated with the H1N1 influenza virus: case report and literature review.
A case of fulminant myocarditis associated with the H1N1 influenza virus. This case report describes the patient's clinical course and emphasizes the importance of bedside echocardiography as an aid in the early diagnosis and management of children with severe myocardial dysfunction. It also discusses aspects relevant to the treatment and prognosis of fulminant myocarditis. The patient was a female, 4 years and 8 months old, previously healthy and with a history of flu symptoms in the past two weeks. The patient was admitted to the emergency room with signs of hemodynamic instability, requiring ventilatory support and vasoactive drugs. The laboratory tests, chest X-ray and echocardiogram suggested the presence of myocarditis. The test for H1N1 in nasopharyngeal secretions was positive. The patient evolved to refractory cardiogenic shock despite the clinical measures applied and died 48 hours after admission to the intensive care unit. The H1N1 influenza virus is an etiological agent associated with acute myocarditis, but there are few reported cases of fulminant myocarditis caused by the H1N1 virus. The identification of signs and symptoms suggestive of fulminant progression should be immediate, and bedside echocardiography is a useful tool for the early detection of myocardial dysfunction and for therapeutic guidance. The use of immunosuppressive therapy and antiviral therapy in acute myocarditis of viral etiology is controversial; hence,the treatment is based on hemodynamic and ventilatory support. The use of hemodynamic support by extracorporeal membrane oxygenation emerges as a promising treatment.


Selective Bonding Effect of Heterologous Oxygen Vacancies in Z-Scheme Cu2O/SrFe0.5Ta0.5O3 Heterojunctions for Constructing Efficient Interfacial Charge-Transfer Channels and Enhancing Photocatalytic NO Removal Performances.
An interfacial structure is crucial to the photoinduced electron transport for a heterostructure photocatalyst. Constructing an interfacial electron channel with an optimized interfacial structure can efficiently improve the electron-transfer efficiency. Herein, the rapid electron-transfer channels were built up in a Cu2O/SrFe0.5Ta0.5O3 heterojunction (Cu2O/SFTO) based on the selective bonding effect of heterologous surface oxygen vacancies in the SFTO component. The heterologous surface oxygen vacancies, namely, VO-Fe and VO-Ta, respectively, adjacent to Fe and Ta atoms, were introduced into fabricating the Z-scheme Cu2O/SFTO heterojunction. Compared with sample Cu2O/SFTO with VO-Fe, the photocatalytic NO removal efficiency of sample Cu2O/SFTO with VO-Fe and VO-Ta was increased by 22.5%. The enhanced photocatalytic performance originated from the selective bonding effect of heterologous VO-Fe and VO-Ta on the interfacial electron-separating and -transfer efficiency. VO-Fe is the main body to construct the interfacial electron-transfer channels by forming interfacial Fe-O-Cu(I) bonds, which causes lattice distortion at the interface, and VO-Ta can optimize the structure of interfacial channels by balancing the electron density of SFTO to control the average space of the interface transition zone. This research provides a new cognitive perspective for constructing double perovskite oxide-based heterostructure photocatalysts.


[Osteosynthesis with Kirschner pin fixation in treatment of fractures with dislocation of the lateral condyle of the humerus in a pediatric population].
Fractures of lateral condyle represent 17% of all pediatric fractures of the distal humerus, and in current pediatric orthopedics there is still no agreement regarding optimal treatment modalities. We presented a treatment protocol for pediatric dislocated fractures of the lateral condyle of the humerus used at the Pediatric Surgery Clinic in Novi Sad. Over the study period (1991-2000) a total of 48 patients with dislocated fractures of the lateral condyle of the humerus were hospitalized at the Pediatric Surgery Clinic. Orthopedic reduction and percutaneous pin fixation under radiological supervision was done in 15 patients, while 33 patients needed surgical reduction and pin fixation. Satisfactory results were obtained in 42 patients (91.3%), out of which 29 patients (63.1%) presented with excellent results. Good results were obtained in 8 patients (17.4%), and fair results in 5 patients (10.8%). Unsatisfactory results were present in 4 patients (8.7%). Two patients were lost to follow-up. Dislocation fractures of the lateral condyle represent high risk for development of complications. Adequate diagnosis and treatment represent basic conditions for successful postinterventional result. Orthopedic reduction with percutaneous pin fixation is recommended for fractures that may be anatomically reduced. In cases of unsatisfactory results of reduction, as well as in cases with completely dislocated and rotated fragments, surgical reduction and pin fixation is necessary. Satisfactory results in 91.3% of cases, and long-term experience suggest that the recommended therapeutic option is adequate in treatment of dislocated fractures of the lateral condyle of the humerus in pediatric population.


Selection of aphasic stroke patients for intensive speech therapy.
Selection criteria for intensive speech therapy and the number of patients fulfilling these were investigated in 441 acute strokes coming from a Health District population during one year. Five patients from a total of 71 referred with speech and/or language difficulties were considered suitable for intensive speech therapy at 4 weeks after stroke. Although such therapy was not actually given, by 26 weeks three of the five had recovered and 14 further patients were considered suitable to receive intensive therapy. The most important selection criteria were Functional Communication Profile score of less than 85 and a clinical judgement that the patient was well enough to take part. It is recommended that decisions as to appropriateness of patients for intensive speech therapy be delayed beyond 4 weeks after stroke.


Reverse physiology: discovery of the novel neuropeptide, orphanin FQ/nociceptin.
The search for novel neurotransmitters and neuropeptides has been recently revolutionized by the development of a purification strategy based on orphan G protein-coupled receptors, cloned receptors for which no natural ligands are known. This strategy uses the orphan receptor as bait to identify its natural ligand. This article will review the discovery of the first natural ligand isolated following this strategy. This ligand is a peptide that shares some striking sequence similarity to the opioid peptides and has been named Orphanin FQ or Nociceptin (OFQ/NOC). The discovery of OFQ/NOC will be described as one example of the use of orphan receptors in identifying novel neurotransmitters and neuropeptides, an example that has already been followed in the identification of other novel neuropeptides. After reviewing the conceptual and technological basis of the strategy and its successful first application, we discuss the criteria used to validate OFQ/NOC as the natural ligand of the orphan receptor and as a genuine neuropeptide. We also discuss the importance and implications of discovering OFQ/NOC mode of synthesis, which is synthesized as expected in the form of a larger polypeptide precursor, which in turn raises the question of the existence of other OFQ/NOC-related peptides. We then present an overview of the numerous studies that have blossomed after the OFQ/NOC discovery and describe the numerous physiological roles that have already been attributed to OFQ/NOC, and in particular the controversy regarding its involvement in pain perception. Because of the similarities between the OFQ/NOC and opioid systems, we also discuss overlaps between these systems and present evidence favoring a pharmacological separation between these systems. We finish by outlining the power of the orphan receptor strategy and by discussing some of its pitfalls.


Packing volumes by spheres.
In this note we present an algorithm for packing spheres in an arbitrary shaped volume. This algorithm is similar to Blum's transform in that it fits spheres into a volume, but it is different in that it fits only tangential spheres, and thereby the data reduction is larger than by Blum's transform. The spheres are of variable radii, which enables us to achieve a hierarchy of intrinsic volume properties, i.e., from gross to more detailed. The result of this algorithm is a graph where the nodes are the centers of spheres and the arcs are the connections between two tangent spheres. Analysis of computational complexity and the time and error considerations are provided.


A randomized, controlled, single-blind, 6-month pilot study to evaluate the efficacy of MS-Line!: a cognitive rehabilitation programme for patients with multiple sclerosis.
MS-Line! was created to provide an effective treatment for cognitive impairment in multiple sclerosis (MS) patients. To assess the efficacy of MS-Line!. A randomized, controlled, single-blind, 6-month pilot study. Patients were randomly assigned to an experimental group (cognitive rehabilitation with the programme) or to a control group (no cognitive rehabilitation). Randomization was stratified by cognitive impairment level. Cognitive assessment included: selective reminding test, 10/36 spatial recall test (10/36 SPART), symbol digit modalities test, paced auditory serial addition test, word list generation (WLG), FAS test, subtests of WAIS-III, Boston naming test (BNT), and trail making test (TMT). Forty-three patients (22 in the experimental group, 21 in the control group) were analyzed. Covariance analysis showed significant differences in 10/36 SPART (P=0.0002), 10/36 SPART delayed recall (P=0.0021), WLG (P=0.0123), LNS (P=0.0413), BNT (P=0.0007) and TMT-A (P=0.010) scores between groups. The study showed a significant improvement related to learning and visual memory, executive functions, attention and information processing speed, and naming ability in those patients who received cognitive rehabilitation. The results suggest that MS-Line! is effective in improving cognitive impairment in MS patients.


A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients.
A prospective, single-arm, open-label, nonrandomized phase II combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus radioimmunotherapy trial was conducted to evaluate the efficacy and safety in untreated elderly diffuse large B-cell lymphoma (DLBCL) patients. From February 2005 to April 2006, in our institute we treated 20 eligible elderly (age > or =60 years) patients with previously untreated DLBCL using a novel regimen consisting of six cycles of CHOP chemotherapy followed 6-10 weeks later by (90)Y ibritumomab tiuxetan. The overall response rate to the entire treatment regimen was 100%, including 95% complete remission (CR) and 5% partial remission. Four (80%) of the five patients who achieved less than a CR with CHOP improved their remission status after radioimmunotherapy. With a median follow-up of 15 months, the 2-year progression-free survival was estimated to be 75%, with a 2-year overall survival of 95%. The (90)Y ibritumomab tiuxetan toxicity included grade > or =3 hematologic toxicity in 12 of 20 patients; the most common grade > or =3 toxic effects were neutropenia (12 patients) and thrombocytopenia (7 patients). Transfusions of red blood cells and/or platelets were given to one patient. This study has established the feasibility, tolerability, and efficacy of this regimen for elderly patients with DLBCL.


The Cochrane tobacco addiction group.
The Cochrane Tobacco Addiction Group produces up-to-date systematic reviews of interventions for the cessation and prevention of tobacco use. Many of our Cochrane Reviews have also been published in scientific journals. Our review prioritization schedule is informed by our group's experience and expertise as well as identifying topics for reviews via regular searches of current scientific literature and from other news sources, such as the Action on Smoking and Health updates. The Cochrane Register of Studies allows identification of new trials, which might be eligible for review updates. Everyday challenges include timely publishing and updating of our reviews, and ensuring compliance to Cochrane methodological expectations of Cochrane intervention review standards. We are grateful for the contributions of our authors and peer reviewers, with whom we aim to have close working and productive relationships. We look forward to continuing our contribution toward a reliable evidence base on interventions to combat tobacco addiction.


Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level.
Mitochondria play a central role in the maintenance of the naive state of embryonic stem cells. Many details of the mechanism remain to be fully elucidated. Solute carrier family 25 member 36 (Slc25a36) might regulate mitochondrial function through transporting pyrimidine nucleotides for mtDNA/RNA synthesis. Its physical role in this process remains unknown; however, Slc25a36 was recently found to be highly expressed in naive mouse embryonic stem cells (mESCs). Here, the function of Slc25a36 was characterized as a maintenance factor of mESCs pluripotency. Slc25a36 deficiency (via knockdown) has been demonstrated to result in mitochondrial dysfunction, which induces the differentiation of mESCs. The expression of key pluripotency markers (Pou5f1, Sox2, Nanog, and Utf1) decreased, while that of key TE genes (Cdx2, Gata3, and Hand1) increased. Cdx2-positive cells emerged in Slc25a36-deficient colonies under trophoblast stem cell culture conditions. As a result of Slc25a36 deficiency, mtDNA of knockdown cells declined, leading to impaired mitochondria with swollen morphology, decreased mitochondrial membrane potential, and low numbers. The key transcription regulators of mitochondrial biogenesis also decreased. These results indicate that mitochondrial dysfunction leads to an inability to support the pluripotency maintenance. Moreover, down-regulated glutathione metabolism and up-regulated focal adhesion reinforced and stabilized the process of differentiation by separately enhancing OCT4 degradation and promoting cell spread. This study improves the understanding of the function of Slc25a36, as well as the relationship of mitochondrial function with naive pluripotency maintenance and stem cell fate decision.


Intelligence, gender, and assessment method affect the accuracy of self-estimated intelligence.
Self-estimates of intelligence (SEI), which influence to what extent people engage in and how well they perform at a task, are subject to distortion. Here, the distortion effects of individual differences in intelligence (IQ), gender, and proximal (with reference to test performance) and distal (with reference to IQ score distributions) assessments of SEI were tested in a sample of 200 British adults. The results showed that (1) people with lower IQ misestimated their SEI to a greater extent than people with high IQ; (2) this effect was more pronounced in distal than proximal measures of SEI; (3) SEI means did not differ significantly across gender but the IQ-related level of SEI distortion did; (4) this effect was greater for distal than proximal measurement; and (5) proximal SEI were on average less distorted than distal SEI scores and also correlated more closely with IQ. Overall, the findings suggest that the distal SEI assessment method resulted in greater gender- and IQ-related distortions of SEI.


Effect of home-based peer support on maternal-infant interactions among women with postpartum depression: a randomized, controlled trial.
Approximately 15% of new mothers experience postpartum depression, representing the most common source of maternal morbidity post-delivery. Postpartum depression may impair maternal-infant interactions, contributing to poor developmental outcomes in the offspring of mothers with depression. The purpose of this study was to test the effectiveness of home-based peer support that included maternal-infant interaction teaching for mothers with symptoms of postpartum depression and their infants. Mothers with postpartum depression were randomly assigned to control (n = 33) or intervention groups (n = 27). Intervention group mothers received 12 weeks of home-based peer support that included maternal-infant interaction teaching; peers were mothers who had recovered from postpartum depression and were trained to provide support. Data were collected from all mothers at baseline, as well as 6 and 12 weeks' post-randomization. Contrary to the hypothesized direction of relationships, results favoured the control group. A significant difference between the groups was observed for one of the two measures of maternal-infant interactions. Several other measures favoured the control group, including mothers' depressive symptoms and social support scores. No significant treatment effects were observed in infant IQ scores or diurnal salivary cortisol levels in mothers or infants. The findings suggest that maternal-infant interaction teaching by peers is not well received by mothers with postpartum depression and might be more optimally delivered by professional nurses.


Strengthening of accountability systems to create healthy food environments and reduce global obesity.
To achieve WHO's target to halt the rise in obesity and diabetes, dramatic actions are needed to improve the healthiness of food environments. Substantial debate surrounds who is responsible for delivering effective actions and what, specifically, these actions should entail. Arguments are often reduced to a debate between individual and collective responsibilities, and between hard regulatory or fiscal interventions and soft voluntary, education-based approaches. Genuine progress lies beyond the impasse of these entrenched dichotomies. We argue for a strengthening of accountability systems across all actors to substantially improve performance on obesity reduction. In view of the industry opposition and government reluctance to regulate for healthier food environments, quasiregulatory approaches might achieve progress. A four step accountability framework (take the account, share the account, hold to account, and respond to the account) is proposed. The framework identifies multiple levers for change, including quasiregulatory and other approaches that involve government-specified and government-monitored progress of private sector performance, government procurement mechanisms, improved transparency, monitoring of actions, and management of conflicts of interest. Strengthened accountability systems would support government leadership and stewardship, constrain the influence of private sector actors with major conflicts of interest on public policy development, and reinforce the engagement of civil society in creating demand for healthy food environments and in monitoring progress towards obesity action objectives.


Consequence of temperature changes on cercarial shedding from Galba truncatula infected with Fasciola hepatica or Paramphistomum daubneyi.
Experimental infections of Galba truncatula (two populations) with Fasciola hepatica or Paramphistomum daubneyi were carried out to study the effect of water temperature changes (3 h at a mean of 12 °C every week) on cercarial shedding during the patent period. The results were compared with those of control snails infected according to the same protocol and always maintained at 20 °C. Compared to controls, a significant increase in the number of cercariae-shedding snails, a significantly longer patent period and significantly greater cercarial production were noted in temperature-challenged snails, regardless of the type of digenean infection. In contrast, the number of incompletely formed metacercariae was significantly higher in temperature-challenged snails than in controls. Incompletely formed metacercariae of F. hepatica consisted of cysts whose colour remained whitish after shedding (25.4% for temperature-challenged snails) or whose dome was flattened after encystment (74.6%). Those of P. daubneyi were totally dark brown or blackish after formation. These incomplete metacercariae might originate from young differentiating cercariae within the snail body (F. hepatica) or from cercariae which died just after encystment (P. daubneyi). The use of regular temperature changes for snails infected with F. hepatica or P. daubneyi must be monitored carefully during collection of metacercariae to select completely formed cysts for infecting definitive hosts.