Androgens alter the cytokine profile and reduce encephalitogenicity of myelin-reactive T cells.
Adoptive transfer of proteolipid protein 139-151-specific T cell lines was used to examine the role of androgens in regulating T cell cytokine secretion and the severity of experimental autoimmune encephalomyelitis (EAE) in the SJL mouse. In this study, we found that T cells from female mice transferred more severe EAE than T cells from male mice and that gender differences in clinical disease were due, at least in part, to differences in donor T cell cytokine secretion. T cell lines were selected from proteolipid protein 139-151-immunized female SJL mice in the presence or absence of exogenous androgens. Androgen-selected T cell lines secreted less IFN-gamma and more IL-10 than untreated cell lines. Clinical disease induced by the adoptive transfer of androgen-selected T cell lines was less severe than disease induced with untreated T cell lines. Furthermore, androgen treatment of naive TCR transgenic T cells, during their first encounter with Ag, resulted in a shift in the balance of Th1/Th2 cytokines. This phenotype was maintained during subsequent stimulations in the absence of androgen. These results suggest that androgen present in the lymphoid microenvironment during the induction of an immune response can alter the development of effector T cells and may play an important role in governing gender differences in the immune response and susceptibility to autoimmune disorders.


Real-time, portable genome sequencing for Ebola surveillance.
The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10(-3) and 1.42 × 10(-3) mutations per site per year. This is equivalent to 16-27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15-60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.


L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system.
Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, earlyonset Parkinson's disease. While one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point mutation, L166P, whose precise effects on protein function are unclear. In the present study, we show that L166P destabilizes DJ-1 protein and promotes its degradation through the ubiquitin-proteasome system. A double mutant (K130R, L166P) was more stable than L166P, suggesting that this lysine residue contributes to stability of the protein. Subcellular localization was broadly similar for both wild type and L166P forms of the protein, indicating that the effect of the mutation is predominantly on protein stability. These observations are reminiscent of other recessive gene mutations that produce an effective loss of function. The L166P mutation has the simple effect of promoting DJ-1 degradation, thereby reducing net DJ-1 protein within the cell.


Sugar coating: bacterial protein glycosylation and host-microbe interactions.
Bacterial surfaces are rich in glycoconjugates such as capsules, lipopolysaccharides, and peptidoglycans. The discovery of prokaryotic protein glycosylation systems has revealed that many bacteria also have the capacity to synthesise a diverse array of protein glycans, in some cases using novel strategies that differ from those of eukaryotes. Despite advances in our understanding of glycan biosynthesis and the proteins that are targets of glycosylation in bacteria, the roles of these modifications are relatively less well explored. We present an overview of bacterial protein glycosylation systems in bacteria that are relevant to human health, and discuss current evidence which indicates that glycosylation of proteins may impact upon fundamental processes such as bacterial motility, adhesion, and the modulation of immune responses.


Patient and clinician characteristics and preferences for increasing participation in placebo surgery trials: a scoping review of attributes to inform a discrete choice experiment.
Orthopaedic surgeries include some of the highest volume surgical interventions globally; however, studies have shown that a significant proportion of patients report no clinically meaningful improvement in pain or function after certain procedures. As a result, there is increasing interest in conducting randomised placebo-controlled trials in orthopaedic surgery. However, these frequently fail to reach recruitment targets suggesting a need to improve trial design to encourage participation. The objective of this study was to systematically scope the available evidence on patient and clinician values and preferences which may influence the decision to participate in placebo surgery trial. A systematic review was conducted via a literature search in the MEDLINE, Embase, PsycInfo, CINAHL, and EconLit databases as of 19 July 2021, for studies of any design (except commentaries or opinion pieces) based on two key concepts: patient and clinician characteristics, values and preferences, and placebo surgery trials. Of 3424 initial articles, we retained 18 eligible studies. Characteristics, preferences, values, and attitudes of patients (including levels of pain/function, risk/benefit perception, and altruism) and of clinicians (including concerns regarding patient deception associated with placebo, and experience/training in research) influenced their decisions to participate in placebo-controlled trials. Furthermore, some aspects of trial design, including randomisation procedures, availability of the procedure outside of the trial, and the information and consent procedures used, also influenced decisions to participate. Participant recruitment is a significant challenge in placebo surgery trials, and individual decisions to participate appear to be sensitive to preferences around treatment. Understanding and quantifying the role patient and clinician preferences may play in surgical trials may contribute to the optimisation of the design and implementation of clinical trials in surgery.


Assembly of staphylococcal leukocidin into a pore-forming oligomer on detergent-resistant membrane microdomains, lipid rafts, in human polymorphonuclear leukocytes.
Staphylococcal leukocidin (Luk) consists of LukS and LukF, which cooperatively lyse human polymorphonuclear leukocytes (HPMNLs), monocytes, and macrophages. Here we found that LukS and LukF assembles into hetero-oligomeric pore complexes on the detergent-resistant membrane microdomains, lipid rafts of HPMNLs. When HPMNLs were treated with LukS alone, 24% of the added LukS was localized in lipid rafts. Furthermore, in HPMNLs treated with both LukS and LukF simultaneously, about 90% of high molecular-mass complexes of 100 kDa, which consists of LukS and LukF, were detected in the lipid raft fractions. In contrast, in HPMNLs treated with LukF alone, LukF was not localized in lipid rafts despite binding to the target cell membranes. Ten mM methyl-beta-cyclodextrin, a dysfunctioning agent of lipid rafts, completely inhibited assembly of Luk on lipid rafts, and resulted in null leukocytolytic activity of Luk. Hence, we concluded that assembly of LukS and LukF into the pore-complex occurs in lipid rafts in HPMNLs and that LukF can bind to LukS, which had already bound to lipid rafts, to assemble into hetero-oligomers.


Mutations within lncRNAs are effectively selected against in fruitfly but not in human.
Previous studies in Drosophila and mammals have revealed levels of long non-coding RNAs (lncRNAs) sequence conservation that are intermediate between neutrally evolving and protein-coding sequence. These analyses compared conservation between species that diverged up to 75 million years ago. However, analysis of sequence polymorphisms within a species' population can provide an understanding of essentially contemporaneous selective constraints that are acting on lncRNAs and can quantify the deleterious effect of mutations occurring within these loci. We took advantage of polymorphisms derived from the genome sequences of 163 Drosophila melanogaster strains and 174 human individuals to calculate the distribution of fitness effects of single nucleotide polymorphisms occurring within intergenic lncRNAs and compared this to distributions for SNPs present within putatively neutral or protein-coding sequences. Our observations show that in D.melanogaster there is a significant excess of rare frequency variants within intergenic lncRNAs relative to neutrally evolving sequences, whereas selection on human intergenic lncRNAs appears to be effectively neutral. Approximately 30% of mutations within these fruitfly lncRNAs are estimated as being weakly deleterious. These contrasting results can be attributed to the large difference in effective population sizes between the two species. Our results suggest that while the sequences of lncRNAs will be well conserved across insect species, such loci in mammals will accumulate greater proportions of deleterious changes through genetic drift.


An anatomical study on the position of the summit of the zygoma: theoretical bases for reduction malarplasty.
To achieve optimal outcomes in reduction malarplasty, the area of zygoma from which volume should be reduced must be accurately identified. This anatomical study aims to evaluate the location of the zygoma region that contributes most to the protrusion of the cheek. The morphology of the zygoma was studied on 121 Japanese adults (73 men and 48 women). The midpoint of the inferior orbital rim, zygomaticomaxillary junction, the junction between the frontal process and the zygomatic arch, and the lateral orbital rim were marked to be used as anatomical reference points. Then, a vertical plane intersecting the anterior and posterior edges of the zygoma was marked. The point of the zygoma most distant from the plane was defined as the summit of the zygoma. Three-dimensional measurement using graphic software was performed, and the positional relationships between the summit and the four reference points were evaluated. In terms of horizontal position, the summit is located lateral to the lateral orbital rim and medial to the junction between the frontal process and the zygomatic arch. Regarding vertical position, the summit exists at higher positions in men than in women. The summit of the zygoma is located medial to the junction of the frontal process and zygomatic arch. Therefore, bone incision lines should be placed medial to the posterior edge of the frontal process in reduction malarplasty; effective correction of the protrusion cannot be achieved solely by detachment of the zygomatic arch. The summit is located higher for men than for women. Therefore, bone incision lines should be placed higher for men than for women.


First Report of Fusarium armeniacum Causing Seed Rot and Root Rot on Soybean (Glycine max) in the United States.
In a survey for Fusarium root rot, soybean plants were sampled from eight counties across Iowa in 2008 to 2009. Fusarium isolates were recovered from surface-sterilized symptomatic and asymptomatic root tissue by culturing on peptone PCNB agar (2). Single-spore isolates were transferred to carnation leaf agar (CLA) and potato dextrose agar (PDA) for morphological identification; 11 isolates were identified as F. armeniacum (Forbes, Windels, and Burgess) Burgess and Summerell (previously F. acuminatum ssp. armeniacum) (2). Colonies on PDA produced white aerial mycelium, red to apricot pigment in agar, and bright orange sporodochia in the center of the culture. Some isolates produced a pionnotal form of slow-growing colonies with little aerial mycelium and abundant orange sporodochia. On CLA, macroconidia in orange sporodochia on carnation leaves and chlamydospores formed abundantly, but microconidia were absent (2). Species identity for the 11 isolates was confirmed by sequencing of the elongation factor gene (EF1-α) using ef1 and ef2 primers (4) (reference sequences deposited in GenBank JX101763 and JX101764). Pathogenicity of seven F. armeniacum isolates was tested using surface-sterilized soybean seed, cv. AG2403, in a petri dish assay with 3-day-old cultures on 2% water agar (1). Germination, seed rot, and lesion development were scored 7 dai using an ordinal scale (1). The experiment was a completely randomized design (CRD), had three replicate plates per isolate, and was conducted twice. All seven isolates were pathogenic on soybean, though variation in aggressiveness was observed among isolates (P < 0.0001) related to colony morphology on PDA. Seed germination was 0 to 40% when inoculated with four isolates showing white fluffy aerial mycelium on PDA. Seedlings were severely stunted with dark brown lesions covering a majority of the root system. When inoculated with three isolates showing the pionnotal form of slow-growing mycelium, germination was 70 to 100%, with few small brown lesions (~5 to 10 mm) on the roots. Noninoculated controls showed 100% germination and no symptoms. Pathogenicity was also tested in a growth chamber assay at 18°C using autoclaved soil mixed with an infested sand-cornmeal inoculum (3). Data for dry root and shoot weights and root rot severity (visually scored on a % scale) were collected at 6 weeks. The CRD experiment had five replications (single plant in a cone containing 150 ml infested soil), and was conducted twice. Root symptoms and similar variation in aggressiveness among isolates (based on colony morphology) was observed in inoculated plants. Isolates differed significantly for effects on root weight (P = 0.0125), shoot weight (P = 0.0035), and root rot severity (P = 0.0158). F. armeniacum was reisolated from infected root tissue, but not from noninoculated controls. Recovered isolates maintained their original colony morphology. F. armeniacum was previously reported in Minnesota on symptomless corn (2), but it has not been reported on soybean and its pathogenicity has not been established on any crop. To our knowledge, this is the first report of F. armeniacum as a pathogen on soybean in the United States. References: (1) K. E. Broders et al. Plant Dis. 91:727, 2007. (2) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Oxford, UK, 2006. (3) G. P. Munkvold and J. K. O'Mara. Plant Dis. 86:143, 2002. (4) K. O'Donnell et al. Proc. Natl. Acad. Sci. 95:2044, 1998.


A Chemo-Genomic Approach Identifies Diverse Epigenetic Therapeutic Vulnerabilities in MYCN-Amplified Neuroblastoma.
Although a rare disease, neuroblastoma accounts for the highest proportion of childhood cancer deaths. There is a lack of recurrent somatic mutations in neuroblastoma embryonal tumours, suggesting a possible role for epigenetic alterations in driving this cancer. While an increasing number of reports suggest an association of MYCN with epigenetic machinery, the mechanisms of these interactions are poorly understood in the neuroblastoma setting. Utilising chemo-genomic approaches we revealed global MYCN-epigenetic interactions and identified numerous epigenetic proteins as MYCN targets. The epigenetic regulators HDAC2, CBX8 and CBP (CREBBP) were all MYCN target genes and also putative MYCN interactors. MYCN-related epigenetic genes included SMARCs, HDACs, SMYDs, BRDs and CREBBP. Expression levels of the majority of MYCN-related epigenetic genes showed predictive ability for neuroblastoma patient outcome. Furthermore, a compound library screen targeting epigenetic proteins revealed broad susceptibility of neuroblastoma cells to all classes of epigenetic regulators, belonging to families of bromodomains, HDACs, HATs, histone methyltransferases, DNA methyltransferases and lysin demethylases. Ninety-six percent of the compounds reduced MYCN-amplified neuroblastoma cell viability. We show that the C646 (CBP-bromodomain targeting compound) exhibits switch-like temporal and dose response behaviour and is effective at reducing neuroblastoma viability. Responsiveness correlates with MYCN expression, with MYCN-amplified cells being more susceptible to C646 treatment. Thus, exploiting the broad vulnerability of neuroblastoma cells to epigenetic targeting compounds represents an exciting strategy in neuroblastoma treatment, particularly for high-risk MYCN-amplified tumours.


Global decrease in the expression of signalling pathways' genes in murine uterus during preimplantation pregnancy.
Early preimplantation embryo-maternal communication is crucial for the establishment and development of pregnancy. Though the involvement of several candidate genes and proteins in this complex event has been described, the hierarchy of molecular networks governing this communication remains unknown. The primary objective of this study was to determine whether the presence of embryos in the uterine lumen stimulated or inhibited gene expression in the uterine tissue on day 3.5 post coitum. To answer this question, we investigated the gene expression of dedicated signal transduction pathways in the uterus of CD-1 mice during the preimplantation stage of pregnancy and compared this expression to mice with induced pseudopregnancy. The expression levels of 84 genes assigned to nine intracellular signalling pathways were investigated by real-time PCR. The results demonstrated down-regulation of the uterine gene expression in the majority of pathways. Among target genes, 27 were significantly (p<0.05) down-regulated, and only three were significantly up-regulated. A majority of the down-regulated genes were found to be regulated by the TGFB and NFKB pathways, which suggests that the presence of the embryo selectively regulates signalling within signal transduction pathways. One of the up-regulated genes crucial for early pregnancy was Ptgs2 (p<0.05). The increased amount of both Ptgs2 gene and protein products indicates that Ptgs2 expression may be the earliest positive embryo signal for implantation and pregnancy recognition in mice. In conclusion, our results not only underline which signalling pathways are regulated in embryo-maternal communication before implantation but also support "the quiet state hypothesis" of silencing gene expression.


Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases.
Patients and physicians often have many questions regarding the role of complementary and alternative medicines (CAMs), or nonallopathic therapies, for inflammatory bowel diseases (IBDs). CAMs of various forms are used by more than half of patients with IBD during some point in their disease course. We summarize the available evidence for the most commonly used and discussed CAMs. We discuss evidence for the effects of herbs (such as cannabis and curcumin), probiotics, acupuncture, exercise, and mind-body therapy. There have been few controlled studies of these therapies, which have been limited by their small sample sizes; most studies have been uncontrolled. In addition, there has been a lack of quality control for herbal preparations. It has been a challenge to design rigorous, randomized, placebo-controlled trials, in part owing to problems of adequate blinding for psychological interventions, acupuncture, and exercise. These barriers have limited the acceptance of CAMs by physicians. However, such therapies might be used to supplement conventional therapies and help ease patient symptoms. We conclude that physicians should understand the nature of and evidence for CAMs for IBD so that rational advice can be offered to patients who inquire about their use. CAMs have the potential to aid in the treatment of IBD, but further research is needed to validate these approaches.


Mummified precocial bird wings in mid-Cretaceous Burmese amber.
Our knowledge of Cretaceous plumage is limited by the fossil record itself: compression fossils surrounding skeletons lack the finest morphological details and seldom preserve visible traces of colour, while discoveries in amber have been disassociated from their source animals. Here we report the osteology, plumage and pterylosis of two exceptionally preserved theropod wings from Burmese amber, with vestiges of soft tissues. The extremely small size and osteological development of the wings, combined with their digit proportions, strongly suggests that the remains represent precocial hatchlings of enantiornithine birds. These specimens demonstrate that the plumage types associated with modern birds were present within single individuals of Enantiornithes by the Cenomanian (99 million years ago), providing insights into plumage arrangement and microstructure alongside immature skeletal remains. This finding brings new detail to our understanding of infrequently preserved juveniles, including the first concrete examples of follicles, feather tracts and apteria in Cretaceous avialans.


Changing what it means to 'become a man': participants' reflections on a school-based programme to redefine masculinity in the Balkans.
Calls to engage men and boys in efforts to promote health, prevent violence and advance gender equality have grown in recent years. However, there remains little evidence or reflection on how most effectively to change harmful norms related to masculinity. The study addresses this gap by exploring the perspectives of participants in the Young Men Initiative (YMI), an innovative programme that aimed to promote healthier masculinities among boys attending vocational high schools in several Balkan countries through educational workshops, residential retreats and a social marketing campaign. Qualitative data were collected through 37 in-depth interviews and 11 focus-group discussions with boys, youth facilitators and teachers. Findings from four schools (in Belgrade, Sarajevo, Prishtina and Zagreb) suggest that several elements of the programme resonated strongly with participants and supported their meaningful engagement in project activities. Five themes emerged as most salient in identifying how and why specific aspects of YMI positively influenced participants: personal reflection, experience-based learning, connections with youth facilitators, new peer groups and aspirational messaging. Building on these insights, the study highlights potentially useful strategies for other programmes seeking to reach boys and transform their understanding of masculinity.


Serum micronutrients and cervical dysplasia in Southwestern American Indian women.
We carried out a clinic-based case-control study to assess serum micronutrients as risk factors for cervical dysplasia among Southwestern American Indian women, a group with high rates of cervical preinvasive lesions. Cases were American Indian women with biopsy-proven cervical intraepithelial neoplasia (CIN I or CIN II/III). Controls were from the same Indian Health Service clinics with normal cervical epithelium. We interviewed women about histories of sexually transmitted diseases, sexual behavior, diet, hygienic practices, cigarette smoking, and reproductive factors. Laboratory assays included serum for retinol (vitamin A), ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), and red blood cell folate levels, DNA for human papillomavirus (HPV) typing, and tests for other sexually transmitted diseases. The strongest risks for cervical dysplasia were associated with cervical HPV infection [odds ratio (OR) = 3.2, 95% confidence interval (CI) = 2.2-4.6 and OR = 7.9, 95% CI = 4.8-13.1 for CIN I and CIN II/III, respectively]. With adjustments made for HPV infection and other relevant confounders, subjects in the lowest serum retinol quartile were at increased risk of CIN I compared with women in the highest quartile (OR = 2.3, 95% CI = 1.3-4.1). The data suggest that low serum alpha-tocopherol was associated with CIN I/III, although the adjusted OR was not statistically significant (OR = 2.0, 95% CI = 0.9-4.8). Low serum ascorbic acid and red blood cell folate were not associated with cervical dysplasia.


A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial.
Studies suggest that patients with relapsing-remitting multiple sclerosis (RRMS) who do not benefit from other disease-modifying treatments (DMTs) may benefit from converting to glatiramer acetate (GA). COPTIMIZE was a 24-month observational study designed to assess the disease course of patients converting to GA 20 mg daily from another DMT. Eligible patients had converted to GA and had received prior DMT for 3-6 months, depending on the reasons for conversion. Patients were assessed at baseline and at 6, 12, 18, and 24 months. In total, 672 patients from 148 centers worldwide were included in the analysis. Change of therapy to GA was prompted primarily by lack of efficacy (53.6 %) or intolerable adverse events (AEs; 44.8 %). Over a 24-month period, 72.7 % of patients were relapse free. Mean annual relapse rate decreased from 0.86 [95 % confidence interval (CI) 0.81-0.91] before the change to 0.32 (95 % CI 0.26-0.40; p < 0.0001) at last observation, while the progression of disability was halted, as the Kurtzke Expanded Disability Status Scale (EDSS) scores remained stable. Patients improved significantly (p < 0.05) on measures of fatigue, quality of life, depression, and cognition; mobility scores remained stable. The results indicate that changing RRMS patients to GA is associated with positive treatment outcomes.


Increased duration of co-contraction of medial knee muscles is associated with greater progression of knee osteoarthritis.
As knee osteoarthritis (OA) cannot be cured, treatments that slow structural disease progression are a priority. Knee muscle activation has a potential role in OA pathogenesis. Although enhanced knee muscle co-contraction augments joint stability; this may speed structural disease progression by increased joint load. This study investigated the relationship between cartilage loss and duration of co-contraction of medial/lateral knee muscles in medial knee OA. Prospective cohort study. Medial (vastus medialis; semimembranosus) and lateral (vastus lateralis; biceps femoris) knee muscle myoelectric activity was recorded in 50 people with medial knee OA during natural speed walking at baseline. Medial tibial cartilage volume was measured from MRI at baseline and 12 months. Relationships between percent volume loss and duration of co-contraction of medial/lateral muscles around stance phase and ratio of duration of medial to lateral muscle co-contraction were evaluated with multiple linear regression. Greater duration of medial muscle co-contraction and greater duration of medial relative to lateral co-contraction correlated positively with annual percent loss of medial tibial cartilage volume (P = 0.003). Estimated cartilage loss was 0.14 (95% confidence interval -0.23 to -0.05) greater for each increase in medial muscle co-contraction duration of 1% of the gait cycle. Lateral muscle co-contraction inversely correlated with cartilage loss. Data support the hypothesis that augmented medial knee muscle co-contraction underpins faster progression of medial knee OA. Increased duration of lateral muscle co-contraction protected against medial cartilage loss. Exercise and biomechanical interventions to change knee muscle activation patterns provide possible candidates to slow progression of knee OA.


Study of Crocin & Radiotherapy-induced Cytotoxicity and Apoptosis in the Head and Neck Cancer (HN-5) Cell Line.
Malignant tumors of head and neck carcinomas are the sixth most common type of cancer. Current systemic therapies for cancer show side effects in normal tissues and short-term efficacy due to drug resistance. Consequently, there is much interest in identifying new drugs for cancer treatment. Crocin (an active ingredient of saffron) has been shown to have cytotoxic effects on cancer cell lines. Chemo radiotherapy is the standard treatment for head and neck cancer. In the present study, the cytotoxic effects, inducing apoptosis and the radiation sensitivity of crocin were evaluated in the head and neck cancer cell line (HN-5). HN-5 cells were cultured in a DMEM medium and incubated with different concentrations of crocin (12.5-1000 µg/mL). They were exposed to 2 Gy γ-rays. Cell viability was quantified by the MTT assay. Apoptotic cells were determined using PI staining of DNA fragmentation by flowcytometry (sub-G1 peak). Crocin decreased cell viability in HN-5 cells in a time and concentration dependent manner. Crocin also induced a sub-G1 peak in the flowcytometery histogram of treated cells compared with the control, suggesting that apoptotic cell death is caused by its toxicity. Crocin was also shown to sensitize cells to radiation-induced toxicity and apoptosis. The simultaneous use of crocin and radiation therefore increases radiation sensitivity and cell death. Thus, after further study crocin can be considered as a potential drug and sensitizer in cancer treatment.


Functional Outcomes after Behavioral Treatment of Paradoxical Vocal Fold Motion in Adults.
Paradoxical vocal fold motion (PVFM) is responsive to behavioral therapy, often resulting in a remission of symptoms, but little is known about whether treatment is beneficial with regard to PVFM-associated psychological symptoms or functional limitations. The goal of the study was to identify patient perceptions of the impact of treatment for PVFM and characteristics associated with treatment outcomes. A survey was conducted of all adults who had received at least 1 session of treatment for PVFM in our outpatient clinic over a 2-year period. The 39 participants ranged in age from 18 to 82 and had received a median of 3 treatment sessions. At a median follow-up of 10 months following treatment, respondents reported improvements in a wide range of areas, including sports and leisure, daily activities, and social participation. The majority reported improvements in feelings of anxiety, helplessness, and control. Poorer outcomes were associated with more severe voice symptoms, fewer treatment sessions, and needing oral steroids for asthma control. There was a reduction in a wide range of activity limitations after treatment. Feelings of control were strongly associated with positive outcomes. The therapy appeared to be equally effective for adults with exercise-induced and environmental variants of PVFM.


The role of B cells in the early onset of the first demyelinating event of acute optic neuritis.
We evaluated the molecular pathways that operate in the early phase of acute optic neuritis (ON) by studying gene expression profiles of peripheral blood mononuclear cells (PBMCs) subpopulations, including CD19(+) B cells, CD14(+) macrophages, and CD4(+) and CD8(+) T cells. Samples of PBMC subpopulations were obtained from 18 MS patients within 96 hours of the acute onset of the first demyelinating event of ON, and from 14 age- and sex-matched healthy subjects. High throughput gene expression analysis was performed on samples from six ON patients and nine healthy subjects using Affymetrix technology. Data were analyzed using Partek software, and most informative genes (MIGs) were defined as genes with P < 0.01 and fold change > 2.0. Molecular pathways were analyzed by Ingenuity software. Verification of key MIGs was done on samples from five independent ON patients and five healthy subjects by quantitative (Q) RT-PCR and Western blot. Functional assay to test antigen presentation ability of sorted B cells was performed on blood samples from seven additional ON patients. Significantly differentiating gene expression signatures consisting of 467, 55, and 55 MIGs respective of CD19(+), CD14(+), and CD4(+) cells, were identified between ON and healthy subjects. No MIGs were detected for CD8(+) cells. The major involvement of CD19(+) B cells in the early stage of ON was characterized by enrichment of genes involved in activation of immune mechanisms (P = 3.2 × 10(-25) to 2.5 × 10(-3)), including cellular immune response (P = 7.1 × 10(-12)), B-cell cellular growth and proliferation (P = 1.0 × 10(-7)), activation of immune cells trafficking pathways (P = 5.4 × 10(-15) to 2.0 × 10(-3)), and stimulation of antigen presentation (P = 8.9 × 10(-11)). This massive B-cell-restricted initiation of the immune response in the early disease process of ON was followed by low CD14(+) and CD4(+) cells activity and CD8(+) cells anergy. Our findings demonstrate that CD19(+) B cells have a significant role in the pathogenesis of the first demyelinating event of acute ON and suggest their role as a possible target for immunomodulation.


Outcome of severe unilateral cerebellar hypoplasia.
Complete or subtotal absence of one cerebellar hemisphere is exceptional; only single cases have been described. We aimed to assess the long-term outcome in children with severe unilateral cerebellar hypoplasia (UCH). As part of a retrospective study we describe neuroimaging features, clinical findings, and cognitive outcomes of seven children with UCH (five males, two females; age at first magnetic resonance imaging [MRI]: median 1y 3mo, range 9d-8y 10mo; age at latest follow-up: median 6y 6mo, range 2y 3mo-14y 11mo). One child had abnormalities on prenatal MRI at 21 weeks' gestation. The left cerebellar hemisphere was affected in five children, and the right hemisphere in two children. The vermis was involved in five children. The volume of the posterior fossa was variable. At the latest follow-up, neurological findings included truncal ataxia and muscular hypotonia in five children, limb ataxia in three patients, and head nodding in two patients. Three children had learning disability*, five had speech and language disorders, and one had a severe behavioural disorder. Severe UCH is a residual change after a disruptive prenatal cerebellar insult, most likely haemorrhagic. The outcome is variable, ranging from almost normal development to marked developmental impairment. Ataxia is a frequent but not a leading sign. It seems that involvement of the cerebellar vermis is often, but not consistently, associated with a poorer cognitive outcome, whereas an intact vermis is associated with normal outcome and no truncal ataxia.


Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review.
Chronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections. At the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3'-kinase (PI3K) inhibitors (idelalisib and duvelisib) can be prescribed for disease that progresses with BTK inhibitors and venetoclax, but patients require close monitoring for adverse events such as autoimmune conditions and infections. In patients with multiple relapses, chimeric antigen receptor T-cell (CAR-T) therapy with lisocabtagene maraleucel was associated with a 45% complete response rate. The only potential cure for CLL is allogeneic hematopoietic cell transplant, which remains an option after use of targeted agents. More than 200 000 people in the US are living with a CLL diagnosis, and CLL causes approximately 4410 deaths each year in the US. Approximately two-thirds of patients eventually need treatment. Highly effective novel targeted agents include BTK inhibitors such as acalabrutinib, zanubrutinib, ibrutinib, and pirtobrutinib or BCL2 inhibitors such as venetoclax.


High concordance of daidzein-metabolizing phenotypes in individuals measured 1 to 3 years apart.
Particular intestinal bacteria are capable of metabolizing the soya isoflavone daidzein to equol and/or O-desmethylangolensin (O-DMA), and the presence of these metabolites in urine after soya consumption are markers of particular intestinal bacteria profiles. Prevalences of equol producers and O-DMA producers are approximately 30-50 % and 80-90 %, respectively, and limited observations have suggested that these daidzein-metabolizing phenotypes are stable within individuals over time. Characterizing stability of these phenotypes is important to understand their potential as markers of long-term exposure to particular intestinal bacteria and their associations with disease risk. We evaluated concordance within an individual for the equol-producer and O-DMA-producer phenotypes measured at two time points (T1, T2), 1-3 years apart. Phenotypes were ascertained by analysing equol and O-DMA using GC-MS in a spot urine sample collected after 3 d soya (source of daidzein) supplementation. In ninety-two individuals without recent (within 3 months before phenotyping) or current antibiotics use, 41 % were equol producers at T1 and 45 % were equol producers at T2, and 90 % were O-DMA producers at T1 and 95 % were O-DMA producers at T2. The percentage agreement for the equol-producer phenotype was 82 and for the O-DMA-producer phenotype was 89. These results indicate that these phenotypes are stable in most individuals over time, suggesting that they provide a useful biomarker for evaluating disease risk associated with harbouring particular intestinal bacteria responsible for, or associated with, the metabolism of the soya isoflavone daidzein.


Probing the role of tryptophans in Aequorea victoria green fluorescent proteins with an expanded genetic code.
The expanded genetic code in combination with site-directed mutagenesis was used to probe spectroscopic and structural roles of tryptophan (Trp) residues in Aequorea victoria green fluorescent proteins (avGFPs). Nine different halogen-, chalcogen-, and methyl-containing Trp isosteric analogues and surrogates were incorporated into avGFPs containing indole moieties in, and outside of, the chromophore, by the use of the selective pressure incorporation method. Such isosteric replacements introduced minimal local geometry changes in indole moieties, often to the level of single atomic exchange ('atomic mutation') and do not affect three-dimensional structures of avGFPs but induce changes in spectral properties. Our approach offers a new platform to re-evaluate issues like resonance transfer, mechanisms of chromophore formation and maturation, as well as the importance of local geometry and weak sulphur-aromatic interactions for avGFP spectral properties and structural stability. The library of novel tailor-made avGFP mutants and variants generated in this work has demonstrated not only the potentials of the expanded genetic code to study spectroscopic functions, but also a new approach to generate tailor-made proteins with interesting and useful spectral properties.


Bacteriocins: Novel Solutions to Age Old Spore-Related Problems?
Bacteriocins are ribosomally synthesized antimicrobial peptides produced by bacteria, which have the ability to kill or inhibit other bacteria. Many bacteriocins are produced by food grade lactic acid bacteria (LAB). Indeed, the prototypic bacteriocin, nisin, is produced by Lactococcus lactis, and is licensed in over 50 countries. With consumers becoming more concerned about the levels of chemical preservatives present in food, bacteriocins offer an alternative, more natural approach, while ensuring both food safety and product shelf life. Bacteriocins also show additive/synergistic effects when used in combination with other treatments, such as heating, high pressure, organic compounds, and as part of food packaging. These features are particularly attractive from the perspective of controlling sporeforming bacteria. Bacterial spores are common contaminants of food products, and their outgrowth may cause food spoilage or food-borne illness. They are of particular concern to the food industry due to their thermal and chemical resistance in their dormant state. However, when spores germinate they lose the majority of their resistance traits, making them susceptible to a variety of food processing treatments. Bacteriocins represent one potential treatment as they may inhibit spores in the post-germination/outgrowth phase of the spore cycle. Spore eradication and control in food is critical, as they are able to spoil and in certain cases compromise the safety of food by producing dangerous toxins. Thus, understanding the mechanisms by which bacteriocins exert their sporostatic/sporicidal activity against bacterial spores will ultimately facilitate their optimal use in food. This review will focus on the use of bacteriocins alone, or in combination with other innovative processing methods to control spores in food, the current knowledge and gaps therein with regard to bacteriocin-spore interactions and discuss future research approaches to enable spores to be more effectively targeted by bacteriocins in food settings.


The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making.
Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes.


Perineural invasion in head and neck cancers - a review.
perineural invasion is an under-recognized way of metastatic spread via tumoral invasion of the nerves. It is encountered in malignancies located in the head and neck but also in cancers involving the pancreas, colon and rectum, prostate, biliary tract and stomach. For some tumors, it may be the only way of metastatic spread. It represents a marker for poor outcome, with increased risk for locoregional recurrence and reduced survival rates. The molecular mechanisms behind this process are not yet fully understood; research is done to identify new therapeutic targets in order to achieve disease control. to make a rigorous analysis of this phenomenon and to highlight the best therapeutic approach. a review of the current literature in order to harmonize the international protocols to our local pathology. the surgical intervention is decisive to defeat the malignant process but must be associated with modern therapeutic methods, such as the image-guided radiation therapy and immunotherapy.


Salivary Antioxidants Status Following Progressive Aerobic Exercise: What Are the Differences between Waterpipe Smokers and Non-Smokers?
Waterpipe tobacco (WPT) smoking is a public health problem with similar or even stronger effects than cigarette smoking. Although it appears to be associated with extensive oxidative stress, there is a limited number of studies on the oxidative effects of WPT smoking in stressful conditions. We, therefore, compared the responses of salivary flow rate (SFR), uric acid (UA) concentration, and peroxidase (POX) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) activities between WPT smokers and non-smokers following a bout of exhaustive aerobic exercise (AE). Twenty-three sedentary young women (age: 22.95 ± 2.83 years) participated in this study, including 11 smokers (7.00 ± 1.41 uses/week) and 12 non-smokers. All participants were required to perform the Bruce protocol treadmill test at an initial gradient of 10% at 1.7 mph, with increases of these parameters every 3 min until exhaustion. Unstimulated saliva samples were collected before, immediately after, and 1 hour after AE. WPT smokers showed lower SFR compared with non-smokers at all time points (p < 0.05). In comparison to WPT smokers, a larger increase in POX activity (approximately 23% vs. 14%; p = 0.009) and a smaller decline in DPPH activity (approximately -8% vs. -15%; p = 0.004) were found in non-smokers compared with WPT smokers. While these changes were slowly compensated within 1 hour after exhaustion, the activity of both markers was different from the pre-exercise values (p < 0.001). There was also a trend for UA concentration in non-smokers to be higher during the recovery period, with no significant difference between the groups (p > 0.05). It seems that WPT smoking is associated with negative effects on important human antioxidants and a diminished antioxidative response following acute exercise.


Absolute mRNA concentrations from sequence-specific calibration of oligonucleotide arrays.
Oligonucleotide microarrays are based on the hybridization of labeled mRNA molecules to short length oligonucleotide probes on a glass surface. Two effects have been shown to affect the raw data: the sequence dependence of the probe hybridization properties and the chemical saturation resulting from surface adsorption processes. We address both issues simultaneously using a physically motivated hybridization model. Based on publicly available calibration data sets, we show that Langmuir adsorption accurately describes GeneChip hybridization, with model parameters that we predict from the sequence composition of the probes. Because these parameters have physical units, we are able to estimate absolute mRNA concentrations in picomolar. Additionally, by accounting for chemical saturation, we substantially reduce the compressive bias of differential expression estimates that normally occurs toward high concentrations.


A role for spiritual change in the benefits of 12-step involvement.
Emerging evidence implies a role for spirituality in recovery from substance abuse. The current study examines the hypothesis that spiritual change helps mediate (or explain) effects for involvement in 12-step groups on recovery outcomes among substance-abusing populations. Participants (baseline N = 733) received treatment at 1 of 5 day hospital and 7 residential substance abuse treatment programs in California. Assessments included a baseline interview and 1-year follow-up; analyses incorporated regressions informed by Baron and Kenny (1986) and Sobel's (1982) test. To assess spirituality, measures included (1) the Religious Background and Behaviors scale and (2) an item assessing whether or not participants had had a spiritual awakening through their involvement with 12-step groups. Results confirmed the hypothesis. Increases in 12-step involvement from baseline to follow-up predicted higher odds of total abstinence at follow-up, and this relationship was partially explained by increases in spirituality. Results held in multivariate analyses and regardless of which spirituality measure was analyzed. The present study provides further evidence that spiritual change contributes to recovery, at least within the context of 12-step involvement. The study also deepens our understanding of how 12-step involvement works.


Description and validation of a magnetic resonance imaging-guided stereotactic brain biopsy device in the dog.
A stereotactic brain biopsy system that is magnetic resonance (MR) imaging-guided has not been validated in dogs. Our purpose was to determine the mean needle placement error in the caudate nucleus, thalamus, and midbrain of a canine cadaver brain using the modified Brainsight stereotactic system. Relocatable reference markers (fiducial markers) were attached to the cadaver head using a dental bite block. A T1-weighted gradient echo three-dimensional (3D) sequence was acquired using set parameters. Fiducial markers were used to register the head to the acquired MR images in reference to a 3D position sensor. This allowed the planning of trajectory path to brain targets in real time. Coordinates (X, Y, Z) were established for each target and 0.5 microl of diluted gadolinium was injected at each target using a 26-gauge needle to create a lesion. The center of the gadolinium deposition was identified on the postoperative MR images and coordinates (X', Y', Z') were established. The precision of this system in bringing the needle to target (needle placement error) was calculated. Seventeen sites were targeted in the brain. The mean needle placement error for all target sites was 1.79 +/- 0.87 mm. The upper bound of error for this stereotactic system was 3.31 mm. There was no statistically significant relationship between needle placement error and target depth (P = 0.23). The ease of use and precision of this stereotactic system support its development for clinical use in dogs with brain lesions > 3.31 mm.


In vitro assessment of artifacts induced by titanium, titanium-zirconium and zirconium dioxide implants in cone-beam computed tomography.
The aim of this study was to test whether or not the intensity of artifacts around implants in cone-beam computed tomography (CBCT) differs between titanium, titanium-zirconium and zirconium dioxide implants. Twenty models of a human mandible, each containing one implant in the single-tooth gap position 45, were cast in dental stone. Five test models were produced for each of the following implant types: titanium 4.1 mm diameter (Ti4.1 ), titanium 3.3 mm diameter (Ti3.3 ), titanium-zirconium 3.3 mm diameter (TiZr3.3 ) and zirconium dioxide 3.5-4.5 mm diameter (ZrO3.5-4.5 ) implants. For control purposes, three models without implants were produced. Each model was scanned using a CBCT device. Gray values (GV) were recorded at eight circumferential positions around the implants at 0.5 mm, 1 mm and 2 mm from the implant surface (GVT est ). GV were assessed in the corresponding volumes of interest (VOI) in the control models without implants (GVC ontrol ). Differences of gray values (ΔGV) between GVT est and GVC ontrol were calculated as percentages. One-way ANOVA and post hoc tests were applied to detect differences between implant types. Mean ΔGV for ZrO3.5-4.5 presented the highest absolute values, generally followed by TiZr3.3 , Ti4.1 and Ti3.3 implants. The differences of ΔGV between ZrO3.5-4.5 and the remaining groups were statistically significant in the majority of the VOI (P ≤ 0.0167). ΔGV for TiZr3.3 , Ti4.1 and Ti3.3 implants did not differ significantly in the most VOI. For all implant types, ΔGV showed positive values buccally, mesio-buccally, lingually and disto-lingually, whereas negative values were detected mesially and distally. Zirconium dioxide implants generate significantly more artifacts as compared to titanium and titanium-zirconium implants. The intensity of artifacts around zirconium dioxide implants exhibited in average the threefold in comparison with titanium implants.


Association of hypercholesterolemia and cardiac function evaluated by speckle tracking echocardiography in a rabbit model.
Although hypercholesterolemia is a major risk factor for coronary artery disease (CAD), only limited data are available regarding its direct effect on myocardial function apart from CAD. The aim of this study was to evaluate LV systolic function using speckle-tracking echocardiography and investigate the relationship between hypercholesterolemia and myocardial function. Twenty-eight rabbits were randomly divided into three groups: 8 were fed normal chow for 3 months (group 1) and the remaining 20 were fed an atherogenic diet for 2 (group 2) or 3 months (group 3). Global systolic radial, circumferential and longitudinal peak strain were calculated. Serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and myocardial cholesterol levels were measured. Global systolic longitudinal strain were both decreased in the group 2 and 3 (P < 0.001), whereas radial strain were increased (P < 0.001) compared with group 1. Global circumferential strain in the group 3 was significantly reduced (P < 0.001). Serum and myocardial cholesterol concentration markedly increased in the group 2 and group 3 (P < 0.001). There was a significant inverse correlation between longitudinal strain and serum TC, LDL-C as well as myocardial cholesterol levels (r = - 0.723, r = - 0.794, r = - 0.700, P both < 0.001). A significant negative correlation was also noted between circumferential strain and serum TC, LDL-C as well as myocardial cholesterol levels (r = - 0.518, P = 0.007; r = - 0.691, P < 0.001; r = - 0.659, P < 0.001). A significant positive correlation was found between radial strain and serum TC, LDL-C as well as myocardial cholesterol levels (r = 0.432, P = 0.028; r = 0.602, P = 0.001; r = 0.469, P = 0.016). Although LV morphology and ejection fractions were not different among the three groups, elevated concentration of cholesterol, especially in serum LDL-C, was significantly associated with LV systolic dysfunction. The findings also indicate that reductions in longitudinal was the first appeared, followed by circumferential, and was compensated for by increasing radial strain.


Video Magnification Applied in Ultrasound.
This paper describes a method to enhance, visualize, and reveal subtle motion that can be present in medical images. As proposed in vision applications, the principle is to magnify displacement applied, in this case, to cardiovascular tissues (carotid). In the example presented, ultrasound data were acquired at a high frame rate and two-dimensional motion was estimated, amplified, and reapplied in ultrasound carotid sequences. Video magnification makes fast and complex phenomena of human tissue visible. In fact, not only pulse and reflected wave, but also global radial and longitudinal motion in the example presented are visible with video magnification. Video magnification can be used in medical imaging for subtle motion visualization. One of the many possible applications is direct visualization of a local modification in terms of stiffness of a tissue (due to local necrosis, for instance) from acquisition. Moreover, video magnification can be executed with any type of imaging modality. Video magnification could be a new tool for physicians to highlight new pathology indicators or for long-term disease monitoring.


Whole-brain comparison of rodent and human brains using spatial transcriptomics.
The ever-increasing use of mouse models in preclinical neuroscience research calls for an improvement in the methods used to translate findings between mouse and human brains. Previously, we showed that the brains of primates can be compared in a direct quantitative manner using a common reference space built from white matter tractography data (Mars et al., 2018b). Here, we extend the common space approach to evaluate the similarity of mouse and human brain regions using openly accessible brain-wide transcriptomic data sets. We show that mouse-human homologous genes capture broad patterns of neuroanatomical organization, but the resolution of cross-species correspondences can be improved using a novel supervised machine learning approach. Using this method, we demonstrate that sensorimotor subdivisions of the neocortex exhibit greater similarity between species, compared with supramodal subdivisions, and mouse isocortical regions separate into sensorimotor and supramodal clusters based on their similarity to human cortical regions. We also find that mouse and human striatal regions are strongly conserved, with the mouse caudoputamen exhibiting an equal degree of similarity to both the human caudate and putamen.


Design and analysis of VCSEL based twodimension wavelength converter.
A novel two-dimensional vertical cavity surface emission laser (VCSEL) based wavelength converter is proposed. We developed a twodimensional transmission line laser model (TLLM) to analyze the proposed wavelength converter. This model takes into account Bragg reflectors by using the modified connecting matrix. Therefore, accurate and efficient modeling of the VCSEL structure is achieved. Extinction ratio of the output signal is investigated by considering input signal power, wavelength, facet reflectivity and cavity diameter.


Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial.
Studies suggest that the ingestion of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), can reduce the deleterious side-effects of chemotherapy. The aim of this randomised clinical trial was to evaluate the effect of supplementation with oral FO for 9 weeks on nutritional parameters and inflammatory nutritional risk in patients with haematological malignancies during the beginning of chemotherapy. Twenty-two patients with leukaemia or lymphoma were randomised to the unsupplemented group (UG) (n = 13) or supplemented group (SG) (n = 9). SG received 2 g/day of fish oil for 9 weeks. Nutritional status, serum acute-phase proteins and plasma fatty acids were evaluated before (T0) and after (T1) the intervention period. Data were analysed using two models; model 1, comprising data from all patients included in the study, and model 2, comprising data from UG patients with no increase in the proportions of EPA and DHA in plasma and data from SG patients showing an at least 100% increase in plasma EPA and DHA. SG showed an increased plasma proportion of EPA and DHA in both models. In model 2, C-reactive protein (CRP) and CRP/albumin ratio showed larger reductions in the SG. Overall long-term survival in both models (465 days after the start of the chemotherapy) was higher in the group ingesting fish oil (P < 0.05). These findings indicate an improved nutritional-inflammatory risk and potential effects on long-term survival in patients with haematological malignancies supplemented with FO during the beginning of chemotherapy.


Mode-field adaptor between large-mode-area fiber and single-mode fiber based on fiber tapering and thermally expanded core technique.
We report a method to fabricate a mode-field adaptor (MFA) for a large-mode-area (LMA) fiber and single-mode fibers (SMFs) based on fiber tapering and the thermally expanded core (TEC) technique. Through adiabatically tapering a LMA fiber by an oxygen-hydrogen flame, the mode-field diameter is decreased effectively with nearly no extra loss, which makes it possible to realize mode-field adaptation between the LMA fiber and SMFs. Both numerical calculation and experimental results show it is workable to realize fundamental mode propagation in LMA fiber and get a low insertion loss by this method. For a LMA fiber (d=25 μm, NA=0.06) and a SMF (d=4 μm, NA=0.2), a low loss with less than 0.4 dB has been obtained both in the forward and backward directions experimentally.


Scale-free structures emerging from co-evolution of a network and the distribution of a diffusive resource on it.
Co-evolution exhibited by a network system, involving the intricate interplay between the dynamics of the network itself and the subsystems connected by it, is a key concept for understanding the self-organized, flexible nature of real-world network systems. We propose a simple model of such coevolving network dynamics, in which the diffusion of a resource over a weighted network and the resource-driven evolution of the link weights occur simultaneously. We demonstrate that, under feasible conditions, the network robustly acquires scale-free characteristics in the asymptotic state. Interestingly, in the case that the system includes dissipation, it asymptotically realizes a dynamical phase characterized by an organized scale-free network, in which the ranking of each node with respect to the quantity of the resource possessed thereby changes ceaselessly. Our model offers a unified framework for understanding some real-world diffusion-driven network systems of diverse types.


Efficient functioning of plant promoters and poly(A) sites in Xenopus oocytes.
Mature Xenopus oocytes were challenged with DNA constructs including plant regulatory elements, namely, the Cauliflower mosaic virus (CaMV) 35S promoter as well as the nopaline synthase (NOS) promoter and polyadenylation signal. The bacterial chloramphenicol acetyl transferase (CAT) was used as a reporter gene. When microinjected into these cells, the plant-derived DNA constructs effectively promoted CAT synthesis in a manner dependent on the presence of the plant promoters and probably also on the polyadenylation signals. Structural studies revealed that the supercoiled structures of the above DNA plasmids were much more active in supporting CAT synthesis in microinjected oocytes than their linear forms, with clear correlation between efficient gene expression and DNA topology. In contrast, the linear forms of these plasmids were considerably more active than the supercoiled ones in transfected plant protoplasts. These findings demonstrate, for the first time, the activity of regulatory elements from plant genes in Xenopus oocytes and shed new light on the specific rules applicable for gene expression in plant and animal cells.


American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2.
To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added. Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.


Discriminating coding, non-coding and regulatory regions using rescaled range and detrended fluctuation analysis.
In this paper we analyse the efficiency of two methods, rescaled range analysis and detrended fluctuation analysis, in distinguishing between coding DNA, regulatory DNA and non-coding non-regulatory DNA of Drosophila melanogaster. Both methods were used to estimate the degree of sequential dependence (or persistence) among nucleotides. We found that these three types of DNA can be discriminated by both methods, although rescaled range analysis performs slightly better than detrended fluctuation analysis. On average, non-coding, non-regulatory DNA has the highest degree of sequential persistence. Coding DNA could be characterised as being anti-persistent, which is in line with earlier findings of latent periodicity. Regulatory regions are shown to possess intermediate sequential dependency. Together with other available methods, rescaled range and detrended fluctuation analysis on the basis of a combined purine/pyrimidine and weak/strong classification of the nucleotides are useful tools for refined structural and functional segmentation of DNA.


Molecular pathology of lung cancer.
Our understanding of the molecular pathology of lung cancer is advancing rapidly with several specific genes and chromosomal regions being identified. Lung cancer appears to require many mutations in both dominant and recessive oncogenes before they become invasive. Several genetic and epigenetic changes are common to all lung cancer histologic types, while others appear to be tumor type specific. The identification of those specific genes undergoing such mutations and the sequence of cumulative changes that lead the neoplastic changes for each lung tumor histologic type remain to be fully elucidated. Recent findings in normal and preneoplastic bronchial epithelium from lung cancer patients and smoker subjects suggest that genetic changes may provide in this neoplasm new methods for early diagnosis, risk assessment and for monitoring response to chemoprevention.


Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation.
Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered. In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity. Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated. From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.


Immunity to non-cerebral severe malaria is acquired after one or two infections.
In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.


Anti diabetic property of aqueous extract of Stevia rebaudiana Bertoni leaves in Streptozotocin-induced diabetes in albino rats.
Stevia (Stevia rebaudiana) natural, non-caloric sugar substitute is rich source of pharmacologically important glycoside stevioside that is linked to the pathology and complications of diabetes. The current research was carried out to explore the anti-diabetic effect of aqueous extract of Stevia rebaudiana leaves in albino rats. For this purpose, diabetes was induced by administration of streptozotocin (40 mg/kg body weight, intraperitoneally). The diabetic rats were administered with aqueous stevia extract at different dose levels (200, 300, 400 and 500 ppm/kg b.w) for 8 weeks; the control rats were fed basal diet during this period. Stevia aqueous extract improved caloric management and weight control by decreasing the feed intake and body weight gain. Furthermore, intake of stevia extract resulted in significant (P < 0.05) decrease in the random blood glucose level (- 73.24%) and fasting blood glucose (- 66.09%) and glycosylated (HbA1c) hemoglobin (5.32%) while insulin (17.82 μIU/mL) and liver glycogen (45.02 mg/g) levels significantly improved in the diabetic rats, compared with the diabetic and non-diabetic control rats after 8 weeks study period. It is concluded that aqueous extact of stevia has anti-diabetic effects in albino rats, and therefore could be promising nutraceutical therapy for the management of diabetes and its associated complications.


Characterising the treatment of thromboembolic events after COVID-19 vaccination in 4 European countries and the US: An international network cohort study.
Background: Thrombosis with thrombocytopenia syndrome (TTS) has been identified as a rare adverse event following some COVID-19 vaccines. Various guidelines have been issued on the treatment of TTS. We aimed to characterize the treatment of TTS and other thromboembolic events (venous thromboembolism (VTE), and arterial thromboembolism (ATE) after COVID-19 vaccination and compared to historical (pre-vaccination) data in Europe and the US. Methods: We conducted an international network cohort study using 8 primary care, outpatient, and inpatient databases from France, Germany, Netherlands, Spain, The United Kingdom, and The United States. We investigated treatment pathways after the diagnosis of TTS, VTE, or ATE for a pre-vaccination (background) cohort (01/2017-11/2020), and a vaccinated cohort of people followed for 28 days after a dose of any COVID-19 vaccine recorded from 12/2020 onwards). Results: Great variability was observed in the proportion of people treated (with any recommended therapy) across databases, both before and after vaccination. Most patients with TTS received heparins, platelet aggregation inhibitors, or direct Xa inhibitors. The majority of VTE patients (before and after vaccination) were first treated with heparins in inpatient settings and direct Xa inhibitors in outpatient settings. In ATE patients, treatments were also similar before and after vaccinations, with platelet aggregation inhibitors prescribed most frequently. Inpatient and claims data also showed substantial heparin use. Conclusion: TTS, VTE, and ATE after COVID-19 vaccination were treated similarly to background events. Heparin use post-vaccine TTS suggests most events were not identified as vaccine-induced thrombosis with thrombocytopenia by the treating clinicians.


Objective assessment in residency-based training for transoral robotic surgery.
To develop a robotic surgery training regimen integrating objective skill assessment for otolaryngology and head and neck surgery trainees consisting of training modules of increasing complexity leading up to procedure-specific training. In particular, we investigated applications of such a training approach for surgical extirpation of oropharyngeal tumors via a transoral approach using the da Vinci robotic system. Prospective blinded data collection and objective evaluation (Objective Structured Assessment of Technical Skills [OSATS]) of three distinct phases using the da Vinci robotic surgical system in an academic university medical engineering/computer science laboratory setting. Between September 2010 and July 2011, eight otolaryngology-head and neck surgery residents and four staff experts from an academic hospital participated in three distinct phases of robotic surgery training involving 1) robotic platform operational skills, 2) set up of the patient side system, and 3) a complete ex vivo surgical extirpation of an oropharyngeal tumor located in the base of tongue. Trainees performed multiple (four) approximately equally spaced training sessions in each stage of the training. In addition to trainees, baseline performance data were obtained for the experts. Each surgical stage was documented with motion and event data captured from the application programming interfaces of the da Vinci system, as well as separate video cameras as appropriate. All data were assessed using automated skill measures of task efficiency and correlated with structured assessment (OSATS and similar Likert scale) from three experts to assess expert and trainee differences and compute automated and expert assessed learning curves. Our data show that such training results in an improved didactic robotic knowledge base and improved clinical efficiency with respect to the set up and console manipulation. Experts (e.g., average OSATS, 25; standard deviation [SD], 3.1; module 1, suturing) and trainees (average OSATS, 15.9; SD, 3.9; week 1) are well separated at the beginning of the training, and the separation reduces significantly (expert average OSATS, 27.6; SD, 2.7; trainee average OSATS, 24.2; SD, 6.8; module 3) at the conclusion of the training. Learning curves in each of the three stages show diminishing differences between the experts and trainees, which is also consistent with expert assessment. Subjective assessment by experts verified the clinical utility of the module 3 surgical environment, and a survey of trainees consistently rated the curriculum as very useful in progression to human operating room assistance. Structured curricular robotic surgery training with objective assessment promises to reduce the overhead for mentors, allow detailed assessment of human-machine interface skills, and create customized training models for individualized training. This preliminary study verifies the utility of such training in improving human-machine operations skills (module 1), and operating room and surgical skills (modules 2 and 3). In contrast to current coarse measures of total operating time and subjective assessment of error for short mass training sessions, these methods may allow individual tasks to be removed from the trainee regimen when skill levels are within the standard deviation of the experts for these tasks, which can greatly enhance overall efficiency of the training regimen and allow time for additional and more complex training to be incorporated in the same time frame.


Dissociate lattice oxygen redox reactions from capacity and voltage drops of battery electrodes.
The oxygen redox (OR) activity is conventionally considered detrimental to the stability and kinetics of batteries. However, OR reactions are often confused by irreversible oxygen oxidation. Here, based on high-efficiency mapping of resonant inelastic x-ray scattering of both the transition metal and oxygen, we distinguish the lattice OR in Na0.6[Li0.2Mn0.8]O2 and compare it with Na2/3[Mg1/3Mn2/3]O2. Both systems display strong lattice OR activities but with distinct electrochemical stability. The comparison shows that the substantial capacity drop in Na0.6[Li0.2Mn0.8]O2 stems from non-lattice oxygen oxidations, and its voltage decay from an increasing Mn redox contribution upon cycling, contrasting those in Na2/3[Mg1/3Mn2/3]O2. We conclude that lattice OR is not the ringleader of the stability issue. Instead, irreversible oxygen oxidation and the changing cationic reactions lead to the capacity and voltage fade. We argue that lattice OR and other oxygen activities should/could be studied and treated separately to achieve viable OR-based electrodes.


Physiology, Metabolism, and Fossilization of Hot-Spring Filamentous Microbial Mats.
The evolutionarily ancient Aquificales bacterium Sulfurihydrogenibium spp. dominates filamentous microbial mat communities in shallow, fast-flowing, and dysoxic hot-spring drainage systems around the world. In the present study, field observations of these fettuccini-like microbial mats at Mammoth Hot Springs in Yellowstone National Park are integrated with geology, geochemistry, hydrology, microscopy, and multi-omic molecular biology analyses. Strategic sampling of living filamentous mats along with the hot-spring CaCO3 (travertine) in which they are actively being entombed and fossilized has permitted the first direct linkage of Sulfurihydrogenibium spp. physiology and metabolism with the formation of distinct travertine streamer microbial biomarkers. Results indicate that, during chemoautotrophy and CO2 carbon fixation, the 87-98% Sulfurihydrogenibium-dominated mats utilize chaperons to facilitate enzyme stability and function. High-abundance transcripts and proteins for type IV pili and extracellular polymeric substances (EPSs) are consistent with their strong mucus-rich filaments tens of centimeters long that withstand hydrodynamic shear as they become encrusted by more than 5 mm of travertine per day. Their primary energy source is the oxidation of reduced sulfur (e.g., sulfide, sulfur, or thiosulfate) and the simultaneous uptake of extremely low concentrations of dissolved O2 facilitated by bd-type cytochromes. The formation of elevated travertine ridges permits the Sulfurihydrogenibium-dominated mats to create a shallow platform from which to access low levels of dissolved oxygen at the virtual exclusion of other microorganisms. These ridged travertine streamer microbial biomarkers are well preserved and create a robust fossil record of microbial physiological and metabolic activities in modern and ancient hot-spring ecosystems.


Characterization of the inositol 1,4,5-trisphosphate-induced Ca2+ release in pancreatic beta-cells.
Pancreatic beta-cells isolated from obese-hyperglycaemic mice released intracellular Ca2+ in response to carbamoylcholine, an effect dependent on the presence of glucose. The effective Ca2+ concentration reached was sufficient to evoke a transient release of insulin. When the cells were deficient in Ca2+, the Ca2+ pool sensitive to carbamoylcholine stimulation was equivalent to that released by ionomycin. Unlike intact cells, cells permeabilized by high-voltage discharges failed to generate either inositol 1,4,5-triphosphate (InsP3) or to release Ca2+ after exposure to carbamoylcholine. However, the permeabilized cells released insulin sigmoidally in response to increasing concentrations of Ca2+. Also in the absence of functional mitochondria these cells exhibited a large ATP-dependent buffering of Ca2+, enabling the maintenance of an ambient Ca2+ concentration corresponding to about 150 nM even after several additional pulses of Ca2+. InsP3, maximally effective at 6 microM, promoted a rapid and pronounced release of Ca2+. The InsP3-sensitive Ca2+ pool was rapidly filled and lost its Ca2+ late after ATP depletion. The transient nature of the Ca2+ signal was not overcome by repetitive additions of InsP3. It was possible to restore the response to InsP3 after a delay of approx. 20 min, an effect which had less latency after the addition of Ca2+. These latter findings argue against degradation and/or desensitization as factors responsible for the transiency in InsP3 response. It is suggested that Ca2+ released by InsP3 is taken up by a part of the endoplasmic reticulum (ER) not sensitive to InsP3. On metabolism of InsP3, Ca2+ recycles to the InsP3-sensitive pool, implying that this pool indeed has a very high affinity for the ion. The presence of functional mitochondria did not interfere with the recycling process. The ER in pancreatic beta-cells is of major importance in buffering Ca2+, but InsP3 only modulates Ca2+ transport for a restricted period of time following immediately upon its formation. Thereafter the non-sensitive part of the ER takes over the continuous regulation of Ca2+ cycling.


A secretomics analysis reveals major differences in the macrophage responses towards different types of carbon nanotubes.
Certain types of carbon nanotubes (CNT) can evoke inflammation, fibrosis and mesothelioma in vivo, raising concerns about their potential health effects. It has been recently postulated that NLRP3 inflammasome activation is important in the CNT-induced toxicity. However, more comprehensive studies of the protein secretion induced by CNT can provide new information about their possible pathogenic mechanisms. Here, we studied protein secretion from human macrophages with a proteomic approach in an unbiased way. Human monocyte-derived macrophages (MDM) were exposed to tangled or rigid, long multi-walled CNT (MWCNT) or crocidolite asbestos for 6 h. The growth media was concentrated and secreted proteins were analyzed using 2D-DIGE and DeCyder software. Subsequently, significantly up- or down-regulated protein spots were in-gel digested and identified with an LC-MS/MS approach. Bioinformatics analysis was performed to reveal the different patterns of protein secretion induced by these materials. The results show that both long rigid MWCNT and asbestos elicited ample and highly similar protein secretion. In contrast, exposure to long tangled MWCNT induced weaker protein secretion with a more distinct profile. Secretion of lysosomal proteins followed the exposure to all materials, suggesting lysosomal damage. However, only long rigid MWCNT was associated with apoptosis. This analysis suggests that the CNT toxicity in human MDM is mediated via vigorous secretion of inflammation-related proteins and apoptosis. This study provides new insights into the mechanisms of toxicity of high aspect ratio nanomaterials and indicates that not all types of CNT are as hazardous as asbestos fibers.


Guided self-help to reduce psychological distress in South Sudanese female refugees in Uganda: a cluster randomised trial.
Innovative solutions are required to provide mental health support at scale in low-resource humanitarian contexts. We aimed to assess the effectiveness of a facilitator-guided, group-based, self-help intervention (Self-Help Plus) to reduce psychological distress in female refugees. We did a cluster randomised trial in rural refugee settlements in northern Uganda. Participants were female South Sudanese refugees with at least moderate levels of psychological distress (cutoff ≥5 on the Kessler 6). The intervention comprised access to usual care and five 2-h audio-recorded stress-management workshops (20-30 refugees) led by briefly trained lay facilitators, accompanied by an illustrated self-help book. Villages were randomly assigned to either intervention (Self-Help Plus or enhanced usual care) on a 1:1 basis. Within 14 villages, randomly selected households were approached. Screening of women in households continued until 20-30 eligible participants were identified per site. The primary outcome was individual psychological distress, assessed using the Kessler 6 symptom checklist 1 week before, 1 week after, and 3 months after intervention, in the intention-to-treat population. All outcomes were measured at the individual (rather than cluster) level. Secondary outcomes included personally identified problems, post-traumatic stress, depression symptoms, feelings of anger, social interactions with other ethnic groups, functional impairment, and subjective wellbeing. Assessors were masked to allocation. This trial was prospectively registered at ISRCTN, number 50148022. Of 694 eligible participants (331 Self-Help Plus, 363 enhanced usual care), 613 (88%) completed all assessments. Compared with controls, we found stronger improvements for Self-Help Plus on psychological distress 3 months post intervention (β -1·20, 95% CI -2·33 to -0·08; p=0·04; d -0·26). We also found larger improvements for Self-Help Plus 3 months post-intervention for five of eight secondary outcomes (effect size range -0·30 to -0·36). Refugees with different trauma exposure, length of time in settlements, and initial psychological distress benefited similarly. With regard to safety considerations, the independent data safety management board responded to six adverse events, and none were evaluated to be concerns in response to the intervention. Self-Help Plus is an innovative, facilitator-guided, group-based self-help intervention that can be rapidly deployed to large numbers of participants, and resulted in meaningful reductions in psychological distress at 3 months among South Sudanese female refugees. Research for Health in Humanitarian Crises (R2HC) Programme.


Provision of antiretroviral therapy in South Africa: the nuts and bolts.
Public sector antiretroviral provision had a slow start in South Africa despite a raging epidemic and a World AIDS conference that shed significant public light on the disparities of therapy access globally. This was largely due to political prevarication in the midst of AIDS denialism. There has been an unprecedented expansion in the HIV treatment programme since 2008. As a result, South Africa now has the largest number of patients on antiretroviral drugs in the world, and South African life expectancy has increased by more than a decade. However, this has led to a number of fiscal, logistic and operational challenges that the country must face as the treatment programme continues to expand. Challenges include increasing detection within communities, linkage and retention in care, while strengthening operational support functions such as consistent drug supply, health staffing and infrastructure, diagnostic services, programme monitoring and sustainable financing. As a middle-income country, albeit with marked income inequality, and the heaviest HIV burden in the world, South Africa is a test case of whether a large-scale public health programme can boast of success in the face of numerous other health-system challenges.


c-Met is a novel tumor associated antigen for T-cell based immunotherapy against NK/T cell lymphoma.
Background: The expression of c-Met and its ligand HGF plays a critical role in cell proliferation and is involved in numerous malignancies. Because c-Met expression and its role in NK/T-cell lymphoma remain unclear, we studied the expression and function of c-Met in NK/T-cell lymphoma cells. In addition, we investigated the possibility that c-Met could function as a tumor-associated antigen for helper T lymphocytes (HTLs). Methods: We evaluated whether HGF and c-Met were expressed in NK/T-cell lymphoma and the capacity of predicted c-Met HTL epitopes to induce antitumor responses in vitro. In addition, c-Met inhibitor was evaluated for the ability to inhibit TGF-β production in tumor and subsequently increase HTL recognition. Results: c-Met and HGF were expressed in NK/T-cell lymphoma cell lines, nasal NK/T-cell lymphoma specimens and patient serum samples. Moreover, HGF was shown to promote NK/T cell lymphoma (NKTCL) proliferation in an autocrine manner. Furthermore, we have identified three novel c-Met HTL epitopes that were restricted by several HLA-DR molecules. Notably, peptide-induced HTL lines directly recognized and killed c-Met expressing NK/T-cell lymphomas and various epithelial solid tumors. The c-Met specific HTLs could also recognize dendritic cells (DCs) pulsed with c-Met expressing tumor cell lysates. In addition, we observed that c-Met inhibition augmented HTL recognition by decreasing TGF-β production by tumor cells. Lastly, autophagy partly regulated the HTL responses against tumors. Conclusions: We identified novel c-Met HTL epitopes that can elicit effective antitumor responses against tumors expressing c-Met. Our results provide the rationale of combining c-Met targeting therapy and immunotherapy for NKTCLs and epithelial tumors.


Iron and arsenic release from aquifer solids in response to biostimulation.
Biostimulation has been used at various contaminated sites to promote the reductive dechlorination of trichloroethylene (TCE), but the addition of carbon and energy donor also stimulates bacteria that use Fe(III) as the terminal electron acceptor (TEA) in potential competition with dechlorination processes. Microcosm studies were conducted to determine the influence of various carbon donors on the extent of reductive dissolution of aquifer solids containing Fe(III) and arsenic. Glucose, a fermentable and respirable carbon donor, led to the production of 1500 mg Fe(II) kg(-1), or 24% of the total Fe in the aquifer sediment being reduced to Fe(II), whereas the same concentration of carbon as acetate resulted in only 300 mg Fe(II) kg(-1) being produced. The biogenic Fe(II) produced with acetate was exclusively associated with the solid phase whereas with fermentable carbon donors as whey and glucose, 22 and 54% of the Fe(II) was in solution. With fermentation, some of the metabolites appear to be electron shuttling chemicals and chelating agents that facilitate the reductive dissolution of even crystalline Fe(III) oxides. Without the presence of electron shuttling chemicals, only surficial Fe in direct contact with the bacteria was bioavailable, as illustrated when acetate was used. Regardless of carbon donor type and concentration, As concentrations in the water exceeded drinking water standards. The As dissolution appears to have been the result of the direct use of As as an electron acceptor by dissimilatory arsenic reducing bacteria. Our findings indicate that selection of the carbon and energy donor for biostimulation for remediation of chlorinated solvent impacted aquifers may greatly influence the extent of the reductive dissolution of iron minerals in direct competition with dechlorination processes. Biostimulation may also result in a significant release of As to the solution phase, contributing to further contamination of the aquifer.


Amylopectin induces fumonisin B1 production by Fusarium verticillioides during colonization of maize kernels.
Fusarium verticillioides, a fungal pathogen of maize, produces fumonisin mycotoxins that adversely affect human and animal health. Basic questions remain unanswered regarding the interactions between the host plant and the fungus that lead to the accumulation of fumonisins in maize kernels. In this study, we evaluated the role of kernel endosperm composition in regulating fumonisin B1 (FB1) biosynthesis. We found that kernels lacking starch due to physiological immaturity did not accumulate FB1. Quantitative polymerase chain reaction analysis indicated that kernel development also affected the expression of fungal genes involved in FB1 biosynthesis, starch metabolism, and nitrogen regulation. A mutant strain of F. verticillioides with a disrupted a-amylase gene was impaired in its ability to produce FB1 on starchy kernels, and both the wild-type and mutant strains produced significantly less FB1 on a high-amylose kernel mutant of maize. When grown on a defined medium with amylose as the sole carbon source, the wild-type strain produced only trace amounts of FB1, but it produced large amounts of FB1 when grown on amylopectin or dextrin, a product of amylopectin hydrolysis. We conclude that amylopectin induces FB1 production in F. verticillioides. This study provides new insight regarding the interaction between the fungus and maize kernel during pathogenesis and highlights important areas that need further study.


A review of technological and clinical aspects of robot-aided rehabilitation of upper-extremity after stroke.
Cerebrovascular accident (CVA) or stroke is one of the leading causes of disability and loss of motor function. Millions of people around the world are effected by it each year. Stroke results in disabled arm function. Restoration of arm function is essential to regaining activities of daily living (ADL). Along with traditional rehabilitation methods, robot-aided therapy has emerged in recent years. Robot-aided rehabilitation is more intensive, of longer duration and more repetitive. Using robots, repetitive dull exercises can turn into a more challenging and motivating tasks such as games. Besides, robots can provide a quantitative measure of the rehabilitation progress. This article overviews the terms used in robot-aided upper-limb rehabilitation. It continues by investigating the requirements for rehabilitation robots. Then the most outstanding works in robot-aided upper-limb rehabilitation and their control schemes have been investigated. The clinical outcomes of the built robots are also given that demonstrates the usability of these robots in real-life applications and their acceptance. This article summarizes a review done along with a research on the design, simulation and control of a robot for use in upper-limb rehabilitation after stroke. Implications for Rehabilitation Reviewing common terms in rehabilitation of upper limb using robots Reviewing rehabilitation robots built up to date Reviewing clinical outcomes of the mentioned rehabilitation robots.