bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term exposure to higher temperature increases the thermal sensitivity of grazer metabolism and movement
Authors: Cloyed Carl S. , Dell Anthony I. , Hayes Tracie , Kordas Rebecca L. , O'Gorman Eoin J.
Published: March 2019

Ecological studies of global warming impacts have many constraints. Organisms are often exposed to higher temperatures for short periods of time, probably underestimating their ability to acclimate or adapt relative to slower but real rates of warming. Many studies also focus on a limited number of traits and miss the multifaceted effects that warming may have on organisms, from physiology to behaviour. Organisms exhibit different movement traits, some of which are primarily driven by metabolic processes and others by decision‐making, which should influence the extent to which temperature affects them.

We collected snails from streams that have been differentially heated by geothermal activity for decades to determine how long‐term exposure to different temperatures affected their metabolism and movement. Additionally, we collected snails from a cold stream (5°C) and measured their metabolism and movement at higher temperatures (short‐term exposure). We used respirometry to measure metabolic rates and automated in situ image‐based tracking to quantify several movement traits from 5 to 21°C.

Long‐term exposure to higher temperatures resulted in a greater thermal sensitivity of metabolic rate compared to snails exposed for short durations, highlighting the need for caution when conducting acute temperature exposures in global warming research. Average speed, which is largely driven by metabolism, also increased more with temperature for long‐term exposure compared to short‐term exposure. Movement traits we interpret as more decision‐based, such as time spent moving and trajectory shape, were less affected by temperature. Step length increased and step angle decreased at higher temperatures for both long‐ and short‐term exposure, resulting in overall straighter trajectories. The power‐law exponent of the step length distributions and fractal dimension of trajectories were independent of temperature, however, suggesting that snails retained the same movement strategy.

The observed changes in snail movement at higher temperatures should lead to higher encounter rates and more efficient searching, providing a behavioural mechanism for stronger plant–herbivore interactions in warmer environments. Our research is among the first to show that temperature has contrasting effects on different movement traits, which may be determined by the metabolic contribution to those behaviours.
Rapid land use change threatens provisioning ecosystem services in miombo woodlands
Authors: Jew Eleanor K.K. , Burdekin Oliver J. , Dougill Andrew J. , Sallu Susannah M.
Published: March 2019

Rural communities in sub‐Saharan Africa rely upon provisioning ecosystem services (ES) to support their livelihoods, yet in areas where rapid land use change is occurring the relationship between environmental change, provisioning ES availability and livelihoods is not fully understood. This relationship is explored here within a typical rural miombo woodland landscape in south‐west Tanzania, which is undergoing rapid land use change due to expanding tobacco cultivation. The types of provisioning ES used, who uses them, changes in their availability, and the possible future impacts of these changes were explored using a mixed‐method approach. Our findings identify 19 provisioning ES used by households regardless of economic status. Firewood, building materials, and fresh water are used by almost all households, and these are perceived to be declining in availability. Households identified this as a negative environmental impact of land use change and that provisioning ES loss would be ‘bad’ for their households. Given the multi‐purpose nature of miombo woodlands, an adaptive co‐management approach, which can achieve multiple objectives through encouraging participation, learning, and empowerment of local communities, could be an appropriate strategy to achieve sustainable land use management and maintain the provision of ES within miombo woodland landscapes of sub‐Saharan Africa.
Oxidative and nitrosative stress markers in obsessive–compulsive disorder: a systematic review and meta‐analysis
Authors: Maia A. , Oliveira J. , Lajnef M. , Mallet L. , Tamouza R. , Leboyer M. , Oliveira‐Maia A. J.
Published: March 2019

Objective

Obsessive–compulsive disorder (OCD) is a chronic, prevalent, and highly impairing psychiatric illness. Although the pathophysiology of OCD remains unknown, pathways involved in oxidative and nitrosative stress (O&NS) have been implicated. The present study aims to systematically review the literature for quantitative evidence that patients with OCD have altered measures of blood O&NS markers.

Methods

Independent random‐effects meta‐analyses using standardized mean differences were conducted to assess each marker separately. Additionally, data from multiple markers were pooled together in a meta‐analysis for measures of oxidant activity and another for measures of antioxidant activity.

Results

Thirteen studies met inclusion criteria, involving 433 OCD patients and 459 controls. Eleven blood O&NS markers were eligible for independent quantitative analyses. We found that, in OCD patients, the oxidant markers 8‐hydroxydeoxyguanosine and malondialdehyde, and the antioxidants glutathione peroxidase and superoxide dismutase, were significantly increased while total antioxidant status, vitamin C, and vitamin E were significantly decreased, when comparing with controls. Regarding pooled meta‐analyses, we found a statistically significant increase in oxidant markers, but non‐significant results regarding antioxidant markers.

Conclusions

Our meta‐analysis suggests that OCD patients have a systemic oxidative imbalance that is not adequately buffered by the antioxidant system. Additional studies are needed in order to support this association.
Patterns of invertebrate food availability and the persistence of an avian insectivore on the brink
Authors: Stone Zoë L. , Tasker Elizabeth , Maron Martine
Published: March 2019

Globally, insectivorous birds are at high risk of decline. One explanation of this relates to changes in invertebrate resources due to anthropogenic pressures. The northern population of the eastern bristlebird (Dasyornis brachypterus) relies heavily on invertebrate food resources, and has experienced an 80% population reduction over the past 40 years. We investigated invertebrate abundance and nutritional quality across 23 currently and historically occupied northern bristlebird sites to determine whether extant territories were associated with more, or more nutritious, invertebrate resources. Pitfall and leaf‐litter invertebrate sampling were done in both breeding and non‐breeding seasons from 2014 to 2016. There was no difference in abundance, biomass or nutritional value of invertebrates between occupied and abandoned territories; however, within territories invertebrate abundance and nutritional value did correspond to the habitat characteristics with which bristlebirds are associated. Nutritional value of invertebrates increased with proximity to rainforest, while the abundance of macro‐invertebrates (>1 mm) was correlated with grass height. Bristlebird territories are often close to rainforest margins, and these ecotones may provide more nutritious mesic‐associated invertebrates. Higher abundances of large invertebrates in tall grasses may also contribute to the known association of bristlebirds with tall grasses. Maintenance of tall grass adjacent to rainforest through appropriate fire and grazing management is likely to be important for northern bristlebird recovery and long‐term persistence of the population.
Lateral bone flap approach for displaced intra‐articular calcaneus fractures
Authors: Wang Shouli , Zhou Xiaobo , Liang Junbo , Liu Fucun , Wang Bin
Published: March 2019

Background

The traditional extended lateral approach for calcaneus fractures can provide sufficient exposure for reduction, but complications are frequent. The minimally invasive approach does limited damage to the soft tissue and its complication rate is low, but provides limited surgical exposure for complicated fracture. Thus, an approach that could provide wide exposure with less soft tissue injury is important.

Methods

The lateral bone flap approach, we proposed, involved the same incision as the extended lateral approach. After incision, osteotomy was performed around the lateral bulged wall of the calcaneus without dissection of soft tissue. The lateral wall was free from calcaneus and connected with the soft tissue, and the lateral bone flap was developed. The reduction of fracture and the fixation of plate were performed as usual. Next, the bone flap was reduced and sutured. This retrospective study of lateral bone flap approach included 63 cases of 58 patients with displaced intra‐articular calcaneus fractures from January 2011 to January 2015. Clinical and radiological outcomes and complications were all recorded.

Results

Radiological outcome was significantly improved at 3 months and 2 years post‐operatively compared with that of pre‐operatively (P < 0.01). The Maryland Foot Score at the last follow up was 87.2 ± 7.0. The excellent/good rate was 90.5%. One case of delayed wound healing occurred. No infection or sural nerve injury occurred.

Conclusion

The lateral bone flap approach is simple, safe and effective for displaced intra‐articular calcaneus.
Diagnostic laparoscopy in penetrating abdominal trauma
Authors: Cocco Annelise Maree , Bhagvan Savitha , Bouffler Clare , Hsu Jeremy
Published: March 2019

Background

Penetrating abdominal trauma is uncommon in Australia. There are multiple potential approaches to the patient without an indication for immediate laparotomy. This study examined the management of patients with a penetrating anterior abdominal injury in a Level 1 trauma centre, and in particular investigated the outcomes of those patients who underwent diagnostic laparoscopy.

Methods

A retrospective review was undertaken of all patients presenting to a Level 1 trauma centre with an anterior abdominal stab wound over a 15‐year period. Patient demographic, injury, examination, treatment and outcome data were extracted. These data were analysed using SPSS PASW version 20.

Results

A total of 318 patients were identified. Immediate laparotomy was performed in 121 of those patients. Of the remaining 197 patients, 146 underwent diagnostic laparoscopy. Peritoneal breach was identified in 87 patients, 79 of whom then had exploratory laparotomy. The laparotomy was therapeutic in 36 of 79 patients (45.6%). Multiple stab wounds were an independent predictor of therapeutic laparotomy (hazard ratio 2.39, 95% CI 1.16–4.93). Diagnostic laparoscopy was 100% sensitive, 60.9% specific and had a negative predictive value of 100% and a positive predictive value of 40%. Non‐therapeutic laparotomy was associated with a median length of stay of 5.5 days and a complication rate of 9.3%.

Conclusion

Diagnostic laparoscopy to detect peritoneal breach is a safe approach in the management of anterior abdominal stab wounds. However, utilizing peritoneal breach as an indication for laparotomy is associated with a moderate incidence of non‐therapeutic laparotomy. Measures to decrease the negative laparotomy rate should be considered.
New drug candidates for bipolar disorder—A nation‐wide population‐based study
Authors: Kessing Lars V. , Rytgaard Helene C. , Gerds Thomas A. , Berk Michael , Ekstrøm Claus T. , Andersen Per K.
Published: March 2019

Objective

Drug repurposing is an increasingly promising idea in many fields of medicine. We systematically used Danish nation‐wide population‐based registers to investigate whether continued use of non‐aspirin non‐steroidal anti‐inflammatory drugs (NSAIDs), low‐dose aspirin, high‐dose aspirin, statins, allopurinol, and angiotensin agents decrease the rate of incident mania/bipolar disorder.

Methods

A nation‐wide population‐based longitudinal study using Poisson regression analyses including all persons in Denmark who purchased the exposure medication of interest and a random sample of 30% of the Danish population. The follow‐up period comprised a 10 years period from 2005 to 2015. Two different outcome measures were included, (1) a diagnosis of mania/bipolar disorder at a psychiatric hospital contact as inpatient or outpatient and (2) a combined measure of a diagnosis of mania/bipolar disorder or initiation of lithium use.

Results

A total of 1,605,365 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015, median age 57 years [quartiles: 43;69], and female proportion of 53.1%. Continued use of low‐dose aspirin, statins, and angiotensin agents were associated with decreased rates of incident mania/bipolar disorder on both outcome measures. Continued uses of non‐aspirin NSAIDs as well as high‐dose aspirin were associated with an increased rate of incident bipolar disorder. There were no statistically significant associations for allopurinol.

Conclusions

The study supports the potential of agents acting on inflammation and the stress response system in bipolar disorder and illustrates that population‐based registers can be used to systematically identify drugs with repurposing potentials.
Expatriate cultural values alignment: The mediating effect of cross‐cultural adjustment level on innovative behaviour
Authors: Tsegaye Wondwossen Kassa , Su Qin , Malik Maria
Published: March 2019

Multinational companies assign expatriates to bridge the scarcity of employees with innovative behaviour from the local labour market. Despite expatriates' significant role in inducing innovative ideas for multinational companies, the existing literature has scarcely examined those antecedent factors that affect their innovative behaviour. Even though previous studies indicated the determinant impact of host countries' culture on the expatriates' work‐related behaviour, little is known about how far it affects their innovative behaviour. Therefore, drawing on the person‐environment fit theory, this study examines the impact of personal value orientation and the host country's culture alignment on expatriates' innovative behaviour. The study covers 149 expatriates, from nine countries, who work in the high‐tech industrial zone of Shenzhen, South China's industrial hub. Moreover, it applies a structural equation model using AmosTM 23 to conduct the analysis. The results reveal that personal value orientation fit with the host country's national culture has a significant impact on expatriates' innovative behaviour. Cross‐cultural adjustment level is found to mediate this relationship. Theoretical and practical implications are discussed, and suggestions for future research are drawn from the study's limitations.
DLL3 regulates the migration and invasion of small cell lung cancer by modulating Snail
Authors: Furuta Megumi , Kikuchi Hajime , Shoji Tetsuaki , Takashima Yuta , Kikuchi Eiki , Kikuchi Junko , Kinoshita Ichiro , Dosaka‐Akita Hirotoshi , Sakakibara‐Konishi Jun
Published: March 2019

Delta‐like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell‐fate decisions and is tumor‐suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss‐of‐function and gain‐of‐function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.
Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting
Authors: Yu Y-R , Ho P-C
Published: March 2019

Cancer immunotherapy unleashing the power of host immunity on eliminating cancer cells represents a critical advance in cancer treatment; however, effective anti-tumor responses are largely dampened by the immunosuppressive tumor microenvironment (TME). Emerging studies have revealed that physiological features in the TME, including glucose deprivation, hypoxia and low pH, established by the metabolically dysregulated cancer cells restrict anti-tumor immunity by impeding the metabolic fitness of tumor-infiltrating cytotoxic CD8+ T cells and natural killer (NK) cells. Furthermore, infiltrating immunomodulatory cells with different metabolic preferences also facilitate the establishment of the immunosuppressive TME. Therefore, deciphering the metabolic cross-talk between immune cells and cancer cells in the TME and elucidating the impact of this process during tumorigenesis are needed to harness anti-tumor immunity more effectively. Herein, we summarize the immunosuppressive features of TME and how these features impair anti-tumor immunity. Moreover, we postulate how immune cells may be involved in shaping the metabolic features of cancer cells and discuss how we might improve the anti-tumor functions of tumor-specific T cells by rewiring their metabolic regulations.
Management of dupilumab‐associated conjunctivitis in atopic dermatitis
Authors: Aszodi Nora , Thurau Stephan , Seegräber Marlene , de Bruin‐Weller Marjolein , Wollenberg Andreas
Published: March 2019

Since September 2017, the monoclonal antibody dupilumab (Dupixent®) has been approved in the EU for the treatment of moderate‐to‐severe atopic dermatitis. By blocking IL‐4 and IL‐13 signaling pathways, dupilumab improves both objective signs and subjective symptoms of the disease. Blocking of the IL‐4aRα subunit leads to improvement of the skin's barrier function and reduction in Th2‐mediated inflammation. While the rate of adverse events on dupilumab is generally low, mild‐to‐moderate conjunctivitis associated with redness as well as a burning and foreign body sensation has been reported in up to 28 % of patients. Treatment options include topical corticosteroids and topical calcineurin inhibitors. The present review highlights the clinical presentation of dupilumab‐associated conjunctivitis and addresses pharmacological and non‐pharmacological options available for the treatment of this clinically highly relevant condition.
Zinc and skin: an update
Authors: Glutsch Valerie , Hamm Henning , Goebeler Matthias
Published: March 2019

The essential trace element zinc (Zn) plays a key role in the development, differentiation and growth of various human tissues. Zinc homeostasis is primarily regulated by two zinc transporter families (solute‐linked carrier families, SLC). Disturbances in zinc metabolism may give rise to disorders that typically manifest themselves on the skin. An autosomal recessive zinc deficiency disorder, acrodermatitis enteropathica is caused by a mutation in the gene coding for the ZIP4 transporter. Due to intestinal malabsorption, affected infants develop clinical signs and symptoms shortly after weaning. Acquired zinc deficiency is a rare but underdiagnosed disorder associated with various etiologies and variable clinical manifestations. Depending on the patient's age, a multitude of causes have to be considered. Given the characteristic periorificial and acral lesions, the clinical diagnosis is usually made by dermatologists. Laboratory confirmation includes measurement of plasma zinc levels and – as a supplementary measure – zinc‐dependent enzymes such as alkaline phosphatase. Oral zinc replacement therapy frequently leads to clinical remission within a few days. Depending on the cause, disease management should include cooperation with pediatricians and gastroenterologists in order to guarantee optimal patient care.
A balance of winners and losers in the Anthropocene
Authors: Dornelas Maria , Gotelli Nicholas J. , Shimadzu Hideyasu , Moyes Faye , Magurran Anne E. , McGill Brian J.
Published: March 2019

Scientists disagree about the nature of biodiversity change. While there is evidence for widespread declines from population surveys, assemblage surveys reveal a mix of declines and increases. These conflicting conclusions may be caused by the use of different metrics: assemblage metrics may average out drastic changes in individual populations. Alternatively, differences may arise from data sources: populations monitored individually, versus whole‐assemblage monitoring. To test these hypotheses, we estimated population change metrics using assemblage data. For a set of 23 241 populations, 16 009 species, in 158 assemblages, we detected significantly accelerating extinction and colonisation rates, with both rates being approximately balanced. Most populations (85%) did not show significant trends in abundance, and those that did were balanced between winners (8%) and losers (7%). Thus, population metrics estimated with assemblage data are commensurate with assemblage metrics and reveal sustained and increasing species turnover.
Reduced exposure to darunavir and cobicistat in HIV‐1‐infected pregnant women receiving a darunavir/cobicistat‐based regimen
Authors: Crauwels HM , Osiyemi O , Zorrilla C , Bicer C , Brown K
Published: March 2019

Objectives

The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV‐1 infection.

Methods

This phase 3b, open‐label study enrolled HIV‐1‐infected pregnant women (18–26 weeks of gestation) receiving combination antiretroviral therapy with once‐daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24–28 and 34–38 weeks of gestation, respectively) and 6–12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration–time curve over 24 h (AUC24 h), maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin)] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated.

Results

Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC24 h, 50–56% lower; Cmax, 37–49% lower; Cmin, 89–92% lower); unbound darunavir exposure was also reduced (AUC24 h, 40–45% lower; Cmax, 32–41% lower; Cmin, 88–92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC24 h, 49–63% lower; Cmax, 27–50% lower; Cmin, 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV‐1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother‐to‐child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants.

Conclusions

In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV‐1‐infected pregnant women.
Germinal center B cell initiation, GC maturation, and the coevolution of its stromal cell niches
Authors: Haberman Ann M. , Gonzalez David G. , Wong Patrick , Zhang Ting‐ting , Kerfoot Steven M.
Published: March 2019

Throughout the developing GC response, B cell survival and fate choices made at the single cell level are dependent on signals received largely through interactions with other cells, often with cognate T cells. The type of signals that a given B cell can encounter is dictated by its location within tissue microarchitecture. The focus of this review is on the initiation and evolution of the GC response at the earliest time points. Here, we review the key factors influencing the progression of GC B cell differentiation that are both stage and context dependent. Finally, we describe the coevolution of niches within and surrounding the GC that influence the outcome of the GC response.
T‐bet+ memory B cells: Generation, function, and fate
Authors: Knox James J. , Myles Arpita , Cancro Michael P.
Published: March 2019

B cells expressing the transcription factor T‐bet have emerged as participants in a number of protective and pathogenic immune responses. T‐bet+ B cells characteristically differentiate in response to combined Toll‐like receptor and cytokine signaling, contribute to protective immunity against intracellular pathogens via IgG2a/c production and antibody‐independent mechanisms, and are prone to produce autoantibodies. Despite recent advances, a number of questions remain regarding the basic biology of T‐bet+ B cells and their functional niche within the immune system. Herein, we review the discovery and defining characteristics of the T‐bet+ B cell subset in both mice and humans. We further discuss their origins, the basis for their persistence, and their potential fate in vivo. Evidence indicates that T‐bet+ B cells represent a distinct, germinal center‐derived memory population that may serve as an important therapeutic target for the improvement of humoral immunity and prevention of autoimmunity.
T cell interactions with B cells during germinal center formation, a three‐step model
Authors: Biram Adi , Davidzohn Natalia , Shulman Ziv
Published: March 2019

Establishment of effective immunity against invading microbes depends on continuous generation of antibodies that facilitate pathogen clearance. Long‐lived plasma cells with the capacity to produce high affinity antibodies evolve in germinal centers (GCs), where B cells undergo somatic hypermutation and are subjected to affinity‐based selection. Here, we focus on the cellular interactions that take place early in the antibody immune response during GC colonization. Clones bearing B‐cell receptors with different affinities and specificities compete for entry to the GC, at the boundary between the B‐cell and T‐cell zones in lymphoid organs. During this process, B cells compete for interactions with T follicular helper cells, which provide selection signals required for differentiation into GC cells and antibody secreting cells. These cellular engagements are long‐lasting and depend on activation of adhesion molecules that support persistent interactions and promote transmission of signals between the cells. Here, we discuss how interactions between cognate T and B cells are primarily maintained by three types of molecular interactions: homophilic signaling lymphocytic activation molecule (SLAM) interactions, T‐cell receptor: peptide‐loaded major histocompatibility class II (pMHCII), and LFA‐1:ICAMs. These essential components support a three‐step process that controls clonal selection for entry into the antibody affinity maturation response in the GC, and establishment of long‐lasting antibody‐mediated immunity.
The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance
Authors: Casola Stefano , Perucho Laura , Tripodo Claudio , Sindaco Paola , Ponzoni Maurilio , Facchetti Fabio
Published: March 2019

Surface expression of a functional B cell antigen receptor (BCR) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐NHL) and chronic lymphocytic leukemia (CLL). Targeting BCR effectors in B‐NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐NHL subtypes and CLL, and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐BCR therapies.
T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments
Authors: Fonseca Válter R. , Ribeiro Filipa , Graca Luis
Published: March 2019

Germinal centers (GC) have been known as key anatomic structures in humoral immunity, where isotype switching and affinity maturation occur. As a consequence, elucidation of GC regulation has potential implications for the understanding of autoantibody‐mediated diseases. It is now accepted that different regulatory mechanisms coexist, including the action of a specialized population of Foxp3+ regulatory T cells with unique access to the B‐cell follicle: the T follicular regulatory (Tfr) cells. Tfr cells develop through a multistep process requiring migration through different compartments of lymphoid tissues. This review discusses the ontogeny and physiology of Tfr cells, their distribution within distinct anatomic compartments, and their function. A greater understanding of Tfr biology and GC regulation is likely to lead to better stratification of patients with autoantibody‐mediated diseases, and to the identification of novel therapeutic targets.
Extrafollicular responses in humans and SLE
Authors: Jenks Scott A. , Cashman Kevin S. , Woodruff Matthew C. , Lee F. Eun‐Hyung , Sanz Ignacio
Published: March 2019

Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long‐standing autoreactive B‐cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody‐secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B‐cell depletion. Long‐lived, highly mutated antibodies are typically generated through T‐cell–dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B‐cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive‐derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B‐cell pathway, its relationship to other effector B‐cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age‐Associated B cells (ABCs), a TLR‐7‐driven B‐cell population that mediates murine autoimmune and antiviral responses.
TFH cells in bystander and cognate interactions with B cells
Authors: Wan Zurong , Lin Yihan , Zhao Yongshan , Qi Hai
Published: March 2019

Follicular T‐helper (TFH) cells play a crucial role in three aspects of the germinal center (GC) response. They promote GC formation, arbitrate competition among GC B cells to determine the outcome of affinity maturation, and regulate GC output of memory and plasma cells to shape the long‐lived humoral immune memory. Of fundamental importance are dynamic physical interactions between TFH and B cells, which are the main platform for TFH cells to deliver “help” factors to B cells and also for reciprocal signaling from B cells to maintain the helper state of TFH cells. Recent work has significantly expanded our understanding of how T‐B interactions are spatiotemporally regulated and molecularly orchestrated to fulfill those TFH functions. In this review, we elaborate two modes of T‐B interactions, the antigen‐specific or cognate mode in which TFH cells engage individual antigen‐presenting B cells and the antigen nonspecific bystander mode in which TFH cells are engaged with the ensemble of follicular B cells. We discuss findings that indicate how short‐lived cognate T‐B contacts coupled with an intercellular positive feedback drive affinity‐based selection and how bystander interactions between T and B cells regulate follicular T‐cell recruitment and maintenance of an appropriate helper state. We argue that this combination of bystander and cognate interactions with B cells constantly shapes the internal state of TFH cells and provides the platform to execute their helper functions.
Plasma cell differentiation during the germinal center reaction
Authors: Ise Wataru , Kurosaki Tomohiro
Published: March 2019

Germinal centers (GCs) are formed in secondary lymphoid tissues upon immunization with T‐dependent antigens. In GCs, somatic hypermutation generates B cells with increased antibody affinity and these high‐affinity B cells preferentially differentiate into plasma cells, which home to bone marrow and confer long‐lived humoral immunity. Recent studies have shed new light on the cellular and molecular basis for initiating the transition from a GC B cell to a plasma cell. Here, we review recent progress in our understanding of how plasma cell generation during the GC reaction is regulated for inducing effective long‐term protective immunity and for preventing harmful autoimmunity.
The continuing story of T‐cell independent antibodies
Authors: Allman David , Wilmore Joel R. , Gaudette Brian T.
Published: March 2019

The purpose of this article is to review the role of extrafollicular and T‐cell independent antibody responses in humoral immunity. We consider two interrelated questions: (a) do T‐cell independent antibody responses dominated by IgM and/or IgA play unique functions in immunity and homeostasis; and (b) is it typical for these responses to result in lifelong protection? In addressing these questions, we consider the established advantages of T‐cell driven responses including the unique role played by germinal center reactions in these responses, and contrast the processes and outcomes of germinal center‐centric responses with germinal center‐ and T‐cell independent antibodies. We suggest that T‐independent and other extrafollicular responses contribute substantially to highly stable antibody repertoires in both the serum and the intestine, providing relatively constitutive humoral barriers with the collective dual function of protecting against invading pathogens and regulating the composition of non‐pathogenic microbial communities.
Sensory ecology of the fish lateral‐line system: Morphological and physiological adaptations for the perception of hydrodynamic stimuli
Authors: Mogdans Joachim
Published: March 2019

Fishes are able to detect and perceive the hydrodynamic and physical environment they inhabit and process this sensory information to guide the resultant behaviour through their mechanosensory lateral‐line system. This sensory system consists of up to several thousand neuromasts distributed across the entire body of the animal. Using the lateral‐line system, fishes perceive water movements of both biotic and abiotic origin. The anatomy of the lateral‐line system varies greatly between and within species. It is still a matter of debate as to how different lateral‐line anatomies reflect adaptations to the hydrodynamic conditions to which fishes are exposed. While there are many accounts of lateral‐line system adaptations for the detection of hydrodynamic signals in distinct behavioural contexts and environments for specific fish species, there is only limited knowledge on how the environment influences intra and interspecific variations in lateral‐line morphology. Fishes live in a wide range of habitats with highly diverse hydrodynamic conditions, from pools and lakes and slowly moving deep‐sea currents to turbulent and fast running rivers and rough coastal surf regions. Perhaps surprisingly, detailed characterisations of the hydrodynamic properties of natural water bodies are rare. In particular, little is known about the spatio‐temporal patterns of the small‐scale water motions that are most relevant for many fish behaviours, making it difficult to relate environmental stimuli to sensory system morphology and function. Humans use bodies of water extensively for recreational, industrial and domestic purposes and in doing so often alter the aquatic environment, such as through the release of toxicants, the blocking of rivers by dams and acoustic noise emerging from boats and construction sites. Although the effects of anthropogenic interferences are often not well understood or quantified, it seems obvious that they change not only water quality and appearance but also, they alter hydrodynamic conditions and thus the types of hydrodynamic stimuli acting on fishes. To date, little is known about how anthropogenic influences on the aquatic environment affect the morphology and function of sensory systems in general and the lateral‐line system in particular. This review starts out by briefly describing naturally occurring hydrodynamic stimuli and the morphology and neurobiology of the fish lateral‐line system. In the main part, adaptations of the fish lateral‐line system for the detection and analysis of water movements during various behaviours are presented. Finally, anthropogenic influences on the aquatic environment and potential effects on the fish lateral‐line system are discussed.
Immunity induced by recombinant attenuated IHNV (infectious hematopoietic necrosis virus)‐GN438A expresses VP2 gene‐encoded IPNV (infectious pancreatic necrosis virus) against both pathogens in rainbow trout
Authors: Chen Yaping , Guo Mengting , Wang Yanxue , Hua Xiaojing , Gao Shuai , Wang Yuting , Li Dechuan , Shi Wen , Tang Lijie , Li Yijing , Liu Min
Published: March 2019

Infectious hematopoietic necrosis virus (IHNV) and infectious pancreatic necrosis virus (IPNV) are important pathogens in rainbow trout farming worldwide. Their co‐infection is also common, which causes great economic loss in juvenile salmon species. Development of a universal virus vaccine providing broadly cross‐protective immunity will be of great importance. In this study, we generated two recombinant (r) virus (rIHNV‐N438A‐ΔNV‐EGFP and rIHNV‐N438A‐ΔNV‐VP2) replacing the NV gene of the backbone of rIHNV at the single point mutation at residue 438 with an efficient green fluorescent protein (EGFP) reporter gene and antigenic VP2 gene of IPNV. Meanwhile, we tested their efficacy against the wild‐type (wt) IHNV HLJ‐09 virus and IPNV serotype Sp virus challenge. The relative per cent survival rates of two recombinant viruses against (wt) IHNV HLJ‐09 virus challenge were 84.6% and 81.5%, respectively. Simultaneously, the relative per cent survival rate of rIHNV‐N438A‐ΔNV‐VP2 against IPNV serotype Sp virus challenge was 88.9%. It showed the two recombinant viruses had high protection rates and induced a high level of antibodies against IHNV or IPNV. Taken together, these results suggest the VP2 gene of IPNV can act as candidate gene for vaccine and attenuated multivalent live vaccines and molecular marker vaccines have potential application for viral vaccine.
Indoles: metabolites produced by intestinal bacteria capable of controlling liver disease manifestation
Authors: Hendrikx T. , Schnabl B.
Published: March 2019

Alterations in the bacteria that reside in our gastrointestinal tract play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative (composition) and quantitative (amount) changes in gut microbes are associated with increased susceptibility to liver disease. Importantly, the intestinal microbiota is involved in the regulation of many host signalling pathways via the generation of different metabolites. Hence, dysbiosis influences disease development and progression by directly affecting the host–bacteria metabolic interaction. Microbe‐derived harmful metabolites can translocate to distant organs due to increased intestinal permeability as observed during dysbiosis. Contrary, certain bacterial metabolites such as tryptophan metabolites contribute to intestinal and systemic homeostasis. Here, we provide an overview of current evidence describing to what extent microbial metabolites modulate the development of chronic liver diseases such as alcoholic steatohepatitis and nonalcoholic fatty liver disease with a special emphasis on indoles.
Rethinking Violence Prevention in Rural and Underserved Communities: How Veteran Peer Support Groups Help Participants Deal with Sequelae from Violent Traumatic Experiences
Authors: Azevedo Kathryn J. , Ramirez Jeremy C. , Kumar Anusha , LeFevre Ann , Factor Adam , Hailu Elon , Lindley Steven E. , Jain Shaili
Published: March 2019

Purpose

Access to mental health care and programs that address violence prevention can be a challenge for veterans residing in rural and underserved areas. A growing number of trauma‐affected veterans are now returning to rural areas upon completion of military service. The Palo Alto VA Health Care System has piloted a program known as the Peer Support Program (PSP) where certified peer support specialists hold group sessions for their fellow veterans in remote, community‐based outpatient clinics.

Methods

A total of 29 peer‐support group participants and 1 certified peer specialist were interviewed. Semistructured interviews began with open‐ended questions regarding participant firsthand experiences with the support group setting. These were followed by direct questions that addressed the role of the PSP, expectations for the PSP, as well as benefits and limitations of the program. We performed a domain analysis using the Spradley ethnographic method on 325 pages of compiled narrative data focusing on violence‐related themes.

Findings

Four key themes emerged, including: 1) Violence in Military Training Not Acceptable in Civilian Life, 2) Peer Support Creates the Trust to Speak Freely, 3) Skills Are Taught to Defuse Violence, and 4) The Veteran Peer Support Specialist Relationship Is Multi‐Dimensional.

Conclusions

These emergent themes illustrate how trauma‐focused assistance rendered by peer support specialists as part of an interdisciplinary mental health team can be implemented to benefit trauma‐affected individuals and their communities in the prevention of future violence.
Geographic Representation in Party‐Dominated Legislatures: A Quantitative Text Analysis of Parliamentary Questions in the German Bundestag
Authors: Zittel Thomas , Nyhuis Dominic , Baumann Markus
Published: March 2019

Political representation in European democracies is widely considered partisan and collectivist. This article, however, stresses that there is more to the representative process in European democracies than just its textbook version. It emphasizes the role of geographic representation as a complementary strategy in party‐dominated legislatures that is characterized by two distinct features. First, legislators employ distinct opportunities to participate in legislative contexts to signal attention to geographic constituents without disrupting party unity. Second, these activities are motivated by individual‐ and district‐level characteristics that supplement electoral‐system‐level sources of geographic representation. We empirically test and corroborate this argument for the German case on the basis of a content analysis of parliamentary questions in the 17th German Bundestag (2009–13). In this analysis, we show that higher levels of localness among legislators and higher levels of electoral volatility in districts result in increased geographic representation.
Neural mechanisms of social homeostasis
Authors: Matthews Gillian A. , Tye Kay M.
Published: March 2019

Social connections are vital to survival throughout the animal kingdom and are dynamic across the life span. There are debilitating consequences of social isolation and loneliness, and social support is increasingly a primary consideration in health care, disease prevention, and recovery. Considering social connection as an “innate need,” it is hypothesized that evolutionarily conserved neural systems underlie the maintenance of social connections: alerting the individual to their absence and coordinating effector mechanisms to restore social contact. This is reminiscent of a homeostatic system designed to maintain social connection. Here, we explore the identity of neural systems regulating “social homeostasis.” We review findings from rodent studies evaluating the rapid response to social deficit (in the form of acute social isolation) and propose that parallel, overlapping circuits are engaged to adapt to the vulnerabilities of isolation and restore social connection. By considering the neural systems regulating other homeostatic needs, such as energy and fluid balance, we discuss the potential attributes of social homeostatic circuitry. We reason that uncovering the identity of these circuits/mechanisms will facilitate our understanding of how loneliness perpetuates long‐term disease states, which we speculate may result from sustained recruitment of social homeostatic circuits.
Optimal cutoff value of bipolar low‐voltage in electroanatomic voltage mapping during atrial fibrillation rhythm
Authors: Kawaji Tetsuma , Hojo Shun , Kushiyama Akihiro , Nakatsuma Kenji , Kaneda Kazuhisa , Kato Masashi , Yokomatsu Takafumi , Miki Shinji
Published: March 2019

Background

Electroanatomic voltage mapping (EAVM) of the left atrium (LA) with multielectrodes is usually acquired during sinus rhythm (SR), and the feasibility of EAVM during atrial fibrillation (AF) rhythm is unclear.

Methods

We performed EAVM of LA during both SR and AF rhythm in 44 patients undergoing catheter ablation for AF and validated the optimal cutoff value of low‐voltage area (LVA) during AF rhythm for detecting LVA defined as bipolar voltages ≤0.5 mV during SR.

Results

In each session, mean 829 and 552 points were acquired by multielectrodes during SR and AF rhythm, respectively. Mean proportion of LVA was 4.9% among LA surface area of 276.2 cm2. Differences of LVA proportions between SR and AF rhythm were 5.8% (P < 0.001), 4.2% (P < 0.001), 2.7% (P < 0.001), 1.2% (P = 0.01), and –0.5% (P = 0.17) at the cutoff value of 0.4, 0.35, 0.3, 0.25, and 0.2 mV during AF rhythm, respectively. There was a good correlation between LVA proportions during SR and AF rhythm with cutoff value of 0.2 mV (R = 0.88, P < 0.001) and 37 patients (84.1%) had the discrepancy of LVA proportions within 3%. Furthermore, there was no significant difference between LVA proportions at each segment of LA. The discrepancy was relatively large in patients with large LA dimension and LVA during SR.

Conclusion

EAVM during AF rhythm was feasible and the optimal cutoff value of LVA was 0.2 mV for detecting LVA ≤ 0.5 mV during SR. However, the evidence is restricted to patients with relatively small LVA.