bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between neuromelanin and dopamine terminals within the Parkinson’s nigrostriatal system
Authors: Martín-Bastida Antonio , Lao-Kaim Nicholas P , Roussakis Andreas Antonios , Searle Graham E , Xing Yue , Gunn Roger N , Schwarz Stefan T , Barker Roger A , Auer Dorothee P , Piccini Paola 
Published: April 2019

AbstractParkinson’s disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson’s disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson’s disease subjects displayed reduced neuromelanin levels in the ventral (−30 ± 28%) and dorsal tiers (−21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson’s disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson’s disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.
Financialisation, institutions and financing constraints in developing countries
Authors: Mertzanis Charilaos 
Published: April 2019

AbstractThe paper uses a consistent firm-level data from the World Banks Enterprise Surveys to explore the impact of financialisation in the economy on firms’ access to finance in 138 developing countries. Access to finance reflects survey-based firms’ perceptions of external financing constraints. Financialisation is proxied by consistent cross-country measures of financial depth. These proxies capture separately the role of bank-based versus market-based financing. Firm-, sector- and country-level information is jointly used for the analysis. Firm-specific characteristics and economic and non-economic national factors are included as controls. The results show that the proxies of financialisation are broadly robust predictors of financing constraints of firms in developing countries. However, the magnitude of the financialisation effect varies between bank-based and market-based channels of financing as well as between low- and high-income countries, and it is influenced by social, institutional and religious factors.
Parallel Progress in Perceived Age and Life Expectancy
Authors: Steiner Ulrich K , Larsen Lisbeth A , Christensen Kaare 
Published: April 2019

Abstract

Background
Human life expectancy continues to rise in most populations. This rise not only leads to longer lives but also is accompanied by improved health at a given age, that is, recent cohorts show a reduction of biological age for a given chronological age. Despite or even because of the diversity of biomarkers of aging, an accurate quantification of a general shift in biological age across time has been challenging.

Methods
Here, we compared age perception of facial images taken in 2001 over a decade and related these changes in age perception to changes in life expectancy.

Results
We show that age perception changes substantially across time and parallels the progress in life expectancy. In 2012, people aged more than 70 years needed to look 2.3 years younger to be rated the same age as in 2002.

Conclusions
Our results suggest that age perception reflects the past life events better than predicts future length of life, that is, it is written in your face how much you have aged so far. We draw this conclusion as age perception among elderly individuals paralleled changes in life expectancy at birth but not changes in remaining life expectancies. We suggest that changes in age perception should be explored for younger age classes to inform on aging processes, including whether aging is delayed or slowed with increasing life expectancy.
Spread through air spaces is an independent predictor of recurrence in stage III (N2) lung adenocarcinoma
Authors: Terada Yuriko , Takahashi Tsuyoshi , Morita Shigeki , Kashiwabara Kosuke , Nagayama Kazuhiro , Nitadori Jun-Ichi , Anraku Masaki , Sato Masaaki , Shinozaki-Ushiku Aya , Nakajima Jun 
Published: April 2019

Abstract

OBJECTIVES
Spread through air space (STAS) is recognized as a pattern of invasion in lung adenocarcinoma and has been reported to be a predictor of recurrence and survival in patients with early-stage lung adenocarcinoma. However, this parameter has not been studied well in stage III (N2) lung adenocarcinoma. In this study, we evaluated the association between STAS invasion patterns and recurrence and survival in stage III (N2) lung adenocarcinoma.

METHODS
We retrospectively reviewed data from 76 patients at University of Tokyo with stage III (N2) lung adenocarcinoma who underwent surgery from August 1998 to December 2013. Statistical analysis was performed to determine the impact of STAS invasion clinicopathological features and clarify the relationship between this pattern of invasion and survival.

RESULTS
Tumour STAS was observed in 46 of 76 patients (60.5%) and was significantly associated with the presence of lymphatic invasion (P < 0.001), papillary components (P < 0.001) and micropapillary components (P < 0.001). STAS was also significantly associated with recurrence (5-year recurrence-free probability: 19.0% vs 46.1%, P < 0.05). Univariate analyses showed that STAS was a significant risk factor for recurrence (hazard ratio 1.94, 95% confidence interval 1.07–3.51; P = 0.029).

CONCLUSIONS
The presence of STAS invasion pattern is a significant risk factor for recurrence in stage III (N2) lung adenocarcinoma.
Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial
Authors: Dorn Christoph , Petroff David , Neumann Nancy , Kratzer Alexander , El-Najjar Nahed , Dietrich Arne , Kloft Charlotte , Zeitlinger Markus , Kees Martin G , Kees Frieder , Wrigge Hermann , Simon Philipp 
Published: April 2019

Abstract

Objectives
To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients.

Methods
Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods.

Results
Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047).

Conclusions
Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.
Rethinking antimicrobial stewardship paradigms in the context of the gut microbiome
Authors: Shahi Farah , Redeker Kelly , Chong James 
Published: April 2019

Abstract
Ongoing concerns over the presence and persistence of antimicrobial resistance (AMR), particularly in Gram-negative bacteria, continue to have significant global health impacts. The gastrointestinal tract, or ‘gut’, environment amplifies AMR in the human gut microbiome, even in the absence of antibiotics. It constitutes a complex and diverse community of organisms, and patterns and alterations within it are increasingly being found to be associated with states of health and disease. Our understanding of the effects of routes of administration of antimicrobials on the gut microbiome is still lacking despite recent advances in metagenomics. In this article we review current evidence for antibiotic effects on gut microbiota and explore possible prescribing and stewardship approaches that would seek to minimize these effects. If we are to preserve existing and new antimicrobials, we need to consider their use in the context of their effect on gut ecology, and the human microbiome in general.
The effects of incomplete milking and increased milking frequency on milk production rate and milk composition1
Authors: Kuehnl Jordan M , Connelly Meghan K , Dzidic Alen , Lauber Megan , Fricke Hannah P , Klister Marisa , Olstad Emma , Balbach Maria , Timlin Emily , Pszczolkowski Virginia , Crump Peter M , Reinemann Doug J , Hernandez Laura L 
Published: April 2019

Abstract
Increased milking frequency and incomplete milking have differential effects on milk yield and mammary gland physiology that are important for optimization of milking practices in dairy herds. The objectives of this experiment were to determine the effects of increased milking frequency and incomplete milking on milk production rate (MPR) and milk composition and to determine if milking 3 times daily (3×) could rescue the negative production effects of incomplete milking. Twenty-two multiparous cows were enrolled onto this experiment beginning at 5 days in milk (DIM) and continuing through 47 DIM. A split-plot design was used to randomize the 2 treatments, which were milking frequency and incomplete milking. Eleven cows were randomly assigned to be milked 2 times (2×) daily and 11 cows were randomly assigned to be milked 3×. Within each cow, a contralateral half-udder was randomly assigned to be incompletely milked (30% milk remaining in the gland; IM), and the other half-udder was randomly assigned to be milked completely (CM). Quarter-level milk yields were recorded at each milking session. Milk samples from all quarters were collected twice weekly at the beginning of the morning milking for analysis. Cows milked 2× tended to have reduced MPR compared with 3× milked cows (1.81 ± 0.06 vs. 1.97 ± 0.06 kg milk/h; P = 0.06). Half-udders that were CM and IM produced 1.09 ± 0.03 and 0.80 ± 0.03 kg milk/h, respectively. There was an interaction between incomplete milking treatment and week of lactation (P = 0.04). No interaction was detected between milking frequency and incomplete milking for MPR or milk components. Cows milked 3× had increased milk fat percent (1.93 ± 0.09% vs. 1.65 ± 0.09%, P = 0.047), decreased milk lactose percent (4.80 ± 0.04% vs. 4.93 ± 0.04%, P = 0.04), and exhibited no differences in milk protein percent or milk somatic cell count (SCC) compared with cows milked 2×. Half-udders that were IM had increased milk fat percent (2.15 ± 0.07% vs. 1.43 ± 0.07%, P &lt; 0.0001), decreased lactose percent (4.75 ± 0.03% vs. 4.99 ± 0.03%, P &lt; 0.0001), increased milk log10SCC (4.22 ± 0.05 vs. 4.41 ± 0.05, P = 0.0004), and no differences in milk protein percent compared with CM half-udders. These results indicate that a 3× milking frequency in IM half-udders was not able to improve milk production compared with IM half-udders milked 2×. Our results indicate that 30% milk remaining in the gland had an irreversible impact on milk yield as increased milking frequency was not able to reverse the milk yield lost.
A hyperintensional logical framework for deontic reasons
Authors: Faroldi Federico L G , Protopopescu Tudor 
Published: April 2019

Abstract
In this paper we argue that normative reasons are hyperintensional and put forward a formal account of this thesis. That reasons are hyperintensional means that a reason for a proposition does not imply that it is also a reason for a logically equivalent proposition. In the first part we consider three arguments for the hyperintensionality of reasons: (i) an argument from the nature of reasons, (ii) an argument from substitutivity and (iii) an argument from explanatory power. In the second part we describe a hyperintensional logic of reasons based on justification logics. Eventually we discuss the philosophical import of this proposal and highlight some limitations and possible developments.
‘Why genes in pieces?’—revisited
Authors: Smithers Ben , Oates Matt , Gough Julian 
Published: April 2019

Abstract
The alignment between the boundaries of protein domains and the boundaries of exons could provide evidence for the evolution of proteins via domain shuffling, but literature in the field has so far struggled to conclusively show this. Here, on larger data sets than previously possible, we do finally show that this phenomenon is indisputably found widely across the eukaryotic tree. In contrast, the alignment between exons and the boundaries of intrinsically disordered regions of proteins is not a general property of eukaryotes. Most interesting of all is the discovery that domain–exon alignment is much more common in recently evolved protein sequences than older ones.
A centrally concentrated sub-solar-mass starless core in the Taurus L1495 filamentary complex
Authors: Tokuda Kazuki , Tachihara Kengo , Saigo Kazuya , André Phillipe , Miyamoto Yosuke , Zahorecz Sarolta , Inutsuka Shu-ichiro , Matsumoto Tomoaki , Takashima Tatsuyuki , Machida Masahiro N , Tomida Kengo , Taniguchi Kotomi , Fukui Yasuo , Kawamura Akiko , Tatematsu Ken’ichi , Kandori Ryo , Onishi Toshikazu 
Published: April 2019

Abstract
The formation scenario of brown dwarfs is still unclear because observational studies to investigate its initial condition are quite limited. Our systematic survey of nearby low-mass star-forming regions using the Atacama Compact Array (aka the Morita array) and the IRAM 30-m telescope in 1.2 mm continuum has identified a centrally concentrated starless condensation with a central H2 volume density of ∼106 cm−3, MC5-N, connected to a narrow (width ∼0.03 pc) filamentary cloud in the Taurus L1495 region. The mass of the core is $\sim {0.2\!-\!0.4}\, M_{\odot }$, which is an order of magnitude smaller than typical low-mass pre-stellar cores. Taking into account a typical core to star formation efficiency for pre-stellar cores (∼20%–40%) in nearby molecular clouds, brown dwarf(s) or very low-mass star(s) may be going to be formed in this core. We have found possible substructures at the high-density portion of the core, although much higher angular resolution observation is needed to clearly confirm them. The subsequent N2H+ and N2D+ observations using the Nobeyama 45-m telescope have confirmed the high-deuterium fractionation (∼30%). These dynamically and chemically evolved features indicate that this core is on the verge of proto-brown dwarf or very low-mass star formation and is an ideal source to investigate the initial conditions of such low-mass objects via gravitational collapse and/or fragmentation of the filamentary cloud complex.
J-103 The International Coalition to Eliminate Hepatitis B (ICE-HBV)
Authors: Revill Peter , Penicaud Capucine 
Published: April 2019

Background:
Over 257 million people worldwide are chronically infected with hepatitis B virus (HBV), resulting in over 880,000 deaths per year from cirrhosis and liver cancer. There is no known cure for chronic HBV, due in part to the continued presence of transcriptionally active DNA in the nucleus which is not directly targeted by current antiviral therapies. Our aim is to inspire and support the discovery of a safe, scalable and effective cure for the benefit of all people living with CHB.

Methods:
To achieve this, we have created an international research driven forum, the International Coalition to Eliminate Hepatitis B (ICE-HBV), which is coordinating collaborative partnerships among researchers and stakeholders to accelerate the search of an HBV cure.

Results:
ICE-HBV working groups have developed a joint global scientific strategy for HBV cure, with input from key stakeholders including the HBV affected community. Through engagement with key stakeholders, ICE-HBV aims to drive changes in governmental policy to ensure more funds are channelled to HBV cure research and drug development. ICE-HBV fosters new collaborations among HBV researchers and industry worldwide and initiate new projects to fast-track the discovery of an HBV cure.

Conclusions:
The push for a cure for chronic HBV infection is particularly timely thanks to the recent development of cell culture infection models that, for the first time, empower truly curative research. Through its global network, ICE-HBV is striving to promote effective collaboration and facilitate opportunities that can produce a cure for chronic HBV infection.
PC-4 The identification of a novel leukocyte population IMLEC unveils a critical role of mTORC1 in innate immune tolerance
Authors: Tang Fei , Zhang Peng , Liu Yang , Zheng Pan 
Published: April 2019

Adaptive autoimmunity is restrained by controlling population sizes and pathogenicity of harmful clones, while innate destruction is controlled at effector phase. We report here that deletion of Rptor (an indispensable component of the mTOR complex 1) in hematopoietic stem/progenitor cells causes self-destructive innate immunity by massively increasing the population of previously uncharacterized innate myelolymphoblastoid effector cells (IMLECs). IMLECs are CD3-B220-NK1.1-Ter119-CD11c low/-CD115-F4/80low/-Gr-1- CD11b+, but surprisingly express high levels of PD-L1. Although they morphologically resemble lymphocytes and actively produce transcripts from Immunoglobulin loci, IMLECs have non-rearranged Ig loci, are phenotypically distinguishable from all known lymphocytes, and have a gene signature that bridges lymphoid and myeloid leukocytes. Rptor deletion unleashes differentiation of IMLECs from common myeloid progenitor cells by reducing expression of Myb. Importantly, IMLECs broadly overexpress pattern-recognition receptors and their expansion causes systemic inflammation in response to Toll-like receptor ligands.
Our data unveil a novel leukocyte population and an unrecognized role of Raptor/mTORC1 in innate immune tolerance. Our work challenges the strict dichotomy of myeloid and lymphoid lineages in the immune system, and suggests a new mode of immune regulation for innate effector cells. The identification of this new cell population may allow us to more effectively regulate inflammation under pathological conditions. These findings might help explain the inflammation caused by mTORC1 inhibitors treatments in some patients with cancers and transplantation. Moreover, since IMLECs constitutively express high levels of PD-L1, it is interesting to investigate their functions in cancer immunotherapy.
PC-8 Novel chemoimmunotherapy combinations for pancreatic cancer
Authors: Smith Peter , Capizzuto Valentina , Dalgleish Angus 
Published: April 2019

Introduction:
Pancreatic cancer (PC) is a devastating malignancy. It is usually diagnosed at an incurable stage and has the poorest of prognoses of any cancer. Despite its relatively low incidence, it is the fourth leading cause of cancer-related death. A few chemotherapies have shown modest efficacy but are associated with significant toxicities and development of tumour resistance. For these reasons the median survival after diagnosis is about 4.6 months, 18% of patients survive one year and less than 5% survive for 5 years. Without improvement in PC therapy it may soon become the second leading cause of cancer related deaths. Immunotherapies are beginning to show efficacy as first line therapies for a number of cancers but have yet to prove effective against PC. This is due to the dense desmoplastic stroma and immune suppressive microenvironment characteristic of advanced disease. Thus novel chemo-immunotherapeutic combinations will likely be required to target the tumour and its microenvironment to create the conditions in which immunotherapies, such as checkpoint inhibition, will be effective. The data presented here details the development of combination chemotherapy capable of killing tumour cells whilst increasing the immunogenicity of the tumour.

Results:
Combinations based upon the chemotherapeutic drug Gemcitabine were studied. Gemcitabine was combined with Zolodronic acid, Pomalidomide, Oxaliplatin and mycobacterial adjuvants. These combinations demonstrated increased cytotoxicity of pancreatic cell lines compared to single agent treatment. Gemcitabine increased markers of immune recognition on these cell lines independently of its cytotoxic properties whilst Oxaliplatin increased markers of immunogenic cell death and uptake of tumour cells into dendritic cells. Combination treatment was able to enhance dendritic cell maturation and the activation of CD8+ T-cells, measured as increases in the expression of IFN-γ.

Discussion:
Taken together the data presented here shows that gemcitabine based combinations exhibit superior in vitro cytotoxicity and immunogenic properties compared to single agent therapy. Each of these agents has previously been paired with gemcitabine for treatment of pancreatic cancer, demonstrating low toxicity and potential clinical efficacy. This supports their development as 3 or 4 agent combinations. Further research using pre-clinical pancreatic cancer models is planned including the use of checkpoint inhibition in combination with Chemoimmunotherapy.