B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of patients with MS harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS

Human fetal microglia acquire homeostatic immune-sensing properties early indevelopment

Microglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal microglia development. Single-cell gene expression and bulk chromatin profiles of microglia at 9 to 18 gestational weeks (GWs) of human fetal development were generated. Microglia were heterogeneous at all studied GWs. Microglia start to mature during this developmental period and increasingly resemble adult microglia with CNS-surveilling properties. Chromatin accessibility increases during development with associated transcriptional networks reflective of adult microglia. Thus, during early fetal development, microglia progress toward a more mature, immune-sensing competent phenotype, and this might render the developing human CNS vulnerable to environmental perturbations during early pregnancy

Artemether-lumefantrine versus artemisinin-naphthoquine in Papua New Guinean children with uncomplicated malaria: A six months post-treatment follow-up study

Background: In a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. To determine whether, consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment. Methods: For children completing trial procedures and who were assessable at six months, all within-trial and subsequent clinical malaria episodes were ascertained, the latter by clinic attendances and/or review of hand-held health records. Presentations with non-malarial illness were also recorded. Differences between allocated treatments for pre-specified endpoints were determined using Kaplan-Meier survival analysis. Results: Of 247 children who were followed to Day 42, 176 (71.3%) were included in the present sub-study, 87 allocated to AM-LM and 89 to artemisinin-NQ. Twenty children in the AM-LM group (32.8%) had a first episode of clinical malaria within six months compared with 10 (16.4%) in the artemisinin-NQ group (P=0.033, log rank test). The median (interquartile range) time to first episode of clinical malaria was 64 (50-146) vs 116 (77-130) days, respectively (P=0.20). There were no between-group differences in the incidence of first presentation with non-malarial illness (P=0.31). Conclusions: The greater effectiveness of artemisinin-NQ over conventional AM-LM extends to at least six months post-treatment for clinical malaria but not non-malarial illness. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000913077

ВЛИЯНИЕ ИНКРУСТАЦИИ СЕМЯН СМЕСЯМИ N-ФОСФОНОМЕТИЛГЛИЦИНА И ЭПИБРАССИНОЛИДА НА РОСТ РАСТЕНИЙ

The dependence of action of an inhibitory dose of N-phosphonomethylglycine mixed with epibrassinolide over a wide concentration range, on the root growth of flax (Linum usitatissimum L.) and barley (Hordeum vulgare L.) seedlings is studied. Specific and varietal specificity of growth responses to the incrustation of seeds by such mixtures is identified. The epibrassinolide concentration range, in which its interaction with N-phosphonomethylglycine is most expressed, is detected. It is characterized by the intensification (in spring barley seedlings) or the weakening (in flax seedlings) of the inhibitory effect of glyphosate on the root system.Исследована зависимость действия N-фосфонометилглицина в ингибирующей дозе в смеси с эпибрассинолидом в широком диапазоне концентраций на рост корневой системы проростков льна-долгунца (Linum usitatissimum L.) и ярового ячменя (Hordeum vulgare L.). Установлена видовая и сортовая специфичность ростовых реакций на обработку семян такими смесями. Обнаружен диапазон концентраций эпибрассинолида, в котором его взаимодействие с N-фосфонометилглицином выражено максимально, что характеризуется усилением (на проростках ярового ячменя) либо ослаблением (на проростках льна-долгунца) ингибирующего эффекта глифосата на корневую систему

Особенности действия брассиностероидов на растения в условиях солевого стресса

The dependence of the protective effect of brassinosteroids (BS) in a wide range of concentrations on the growth of the root system of fiber flax (Linum usitatissimum L.) and spring barley (Hordeum vulgare L.) seedlings under salt stress was studied. A narrow range of BS concentrations was revealed, in which they cause a weakening of the inhibitory effect of salinity on the root system of seedlings. An almost complete coincidence of the BS concentration ranges was noted, in which the maximum stress-protective effect of phytohormones was observed for the both crops (6,9 ⋅ 10–7–5,9 ⋅ 10–8 М for fiber flax and 2,8 ⋅ 10–7–2,4 ⋅ 10–8 М for spring barley). In the experiment with winter wheat (Triticum aestivum L.), which lasted 19 days, already on the 6th day before the seedlings were placed under stress conditions, the elongation of the seedlings treated with exogenous brassinosteroids was noted. By the end of the experiment (in the second leaf unfolding phase), all brassinosteroids showed a pronounced protective-stimulating effect under the salinity conditions that depended on the chemical structure of the hormone and changed in the brassinolide > homobrassinolide > homocastasterone > epibrassinolide series.Исследована зависимость протекторного действия брассиностероидов (БС) в широком диапазоне концентраций на рост корневой системы проростков льна-долгунца (Linum usitatissimum L.) и ярового ячменя (Hordeum vulgare L.) в условиях солевого стресса. Выявлены узкие диапазоны концентраций БС (6,9 ⋅ 10–7–5,9 ⋅ 10–8 М для льна-долгунца и 2,8 ⋅ 10–7–2,4 ⋅ 10–8 М для ярового ячменя), в которых они вызывают ослабление ингибирующего эффекта засоления на корневую систему проростков. Отмечено практически полное совпадение диапазонов концентраций БС, в которых наблюдалось максимальное стресс-протекторное действие фитогормонов для обеих культур. В опыте с озимой пшеницей (Triticum aestivum L.), длившемся 19 суток, уже на 6-е сутки, до помещения растений в стрессовые условия, было отмечено удлинение проростков, обработанных экзогенными брассиностероидами, а к концу эксперимента (в фазу развертывания второго листа) все брассиностероиды показали выраженный защитностимулирующий эффект в условиях засоления, зависящий от химической структуры гормона и изменяющийся в ряду брассинолид > гомобрассинолид > гомокастастерон > эпибрассинолид.

Стимулирующее действие оксикоричных кислот и их конъюгатов с хитозаном на рост и биохимические показатели микроклонов картофеля in vitro

This study determined the effect of exogenously applied hydroxycinnamic acids and their chitosan-based conjugates on growth and biochemical parameters of microclone potato plants (Solanum tuberosum L.) in vitro under optimal conditions. The findings of the present investigation confirm applying of chitosan-caffeic acid and chitosan-ferulic acid conjugates on microclone potato plants to improve growth and development. A significant growth-stimulating effect was found in caffeic acid and its chitosan-based conjugate. Chitosan behaved like a general elicitor inducing oxidative stress in plant cells. In turn, hydroxycinnamic acids acted as antioxidants to scavenge reactive oxygen species. The chitosan-caffeic acid conjugate can be considered as a low stress factor that activates metabolism and adaptation processes of microclonal potato plants.Рассматривается влияние кофейной и феруловой кислот и их конъюгатов на основе хитозана на ростовые и отдельные биохимические показатели микроклонов картофеля (Solanum tuberosum L.) сорта Бриз в культуре in vitro. Выявлен их положительный эффект на рост и развитие растений, при этом максимальное стимулирующее действие наблюдали у кофейной кислоты и ее конъюгата. Добавление хитозана в питательную среду культивирования вызвало развитие оксидативного стресса в клетках микроклональных растений. Оксикоричные кислоты проявили антиоксидантные свойства, снижая образование активных форм кислорода и стресс-индуцируемое накопление пролина. Конъюгат хитозана и кофейной кислоты действовал как умеренной силы стрессор, активизируя метаболизм и адаптационные процессы у формирующихся микроклональных растений

ВЛИЯНИЕ ВНОСИМЫХ В СУБСТРАТ СПОРООБРАЗУЮЩИХ БАКТЕРИЙ РОДА BACILLUS НА КАЧЕСТВО САЛАТА ЛИСТОВОГО (Lactuca sativa L.)

Primal problem of vegetable growing is constant supply of the population with all types of vegetables, including green cultures. Green cultures are vegetables that have high nutritional value and precocity. However they often are infected by phytopathogenic microorganisms already at initial stages of ontogenesis at cultivation in closed soil conditions. It leads to emergence of disjointed shoots, deterioration of growth and development of plants and loss of quality. Now in the Republic of Belarus a number of biological substances on the basis of bacteria Bacillus was developed. They are used against diseases of plants of mushroom and bacterial etiology. However there is not information about influence of bacteria on quality of products of green cultures. The aim of the work was studying of influence of two strains of bacteria Bacillus that were introduced in peat substrate on efficiency and quality of lettuce. Two strains of bacteria Bacillus were used in the work. They were selected from the soil. The strains are Bacillus subtilis M9/6 and Bacillus amyloliquefaciens 23TM that have high antagonistic activity to a wide range of phytopathogens. Cultivation of plants carried out in containers of 250 ml under light installations with illuminating intensity 13-15 thousand luxury and lasting irradiating of 14 hours before technical ripeness of lettuce. It was established that the application of strain Bacillus subtilis M9/6 (in concentration 106 cells/ml, 10 ml/l of substrate) and the strain Bacillus amyloliquefaciens 23TM (5 ml/l of substrate) in substrate before sowing increased nutrition value of lettuce. Dry matter content, water-soluble carbohydrates (mono - and disaccharides) content and vitamin C content increased. The bacterial strain B. amyloliquefaciens 23TM also promoted accumulation of vitamin B2. The content of nitrates in lettuce leaves decreased on 50,3% and 39,1%, respectively. It was shown that the application of bacteria in substrate before sowing of crop has a greater influence on quality of lettuce, than watering of shoots.Основной задачей овощеводства является постоянное снабжение населения всеми видами овощей, в том числе зеленными культурами. Зеленные культуры относятся к листостебельным овощам, обладают высокой питательной ценностью и скороспелостью. Однако при выращивании в условиях защищенного грунта они часто поражаются фитопатогенными микроорганизмами уже на начальных этапах онтогенеза, что приводит к появлению недружных всходов, ухудшению роста и развития растений и потере товарного вида. В настоящее время в Республике Беларусь против болезней растений грибной и бактериальной этиологии разработан ряд биологических препаратов на основе бактерий рода Bacillus. Однако практически отсутствует информация о влиянии бактериальных препаратов на качество продукции зеленных культур. Целью работы являлось изучение влияния вносимых в торфяной субстрат двух штаммов бактерий рода Bacillus на продуктивность и качество продукции салата листового. В работе использовали выделенные из почвы штаммы спорообразующих бактерий Bacillus subtilis М9/6 и Bacillus amyloliquefaciens 23ТМ, проявляющие высокую антагонистическую активность к широкому спектру фитопатогенов. Выращивание растений проводили в контейнерах объемом 250 мл под световыми установками с освещенностью 13-15 тыс. люкс и продолжительностью освещения 14 часов до наступления технической спелости салата. Установлено, что внесение в субстрат при его подготовке к посеву бактериального штамма Bacillus subtilis М9/6 в концентрации 106 клеток/мл в объеме 10 мл/л субстрата, а также штамма Bacillus amyloliquefaciens 23ТМ в количестве 5 мл/л субстрата повышало пищевую ценность данной культуры: увеличивалось содержание сухого вещества, водорастворимых углеводов (моно- и дисахаридов), витамина С. Бактериальный штамм B. amyloliquefaciens 23ТМ в том числе способствовал накоплению листьями салата рутина. Наряду с этим содержание нитратов в готовой продукции снижалось на 50,3% и 39,1%, соответственно. Показано, что внесение бактерий изучаемых штаммов в субстрат перед посевом оказывает большее влияние на качество продукции, чем полив всходов

Point-of-care testing and treatment of sexually transmitted and genital infections during pregnancy in Papua New Guinea (WANTAIM trial): protocol for an economic evaluation alongside a cluster-randomised trial

INTRODUCTION: Left untreated, sexually transmitted and genital infections (henceforth STIs) in pregnancy can lead to serious adverse outcomes for mother and child. Papua New Guinea (PNG) has among the highest prevalence of curable STIs including syphilis, chlamydia, gonorrhoea, trichomoniasis and bacterial vaginosis, and high neonatal mortality rates. Diagnosis and treatment of these STIs in PNG rely on syndromic management. Advances in STI diagnostics through point-of-care (PoC) testing using GeneXpert technology hold promise for resource-constrained countries such as PNG. This paper describes the planned economic evaluation of a cluster-randomised cross-over trial comparing antenatal PoC testing and immediate treatment of curable STIs with standard antenatal care in two provinces in PNG. METHODS AND ANALYSIS: Cost-effectiveness of the PoC intervention compared with standard antenatal care will be assessed prospectively over the trial period (2017-2021) from societal and provider perspectives. Incremental cost-effectiveness ratios will be calculated for the primary health outcome, a composite measure of the proportion of either preterm birth and/or low birth weight; for life years saved; for disability-adjusted life years averted; and for non-health benefits (financial risk protection and improved health equity). Scenario analyses will be conducted to identify scale-up options, and budget impact analysis will be undertaken to understand short-term financial impacts of intervention adoption on the national budget. Deterministic and probabilistic sensitivity analysis will be conducted to account for uncertainty in key model inputs. ETHICS AND DISSEMINATION: This study has ethical approval from the Institutional Review Board of the PNG Institute of Medical Research; the Medical Research Advisory Committee of the PNG National Department of Health; the Human Research Ethics Committee of the University of New South Wales; and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine. Findings will be disseminated through national stakeholder meetings, conferences, peer-reviewed publications and policy briefs. TRIAL REGISTRATION NUMBER: ISRCTN37134032

Point-of-care testing and treatment of sexually transmitted infections to improve birth outcomes in high-burden, low-income settings: Study protocol for a cluster randomized crossover trial (the WANTAIM Trial, Papua New Guinea) [version 1; peer review: 1 approved, 1 approved with reservations]

Background: Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis and bacterial vaginosis have been associated with preterm birth and low birth weight, and are highly prevalent among pregnant women in many low- and middle-income settings. There is conflicting evidence on the potential benefits of screening and treating these infections in pregnancy. Newly available diagnostic technologies make it possible, for the first time, to conduct definitive field trials to fill this knowledge gap. The primary aim of this study is to evaluate whether antenatal point-of-care testing and immediate treatment of these curable sexually transmitted and genital infections (STIs) leads to reduction in preterm birth and low birth weight. Methods : The Women and Newborn Trial of Antenatal Interventions and Management (WANTAIM) is a cluster-randomised crossover trial in Papua New Guinea to compare point-of-care STI testing and immediate treatment with standard antenatal care (which includes the WHO-endorsed STI ‘syndromic’ management strategy based on clinical features alone without laboratory confirmation). The unit of randomisation is a primary health care facility and its catchment communities. The primary outcome is a composite measure of two events: the proportion of women and their newborns in each trial arm, who experience either preterm birth (delivery <37 completed weeks of gestation as determined by ultrasound) and/or low birth weight (<2500 g measured within 72 hours of birth). The trial will also evaluate neonatal outcomes, as well as the cost-effectiveness, acceptability and health system requirements of this strategy, compared with standard care. Conclusions: WANTAIM is the first randomised trial to evaluate the effectiveness, cost-effectiveness, acceptability and health system requirements of point-of-care STI testing and treatment to improve birth outcomes in high-burden settings. If the intervention is proven to have an impact, the trial will hasten access to these technologies and could improve maternal and neonatal health in high-burden settings worldwide. Registration: ISRCTN37134032

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked