bluuebunny/crossref_metadata_2025 huggingface dataset:
Universal Health Coverage
Authors: Reddy K. Srinath , Mathur Manu Raj
Published: July 2019

In the last few decades, several initiatives have been undertaken by Government of India to increase access to essential health services. A framework for UHC was also developed by a High Level Expert Group (HLEG). The recently developed National Health Policy of India also espouses equity, universality, and affordability among its key principles and commits higher financial resources with emphasis on Primary Health Care. For UHC to be viable, it has to be embedded in a broad based framework of health assurance, based on a conceptual model that extends from financial protection, across a well-functioning health system, to the social determinants of health.
‘A Summer Place’
Authors: Bennike Rune
Published: July 2019

From the tales of nineteenth century British explorers to contemporary tourism advertising, representations of Darjeeling circulate far and wide. Across more than a century and a half, Darjeeling is repeatedly pictured as ‘a summer place’: a picturesque landscape of misty tea gardens, quaint cottages, and elusive mountain views. This chapter explores the colonial origins and historical persistence of this ‘tourist gaze’ in producing Darjeeling. Approaching this representational history from a vantage point grounded in the questions of belonging forcefully raised by the Gorkhaland movement, the chapter illustrates how commodified Darjeeling is defined more by its scenery than by its inhabitants, pictured as a place you visit rather than a place of belonging, and sold as a consumable good. It argues that, as this tourist gaze leaves notions of inhabitation and belonging obscured, its global reach and historical persistence complicates ongoing quests for local autonomy in Darjeeling.
Subnational Occupations
Authors: Besky Sarah
Published: July 2019

Darjeeling’s famed tea plantations are staffed almost exclusively by an Indian Nepali (or Gorkha) labour force, whose ability to advance beyond field labour has been severely limited. In 2008, retired Gorkha plantation managers founded the Darjeeling Tea Management Training Centre (DTMTC). Though it was modeled on similar training programs, DTMTC’s goal had a twist: to prepare Gorkhas as plantation managers. According to DTMTC teachers, the contemporary Darjeeling tea industry remains precarious, stemming from a lack of knowledge on the part of Gorkhas as to how to run the industry. The DTMTC, then, was a novel blend of vocational training and political action. This chapter explores how the institute’s goals were interwoven with ideas of connection between people, plants and moral obligations to care for a Gorkha landscape—a landscape that might be improved with the right kinds of training.
In the Shadows of Naga Insurgency
Authors: Wouters Jelle J.P.
Published: July 2019

In the Shadows of Naga Insurgency is a fine-grained critique of the Naga struggle for political redemption, the state’s response to it, and the social corollaries and carry-overs of protracted political conflict on everyday life. Offering an ethnographic underview, Jelle Wouters illustrates an ‘insurgency complex’ that reveals how embodied experiences of resistance and state aggression, violence and volatility, and struggle and suffering link together to shape social norms, animate local agitations, and complicate interpersonal and intertribal relations in expected and unexpected ways. The book locates the historical experiences and agency of the Naga people and relates these to ordinary villagers’ perceptions, actions, and moral reasoning vis-à-vis both the Naga Movement and the state and its lucrative resources. It thus presses us to rethink our views on tribalism, conflict and ceasefire, development, corruption, and democratic politics.
Performing Democracy in Nagaland
Authors: Wouters Jelle J.P.
Published: July 2019

This chapter reveals ethnographically how Naga insurgency, pre-existing political practices and principles, and present-day democratic and electoral politics interrelate in complex and counterintuitive ways. While Naga underground groups formally oppose national elections, in actual practice, national workers intervene and influence election outcomes. More broadly, this chapter explores what ordinary Naga villagers themselves make of modern democracy, and its hallmark of competitive elections, they now have to engage with. To discuss this, the author explores the historical and cultural inferences that guided two crucial episodes that ensued in the run up to Polling Day in Phugwumi. First, the villagers’ (successful) attempt to protect the village electoral list from the deletion of ‘bogus votes’ initiated by the government. Second, the villagers’ (unsuccessful) attempt to agree on a village consensus candidate. The analysis of these events leads the author to critique preconceived definitions of ‘normative democracy’, as Nugent has discussed, and he highlights Naga electors’ agency and imagination to adjust democratic ideals to their own lifeworlds and uses.
Insight through Awareness
Authors: Rodrigues Hillary
Published: July 2019

For over fifty years, Jiddu Krishnamurti (1895–1986) spoke on a wide array of topics, but primarily directed his teachings at the problem of human suffering. He taught that all conflict is intrinsically tied to our psyches, which have been heavily conditioned by our upbringing. Aligned with other renowned Western and Eastern thinkers on the wisdom of self-discovery, Krishnamurti presents a distinctive vision for learning that encourages self-understanding through sensitive observation and choiceless awareness. He calls for a radical transformation of human consciousness, thereby enabling pliant minds to blossom. This flowering of intelligence, through a liberating insight into the mechanisms of conditioning, is at the heart of his educational philosophy. Institutions that embrace his approach must be vigilant not to succumb to the traditional modes of academic training and norms of success, lest they perpetuate the structures of fear, violence, and conformity that continue to stifle the creativity of human spirit.
Curricular Concerns and Practices in a Krishnamurti School
Authors: Chakravarty Abismrita
Published: July 2019

The chapter is an attempt to coherently weave the observations from brief fieldwork conducted in two unique settings to make inquiries into curriculum practices and its production. It interrogates the notion that curriculum is a fixed transactional entity, designed by distant regulatory bodies that is passively transmitted, to reveal its dynamic components constituting it as a continuous process and dialogue. The ethnographical study of the curricular practices in a mixed age group setting, where there is recognition of the different learning positions of each child that leaves enough room for manoeuvre, provides insights on how learning takes place within and also outside the space of premediated instruction. The ‘lived aspect’ of the curriculum emerges in the close interactions between the learner and teacher, both fluid and interchangeable categories that are embedded in an environment that has a very different organisation of time and space.
Communal Violence, Electoral Polarization, and Muslim Representation
Authors: Ahmed Hilal
Published: July 2019

There are a number of commentaries, official reports, and well-researched academic books on communalism in India that directly or indirectly look at the nature of violence-centric electoral politics. However, our understanding of Muslim electoral politics is very limited. The belief that violent events persuade Muslims to vote tactically at the national level is often evoked to substantiate the claim that communal violence always determines Muslim electoral preferences. The idea of Muslim vote bank is also an expanded version of this argument. Focusing upon the Muzaffarnagar riots of 2013, this paper makes an attempt to revisit the idea of electoral polarization in the context of the 2014 general election. The paper critically evaluates the merit of a twofold claim that the communal and targeted violence against Muslims produce electoral polarization; and, violence of this kind could only be prevented if the number of Muslim MPs and MLAs in legislative bodies increases.
Media, Corporates, and Democracy
Authors: Pattnaik Sudhir
Published: July 2019

Indian democracy became increasingly corporatized since the advent of neoliberal economy, resulting in the emergence of a corporate–media–politics nexus. Narendra Modi, as the chief minister of Gujarat, extended patronage to the corporates in the pretext of development. Hence, the corporate world overwhelmingly endorsed his candidature as prime minister. The corporate-controlled media went all out projecting him as a strong charismatic leader and icon of development. Interestingly, the same corporate and media backed Odisha’s Chief Minister Naveen Patnaik in his state for his corporate-friendly record. As a result, Modi’s charisma was not very effective in Odisha and Naveen Patnaik got an outstanding victory. In this light, the chapter argues that democracy is in peril when the corporate and media dictate the policy of political parties and the government.
Justice versus Judiciary
Authors: Ranjan Sudhanshu
Published: July 2019

A pathbreaking work on judicial accountability and independence. The work is remarkable for its extraordinary erudition as well as its straightforwardness. The author has the exemplary courage to speak the truth. He has not spared anyone holding everyone to account. He refuses to treat the judiciary as the holy cow and explains how the independence and accountability of judges are complimentary and complementary to each other. He holds judges accountable both for their conduct as well as for their judgements which are extra-legal. He questions judicial delays which frustrate justice under a design. If his suggestions are followed, delays will be a thing of the past. Lawyers are totally mercenary defending the indefensible in the name of right to defend, and they try to bury justice forgetting their role as the officers of the court. He has also presented beautifully how the law changes colour with the status of the party making a mockery of the right to equality. The author bemoans that judges live in the bygone days with all the trappings of colonial power reflected in the way they are addressed ‘My Lord’.
Supreme Court’s Power to Do Complete Justice
Authors: Ranjan Sudhanshu
Published: July 2019

An extraordinary power given to the apex court under Article 142 to do ‘complete justice’ is being used in a freewheeling manner against the constitutional scheme. Many a time, it is invoked to supersede the substantive law which in many cases is totally uncalled for. Freewheeling of Article 142 is against the constitutional scheme.
The Oxford Guide to Middle High German
Authors: Jones Howard , Jones Martin H.
Published: July 2019

The Oxford Guide to Middle High German is the most comprehensive self-contained treatment of Middle High German available in English. It covers the language, literature, history, and culture of German in the period 1050–1350 and is designed for entry-level readers, advanced study, teaching, and reference. The book includes a large sample of texts, not only from Classical works such as Erec, the Nibelungenlied, Parzival, and Tristan, but also from mystical writing, chronicles, and legal documents; the selection represents all major dialects and the full time span of the period. Chapter 1 (‘Introduction’) defines Middle High German linguistically, geographically, and chronologically. In Chapter 2 (‘Grammar and Lexis’) each section begins with a summary of the main points; together, these form a stand-alone introductory grammar, and they are followed by detailed paragraphs for in-depth study and reference. Chapter 3 (‘Versification’) deals with metre, rhyme, lines of verse in context, and verse forms, and includes practical tips for scansion. Chapter 4 (‘Historical, Cultural, and Literary Background’) offers an account of the political and social structures of medieval Germany and a survey of the principal types of texts that originated in the period. Chapter 5 (‘Selection of Annotated Texts’) comprises over forty texts, each placed in context and provided with explanatory footnotes; the first two texts, to be taken together with the introductory grammar, are aimed at newcomers. A glossary provides full coverage of the vocabulary appearing in the texts and throughout the book.
Coarse Pricing Policies
Authors: Stevens Luminita
Published: July 2019

The muted volatility of inflation during the Great Recession and its aftermath has refocused attention on the constraints that firms face when adjusting prices. Using new empirical and theoretical results, I argue that each firm’s choice of how much information to acquire to set prices plays a central role in determining the patterns of pricing at the product level and the degree of aggregate price rigidity in response to shocks. In support of the information channel, I present product-level evidence that firms price goods using coarse pricing policies that are updated infrequently and consist of a small menu of prices. Firms are heterogeneous in the complexity and duration of their pricing policies, and this heterogeneity is reflected in differential responses to the Great Recession cycle, with firms exhibiting more complex policies responding more aggressively. I develop a theory of information-constrained price setting that generates coarse pricing endogenously, and quantitatively matches the discreteness, duration, and volatility of policies in the data. The information friction dampens the responsiveness of prices to shocks, and, coupled with heightened volatility, induces firms to keep prices relatively high, to protect against losses in an uncertain environment.
Sleep cardiac dysautonomia and EEG oscillations in amyotrophic lateral sclerosis
Authors: Congiu Patrizia , Mariani Sara , Milioli Giulia , Parrino Liborio , Tamburrino Ludovica , Borghero Giuseppe , Defazio Giovanni , Pereira Bruno , Fantini Maria L , Puligheddu Monica
Published: July 2019

Study Objectives

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to loss of motor neurons. However, the autonomic nervous system (ANS) can also be involved. The aim of this research was to assess the sleep macro- and microstructure, the cardiac ANS during sleep, and the relationships between sleep, autonomic features, and clinical parameters in a cohort of ALS patients.

Methods

Forty-two consecutive ALS patients underwent clinical evaluation and full-night video-polysomnography. Only 31 patients met inclusion criteria (absence of comorbidities, intake of cardioactive drugs, or recording artifacts) and were selected for assessment of sleep parameters, including cyclic alternating pattern (CAP) and heart rate variability (HRV). Subjective sleep quality and daytime vigilance were also assessed using specific questionnaires.

Results

Although sleep was subjectively perceived as satisfactory, compared with age- and sex-matched healthy controls, ALS patients showed significant sleep alteration: decreased total sleep time and sleep efficiency, increased nocturnal awakenings, inverted stage 1 (N1)/stage 3 (N3) ratio, reduced REM sleep, and decreased CAP rate, the latter supported by lower amounts of A phases with an inverted A1/A3 ratio. Moreover, a significant reduction in HRV parameters was observed during all sleep stages, indicative of impaired autonomic oscillations.

Conclusion

Our results indicate that sleep is significantly disrupted in ALS patients despite its subjective perception. Moreover, electroencephalogram activity and autonomic functions are less reactive, as shown by a decreased CAP rate and a reduction in HRV features, reflecting an unbalanced autonomic modulation.
Study of a hepatitis E virus outbreak involving drinking water and sewage contamination in Shimla, India, 2015–2016
Authors: Tripathy Anuradha S , Sharma Meenal , Deoshatwar Avinash R , Babar Prasad , Bharadwaj Rakesh , Bharti Omesh Kumar
Published: July 2019

Background

Hepatitis E, caused by hepatitis E virus (HEV), accounts for 50% of acute hepatitis cases in India. We report an outbreak of hepatitis E in Shimla, India, in 2015–2016.

Methods

ICMR-National Institute of Virology (NIV), Pune, received two batches of water samples from Shimla in January 2016 to test for the presence of enterically transmitted hepatitis viruses. Subsequently, 57 icterus patients were tested for various markers of hepatotropic viruses, i.e. anti-HEV IgM/IgG, anti-hepatitis A virus (anti-HAV) IgM/IgG antibodies and HEV RNA. Water samples were screened for HEV and HAV RNA followed by phylogenetic analysis.

Results

Overall, 48/57 patients availing municipal water had evidence of HEV infection, detected by serology and RT-PCR. All the water samples tested positive for HEV and HAV RNA, while the patients were negative for anti-HAV IgM antibody, indicating no recent HAV infection. Phylogenetic analysis confirmed the aetiological agent of the current outbreak to be HEV genotype 1.

Conclusions

Serology and RT-PCR confirmed HEV as the aetiology of the outbreak. The absence of new cases of hepatitis A, despite the presence of HAV in the water supply, could be due to previously acquired immunity. Sewage contamination of water leading to faecal-oral transmission of HEV still remains a concern, thus emphasising the need for a vaccination/control strategy.
Interactions Between Solanaceous Crops and ‘Candidatus Liberibacter solanacearum’ Haplotypes in Relation to Infection and Psyllid Survival on the Hosts
Authors: Workneh Fekede , Paetzold Li , Rush Charles M.
Published: July 2019

‘Candidatus Liberibacter solanacearum’ (Lso), transmitted by the potato psyllid (Bactericera cockerelli), is the putative causal agent of potato zebra chip disease. The bacterial pathogen infects a wide range of solanaceous plants (both wild and cultivated species), among which are peppers, potatoes, and tomatoes. Currently there are two commonly detected, genetically distinct haplotypes of Lso (A and B) identified from potatoes in the United States. To determine whether there are interactions between Lso haplotypes and different solanaceous hosts, experiments were conducted in the greenhouse in which pepper, potato, and tomato plants were infested with psyllids carrying Lso A, B, or an A and B mix (AB) or with psyllids free of Lso. Host plants were grown in pots in cages on the greenhouse benches and infested with six psyllids per plant. In addition, eight pepper cultivars were similarly infested for deeper understanding of host–haplotype interactions. Approximately 7 weeks after infestation, adult psyllids in each cage were counted to determine the impact of Lso haplotype–host interactions on psyllid survival and plants were sampled and tested molecularly for Lso. Individual psyllids carrying haplotypes B or AB and those free of Lso copiously reproduced on all three hosts, and leaf tissue from each plant tested positive for the respective Lso except those infested with Lso-negative psyllids. However, psyllids carrying Lso A did not survive on peppers but survived and abundantly reproduced on potatoes and tomatoes. In addition, samples from peppers infested with psyllids carrying Lso A tested negative for Lso. However, peppers infested with individual psyllids carrying Lso AB tested positive for Lso A, indicating that the presence of B may be required for infection by Lso A and psyllid survival on peppers. The different pepper cultivars infested with psyllids carrying Lso A showed similar results to the haplotype–host interaction tests, suggesting that cultivar may not be a factor in Lso A–pepper host interactions. Results from these studies suggest that Lso A may affect host selection by psyllids either for nutrition or laying of eggs. Mechanisms involved in preventing psyllid reproduction on peppers, once identified, will have significant implications for potential psyllid management.
Exceptional Responders in Oncology
Authors: Cummings Mackenzie , Lehrer Eric J. , Drabick Joseph J. , Gusani Niraj J. , Trifiletti Daniel M. , Zaorsky Nicholas G.
Published: July 2019

Purpose:

We aim to systematically review and analyze the available literature on “exceptional responders” in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors.

Materials and Methods:

A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates.

Results:

The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853).

Conclusions:

There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.
Primary Cutaneous Clonal CD8+ T-Cell Lymphoproliferative Disorder Associated With Immunodeficiency due to RAG1 Mutation
Authors: Avitan-Hersh Emily , Stepensky Polina , Zaidman Irina , Nevet Mariela Judith , Hanna Suhair , Bergman Reuven
Published: July 2019

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8+ lymphocytic infiltrates and cutaneous CD8+ granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8+ T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8+ T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.
Generalized Necrobiotic Palisading Granulomatous Follicular Eruption: A Peculiar Pustular Variant of Perforating Granuloma Annulare or an Individualized Disease?
Authors: Deza Gustavo , Vidal Ainhoa , Gallardo Fernando , Iranzo Pilar , Canal de la Iglesia Laia , Pujol Ramon M.
Published: July 2019

Herein, we report a case of an adult male patient with a chronic and recurrent papulopustular eruption mainly involving the trunk and lower extremities. A dense superficial perifollicular inflammatory infiltrate with palisading necrobiotic granuloma formation and infundibular perforation was observed at the histological examination, with no granulomatous inflammatory infiltrates in deeper areas. The possibility that this peculiar clinicopathological presentation constitutes a case of generalized perforating granuloma annulare (PGA) or an individualized skin condition is discussed. The observation of a pustular follicular generalized PGA represents an exceedingly rare phenomenon and constitutes an infrequent subtype of PGA that can mimic pustular eruptions secondary to many different etiologies. The clinicopathological features of this rare variant may represent a diagnostic challenge, often requiring multiple biopsies to establish a definite diagnosis.
Approach to ocular toxoplasmosis including pregnant women
Authors: Cortés Jorge A. , Roncancio Álvaro , Uribe Luis Guillermo , Cortés-Luna Carlos Fernando , Montoya José G.
Published: July 2019

Purpose of review

To discuss available information on the effectiveness of anti-toxoplasma therapy for ocular toxoplasmosis and to provide clinicians with a practical approach to the disease.

Recent findings

Only eleven randomized studies were identified. In the three studies for acute retinitis, there was a clear trend in favor of treatment. In the two studies for the prevention of recurrences, trimethoprim–sulfamethoxazole prophylaxis was superior to placebo. In the six studies comparing different regimens, there was no statistically significant difference between the regimens. In the setting of acute posterior uveitis suspected to be caused by toxoplasma, serological testing should always be obtained, and anti-toxoplasma drug treatment, and corticosteroids should be instituted for at least 6 weeks. Toxoplasmic chorioretinitis during pregnancy represents a particular challenge.

Treatment with at least two drugs and corticosteroids should be offered to patients with active toxoplasmic chorioretinitis. Pregnant women with confirmed acute infection and concomitant acute retinitis should be treated for the ocular lesion(s) and to prevent vertical transmission. Pregnant women with chronic Toxoplasma infection acquired prior to gestation and concomitant retinitis by reactivation should be treated for the retinitis and monitored for vertical transmission.
sEH Inhibitor Tppu Ameliorates Cecal Ligation and Puncture-Induced Sepsis by Regulating Macrophage Functions
Authors: Chen Zhihui , Tang Ying , Yu Jing , Dong Ruolan , Yang Yan , Fu Menglu , Luo Jinlan , Hu Shuiqing , Wang Dao Wen , Tu Ling , Xu Xizhen
Published: July 2019

Background:

Sepsis is a life-threatening organ dysfunction initiated by a dysregulated response to infection, with imbalanced inflammation and immune homeostasis. Macrophages play a pivotal role in sepsis. N-[1-(1-oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (TPPU) is an inhibitor of soluble epoxide hydrolase (sEH), which can rapidly hydrolyze epoxyeicosatrienoic acids (EETs) to the bio-inactive dihydroxyeicosatrienoic acids. TPPU was linked with the regulation of macrophages and inflammation. Here, we hypothesized that sEH inhibitor TPPU ameliorates cecal ligation and puncture (CLP)-induced sepsis by regulating macrophage functions.

Methods:

A polymicrobial sepsis model induced by CLP was used in our study. C57BL/6 mice were divided into four groups: sham+ phosphate buffer saline (PBS), sham+TPPU, CLP+PBS, CLP+TPPU. Mice were observed 48 h after surgery to assess the survival rate. For other histological examinations, mice were sacrificed 6 h after surgery. Macrophage cell line RAW264.7 was used for in vitro studies.

Results:

TPPU treatment, accompanied with increased EETs levels, markedly improved the survival of septic mice induced by CLP surgery, which was associated with alleviated organ damage and dysfunction triggered by systemic inflammatory response. Moreover, TPPU treatment significantly inhibited systemic inflammatory response via EETs-induced inactivation of mitogen-activated protein kinase signaling due to enhanced macrophage phagocytic ability and subsequently reduced bacterial proliferation and dissemination, and decreased inflammatory factors release.

Conclusion:

sEH inhibitor TPPU ameliorates cecal ligation and puncture-induced sepsis by regulating macrophage functions, including improved phagocytosis and reduced inflammatory response. Our data indicate that sEH inhibition has potential therapeutic effects on polymicrobial-induced sepsis.
An Aging-Related Single-Nucleotide Polymorphism is Associated With Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients
Authors: Lamparello Ashley J. , Namas Rami A. , Schimunek Lukas , Cohen Maria , El-Dehaibi Fayten , Yin Jinling , Barclay Derek , Zamora Ruben , Billiar Timothy R. , Vodovotz Yoram
Published: July 2019

The contribution of individual genetic determinants of aging to the adverse clinical outcomes and altered inflammation mediator networks characteristic of aged trauma patients is unknown. The AA genotype of the aging-related single-nucleotide polymorphism (SNP) rs2075650 in TOMM40 has been associated with longevity, while the AG and GG genotypes are associated with an increased risk of Alzheimer disease. Here, we studied the effect of rs2075650 on clinical outcomes and dynamic biomarker patterns after traumatic injury. Genomic DNA was obtained from blunt trauma patients admitted to the ICU and examined for 551,839 SNPs using an Illumina microarray kit. Plasma was sampled from each patient three times within the first 24 h and daily from day 1 to 7 then assayed for 31 biomarkers using Luminex. Aged patients (65–90 years) were segregated into AA (n = 77) and AG/GG (n = 17) genotypes. Additional comparisons were made with matched groups of young patients (18–30 years), controlling for injury severity score (ISS) and sex ratio, and also segregated into AA (n = 56) and AG/GG (n = 19) genotypes. Aged patients with the AA genotype had a significantly lower requirement for ventilation and fewer days on mechanical ventilation, as well as significantly higher levels of one mediator and lower levels of two mediators. Dynamic Bayesian Network inference revealed IL-23 as a central node in each network regardless of age or genotype, with MIG and IP-10 also as key mediators in the networks of the aged patients. These findings suggest that an aging-related SNP, rs2075650, may influence clinical outcomes and inflammation networks in aged patients following blunt trauma, and thus may serve as a predictive outcome biomarker in the setting of polytrauma.
Microbial metabolites elicit distinct olfactory and gustatory preferences in bumblebees
Authors: Schaeffer Robert N. , Rering Caitlin C. , Maalouf Isabelle , Beck John J. , Vannette Rachel L.
Published: July 2019

Animals such as bumblebees use chemosensory cues to both locate and evaluate essential resources. Increasingly, it is recognized that microbes can alter the quality of foraged resources and produce metabolites that may act as foraging cues. The distinct nature of these chemosensory cues however and their use in animal foraging remain poorly understood. Here, we test the hypothesis that species of nectar-inhabiting microbes differentially influence pollinator attraction and feeding via microbial metabolites produced in nectar. We first examined the electrophysiological potential for bumblebee (
Bombus impatiens
) antennal olfactory neurons to respond to microbial volatile organic compounds (mVOCs), followed by an olfactory preference test. We also assessed gustatory preferences for microbial-altered nectar through both no-choice and choice feeding assays. Antennal olfactory neurons responded to some mVOCs, and bees preferred nectar solutions inoculated with the bacterium
Asaia astilbes
over the yeast
Metschnikowia reukaufii
based on volatiles alone. However,
B. impatiens
foragers consumed significantly more
Metschnikowia
-inoculated nectar, suggesting distinct roles for mVOCs and non-volatile metabolites in mediating both attraction and feeding decisions. Collectively, our results suggest that microbial metabolites have significant potential to shape interspecific, plant–pollinator signalling, with consequences for forager learning, economics and floral host reproduction.
Multi-network-based diffusion analysis reveals vertical cultural transmission of sponge tool use within dolphin matrilines
Authors: Wild Sonja , Allen Simon J. , Krützen Michael , King Stephanie L. , Gerber Livia , Hoppitt William J. E.
Published: July 2019

Behavioural differences among social groups can arise from differing ecological conditions, genetic predispositions and/or social learning. In the past, social learning has typically been inferred as responsible for the spread of behaviour by the exclusion of ecological and genetic factors. This ‘method of exclusion’ was used to infer that ‘sponging’, a foraging behaviour involving tool use in the bottlenose dolphin (
Tursiops aduncus
) population in Shark Bay, Western Australia, was socially transmitted. However, previous studies were limited in that they never fully accounted for alternative factors, and that social learning, ecology and genetics are not mutually exclusive in causing behavioural variation. Here, we quantified the importance of social learning on the diffusion of sponging, for the first time explicitly accounting for ecological and genetic factors, using a multi-network version of ‘network-based diffusion analysis'. Our results provide compelling support for previous findings that sponging is vertically socially transmitted from mother to (primarily female) offspring. This research illustrates the utility of social network analysis in elucidating the explanatory mechanisms behind the transmission of behaviour in wild animal populations.
The evolution of polarization in the legislative branch of government
Authors: Lu Xiaoyan , Gao Jianxi , Szymanski Boleslaw K.
Published: July 2019

The polarization of political opinions among members of the US legislative chambers measured by their voting records is greater today than it was 30 years ago. Previous research efforts to find causes of such increase have suggested diverse contributors, like growth of online media, echo chamber effects, media biases or disinformation propagation. Yet, we lack theoretic tools to understand, quantify and predict the emergence of high political polarization among voters and their legislators. Here, we analyse millions of roll-call votes cast in the US Congress over the past six decades. Our analysis reveals the critical change of polarization patterns that started at the end of 1980s. In earlier decades, polarization within each Congress tended to decrease with time. By contrast, in recent decades, the polarization has been likely to grow within each term. To shed light on the reasons for this change, we introduce here a formal model for competitive dynamics to quantify the evolution of polarization patterns in the legislative branch of the US government. Our model represents dynamics of polarization, enabling us to successfully predict the direction of polarization changes in 28 out of 30 US Congresses elected in the past six decades. From the evolution of polarization level as measured by the Rice index, our model extracts a hidden parameter–polarization utility which determines the convergence point of the polarization evolution. The increase in the polarization utility implied by the model strongly correlates with two current trends: growing polarization of voters and increasing influence of election campaign donors. Two largest peaks of the model’s polarization utility correlate with significant political or legislative changes happening at the same time.
Automated sample preparation with SP3 for low-input clinical proteomics
Authors: Müller Torsten , Kalxdorf Mathias , Longuespée Rémi , Kazdal Daniel N. , Stenzinger Albrecht , Krijgsveld Jeroen
Published: July 2019

High-throughput and streamlined workflows are essential in clinical proteomics for standardized processing of samples originating from a variety of sources, including fresh frozen tissue, FFPE tissue, or blood. To reach this goal, we have implemented single-pot solid-phase-enhanced sample preparation (SP3) on a liquid handling robot for automated processing (autoSP3) of tissue lysates in a 96-well format, performing unbiased protein purification and digestion, and delivering peptides that can be directly analyzed by LCMS. AutoSP3 eliminates hands-on time and minimizes the risk of error, reduces variability in protein quantification and improves longitudinal performance and reproducibility. We demonstrate the distinguishing ability of autoSP3 to process low-input samples, reproducibly quantifying 500-1000 proteins from 100-1000 cells (<100 ng protein). Furthermore, we applied this approach to a cohort of clinical FFPE pulmonary adenocarcinoma (ADC) samples, and recapitulate their separation into known histological growth patterns based on proteome profiles. Collectively, autoSP3 provides a generic, scalable, and cost-effective pipeline for routine and standardized proteomic sample processing that should enable reproducible proteomics in a broad range of clinical and non-clinical applications.
Gene networks with transcriptional bursting recapitulate rare transient coordinated expression states in cancer
Authors: Schuh Lea , Saint-Antoine Michael , Sanford Eric , Emert Benjamin L. , Singh Abhyudai , Marr Carsten , Goyal Yogesh , Raj Arjun
Published: July 2019

Non-genetic transcriptional variability at the single-cell level is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of melanoma cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes. Importantly, these rare cells are able to survive drug treatment and develop resistance. How might these extremely rare states arise and disappear within the population? It is unclear whether the canonical stochastic models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified molecular mechanisms. Here we use mathematical modeling to show that a minimal network comprising of transcriptional bursting and interactions between genes can give rise to rare coordinated high states. We next show that although these states occur across networks of different sizes, they depend strongly on three (out of seven) model parameters and require network connectivity to be ≤ 6. Interestingly, we find that while entry into the rare coordinated high state is initiated by a long transcriptional burst that also triggers entry of other genes, the exit from it occurs through the independent inactivation of individual genes. Finally, our model predicts that increased network connectivity can lead to transcriptionally stable states, which we verify using network inference analysis of experimental data. In sum, we demonstrate that established principles of gene regulation are sufficient to describe this new class of rare cell variability and argue for its general existence in other biological contexts.
Adult dentate gyrus neurogenesis: a functional model
Authors: Gozel Olivia , Gerstner Wulfram
Published: July 2019

In adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells towards stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.
Self-immunity guided identification of threonyl-tRNA synthetase as the molecular target of obafluorin, a β-lactone antibiotic
Authors: Scott Thomas A. , Batey Sibyl F. , Wiencek Patrick , Chandra Govind , Alt Silke , Franklyn Christopher S. , Wilkinson Barrie
Published: July 2019

To meet the ever-growing demand of antibiotic discovery, new chemical matter and antibiotic targets are urgently needed. Many potent natural product antibiotics which were previously discarded can also provide lead molecules and drug targets. One such example is the structurally unique β-lactone obafluorin, produced by Pseudomonas fluorescens ATCC 39502. Obafluorin is active against both Grampositive and -negative pathogens, however the biological target was unknown. We now report that obafluorin targets threonyl-tRNA-synthetase and we identify a homologue, ObaO, which confers self-immunity to the obafluorin producer. Disruption of obaO in P. fluorescens ATCC 39502 results in obafluorin sensitivity, whereas expression in sensitive E. coli strains confers resistance. Enzyme assays demonstrate that E. coli threonyl-tRNA synthetase is fully inhibited by obafluorin, whereas ObaO is only partly susceptible, exhibiting a very unusual partial inhibition mechanism. Altogether, our data highlight the utility of a self-immunity guided approach for the identification of an antibiotic target de novo and will ultimately enable the generation of improved obafluorin variants.
Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys
Authors: Townsend E. Andrew , Negus S. Stevens , Poklis Justin L. , Banks Matthew L.
Published: July 2019

Background

The current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT2C agonist lorcaserin on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by saline substitution and by 7-day treatment with the opioid antagonist naltrexone.

Methods

Adult male (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2h sessions. Heroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV).

Results

Under baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin treatment significantly increased heroin choice.

Conclusions

In contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential of lorcaserin as a candidate OUD treatment.
Distinct neural markers for intentional and unintentional task unrelated thought
Authors: Martel Adrien , Arvaneh Mahnaz , Robertson Ian , Smallwood Jonathan , Dockree Paul
Published: July 2019

Studies suggest that generating thought unrelated to the task in hand is accompanied by a reduction of attention to external task-relevant information. This observations led contemporary theory to suggest multiple component processes contribute to patterns of ongoing thought. The present study used EEG to seek support for these component-process accounts by examining the neural correlates of deliberate and spontaneous task unrelated thought. EEG activity was compared prior to reports of ongoing thought during a test of sustained attention. Event-related potentials, such as the P3, were attenuated during off-task states, regardless of whether they were intentional or not. In contrast, increased alpha power and cortical phase-locking were linked to deliberate off-task thoughts, while reductions of evoked sensory response were prevalent in spontaneous off-task episodes. These data suggest off-task thought shares common and distinct neural features that are differentiated through their relationship to intention, supporting component process accounts of ongoing thought.
Differences in unity: the go/no-go and stop signal tasks rely on different inhibitory mechanisms
Authors: Raud Liisa , Westerhausen René , Dooley Niamh , Huster René J.
Published: July 2019

Response inhibition refers to the suppression of prepared or initiated actions. Typically, the go/no-go task (GNGT) or the stop signal task (SST) are used interchangeably to capture individual differences in response inhibition. Yet, there is some controversy if these tasks assess similar inhibitory processes. We extracted the time-courses of sensory, motor, attentional, and cognitive control networks by group independent component (G-ICA) analysis of electroencephalography (EEG) data from both tasks. Additionally, electromyography (EMG) from the responding effector muscles was recorded to detect the timing of response inhibition. The results indicated that inhibitory performance in the GNGT may be comparable to response selection mechanisms, reaching peripheral muscles at around 316 ms. In contrast, inhibitory performance in the SST is achieved via biasing of the sensory-motor system in preparation for stopping, followed by fast sensory, motor and frontal integration during outright stopping. Inhibition can be detected at the peripheral level at 140 ms after stop stimulus presentation. The GNGT and the SST therefore seem to recruit widely different neural dynamics, implying that the interchangeable use of superficially similar inhibition tasks in both basic and clinical research is unwarranted.
Illuminating microbial species-specific effects on organic matter remineralization in marine sediments
Authors: Mahmoudi Nagissa , Enke Tim N. , Beaupré Steven R. , Teske Andreas P. , Cordero Otto X. , Pearson Ann
Published: July 2019

Marine microorganisms play a fundamental role in the global carbon cycle by mediating the sequestration of organic matter in ocean waters and sediments. A better understanding of how biological factors, such as microbial community composition, influence the lability and fate of organic matter is needed. Here, we explored the extent to which organic matter remineralization is influenced by species-specific metabolic capabilities. We carried out aerobic time-series incubations of Guaymas basin sediments to quantify the dynamics of carbon utilization by two different heterotrophic marine isolates. Continuous measurement of respiratory CO2 production and its carbon isotopic compositions (13C and 14C) shows species-specific differences in the rate, quantity, and type of organic matter remineralized. Each species was incubated with hydrothermally-influenced vs. unimpacted sediments, resulting in a ~3-fold difference in respiratory CO2 yield across the experiments. Genomic analysis indicated that the observed carbon utilization patterns may be attributed in part to the number of gene copies encoding for extracellular hydrolytic enzymes. Our results demonstrate that the lability and remineralization of organic matter in marine environments is not only a function of chemical composition and/or environmental conditions, but also a function of the microorganisms that are present and active.