bluuebunny/crossref_metadata_2025 huggingface dataset:
The microstructure of laminin-111 compensates for dystroglycan loss in functional differentiation of mammary epithelial cells
Authors: Kent A , Mayer N , Inman JL , Hochman-Mendez C , Bissell MJ , Robertson C
Published: January 2019

Laminin-111, an extracellular matrix (ECM) glycoprotein found in the basement membrane of mammary gland epithelia, is essential for lactation. In mammary epithelial cells, dystroglycan (Dg) is believed to be necessary for polymerization of laminin-111 into networks, thus we asked whether correct polymerization could compensate for Dg loss. Artificially polymerized laminin-111 and the laminin-glycoprotein mix Matrigel, both formed branching, spread networks with fractal dimensions from 1.7-1.8, whereas laminin-111 in media formed small aggregates without fractal properties (a fractal dimension of 2). In Dg knockout cells, either polymerized laminin-111 or Matrigel readily attached to the cell surface, whereas aggregated laminin-111 did not. In contrast, polymerized and aggregated laminin-111 bound similarly to Dg knock-ins. Both polymerized laminin-111 and Matrigel promoted cell rounding, clustering, formation of tight junctions, and expression of milk proteins, whereas aggregated Ln-1 did not attach to cells or promote functional differentiation.

Highlights

Laminin assembles into a fractal network when in presence of either the cell surface receptor dystroglycan or acidic glycoproteins or an acidic buffer.

When this microstructure is recreated with an acidic treatment, laminin binds readily to dystroglycan null cells and induces functional differentiation of mammary epithelial cells.
Aqueous synthesis of a small-molecule lanthanide chelator amenable to copper-free click chemistry
Authors: Bishop Stephanie Cara , Winefield Robert , Anbanandam Asokan , Lampe Jed Noah
Published: January 2019

The lanthanides (Ln3+), or rare earth elements, have proven to be useful tools for biomolecular NMR, X-ray crystallographic, and fluorescence analyses due to their unique 4f orbitals. However, their utility in biological applications has been limited because site-specific incorporation of a chelating element is required to ensure efficient binding of the free Ln3+ ion. Additionally, current Ln3+ chelator syntheses complicate efforts to directly incorporate Ln3+ chelators into proteins as the multi-step processes and a reliance on organic solvents promote protein denaturation and aggregation which are generally incompatible with direct incorporation into the protein of interest. To overcome these limitations, herein we describe a two-step aqueous synthesis of a small molecule lanthanide chelating agent amenable to site-specific incorporation into a protein using copper-free click chemistry with unnatural amino acids. The bioconjugate combines a diethylenetriaminepentaacetic acid (DTPA) chelating moiety with a clickable dibenzylcyclooctyne-amine (DBCO-amine) to facilitate the reaction with an azide containing unnatural amino acid. Incorporating the DBCO-amine avoids the use of the cytotoxic Cu2+ ion as a catalyst. The clickable lanthanide chelator (CLC) reagent reacted readily with p-azidophenylalanine (paF) without the need of a copper catalyst, thereby demonstrating proof-of-concept. Implementation of the orthogonal click chemistry reaction has the added advantage that the chelator can be used directly in a protein labeling reaction, without the need of extensive purification. Given the inherent advantages of Cu2+-free click chemistry, aqueous synthesis, and facile labeling, we believe that the CLC will find abundant use in both structural and biophysical studies of proteins and their complexes.
Positive effects of low LDL-C and statins on bone mineral density: an integrated epidemiological observation analysis and Mendelian Randomization study
Authors: Hoi-Yee Li Gloria , Cheung Ching-Lung , Chun-Ming Au Philip , Choon-Beng Tan Kathryn , Chi-Kei Wong Ian , Sham Pak-Chung
Published: January 2019

Background

Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to BMD and assess the effects of LDL-C-lowering drugs on BMD.

Methods

Association between blood lipid levels and BMD was examined by epidemiological observation analyses in US representative cohort NHANES III (N=3,638) and Hong Kong Osteoporosis Study (HKOS; N=1,128). Two-sample Mendelian Randomization (MR), employing genetic data from GWAS of blood lipids (N=188,577), total body BMD (TB-BMD) (N=66,628) and estimated BMD (eBMD) (N=142,487), was performed to infer causality between blood lipids and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs’ effects on BMD.

Results

In NHANES III cohort, each SD decrease in LDL-C was associated with 0.045 SD increase in femoral neck BMD (95% CI: 0.009 to 0.081; P=0.015). A similar increase in BMD was observed in HKOS at femoral neck and lumbar spine. In MR analysis, decrease in genetically predicted LDL-C was associated with increase in TB-BMD [estimate per SD decrease, 0.038 (95% CI: 0.002 to 0.074); P=0.038] and eBMD [0.076 (0.042 to 0.111); P=1.20×10−5]. Reduction of TB-BMD was causally associated with increased LDL-C [0.035 (0.033 to 0.066); P=0.034]. Statins’ LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 to 0.316); P=9.600×10−3] and eBMD [0.143 (0.062 to 0.223); P=5.165×10−4].

Conclusions

Negative causal association exists between LDL-C level and BMD. Statins’ LDL-C-lowering effect increases BMD, suggesting its protective effect on bone.
MmpL3 is a lipid transporter that binds trehalose monomycolate and phosphatidylethanolamine
Authors: Su Chih-Chia , Klenotic Philip , Bolla Jani Reddy , Purdy Georgiana , Robinson Carol , Yu Edward
Published: January 2019

The cell envelope of Mycobacterium tuberculosis is notable for the abundance of mycolic acids (MAs), which are essential to mycobacterial viability, and other species-specific lipids. The mycobacterial cell envelope is extremely hydrophobic, contributes to virulence and antibiotic resistance. Yet, exactly how fatty acids and lipidic elements are transported across the cell envelope for cell wall biosynthesis is unclear. Mycobacterial membrane protein Large 3 (MmpL3) is essential and required for transport of trehalose monomycolates (TMMs), precursors of MA containing trehalose dimycolates (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), but the exact function of MmpL3 remains elusive. Here, we report a high-resolution crystal structure of M. smegmatis MmpL3, revealing a monomeric molecule that is structurally distinct from all known bacterial membrane proteins. A previously unknown MmpL3 ligand, phosphatidylethanolamine (PE), was discovered inside this transporter. We also show, via native mass spectrometry, that MmpL3 specifically binds both TMM and PE, but not TDM, in the micromolar range. These observations provide insight into the function of MmpL3 and suggest a possible role for this protein in shuttling a variety of lipids to strengthen the mycobacterial cell wall.
Pure tones modulate the representation of orientation and direction in the primary visual cortex
Authors: McClure John P , Polack Pierre-Olivier
Published: January 2019

Multimodal sensory integration facilitates the generation of a unified and coherent perception of the environment. It is now well established that unimodal sensory perceptions, such as vision, are improved in multisensory contexts. While multimodal integration is primarily performed by dedicated multisensory brain regions such as the association cortices or the superior colliculus, recent studies have shown that multisensory interactions also occur in primary sensory cortices. In particular, sounds were shown to modulate the responses of neurons located in layers 2/3 (L2/3) of the mouse primary visual cortex (V1). Yet, the net effect of sound modulation at the V1 population level remained unclear. Here, we performed two-photon calcium imaging in awake mice to compare the representation of the orientation and the direction of drifting gratings by V1 L2/3 neurons in unimodal (visual only) or multi-modal (audiovisual) conditions. We found that sound modulation depended on the tuning properties (orientation and direction selectivity) and response amplitudes of V1 L2/3 neurons. Sounds potentiated the responses of neurons that were highly tuned to the cue orientation and direction but weakly active in the unimodal context, following the principle of inverse effectiveness of multimodal integration. Moreover, sound suppressed the responses of neurons untuned for the orientation and/or the direction of the visual cue. Altogether, sound modulation improved the representation of the orientation and direction of the visual stimulus in V1 L2/3. Namely, visual stimuli presented with auditory stimuli recruited a neuronal population better tuned to the visual stimulus orientation and direction than when presented alone.
Inter-individual Variability of Functional Connectivity in Awake and Anesthetized Rhesus Monkeys
Authors: Xu Ting , Sturgeon Darrick , Ramirez Julian S.B. , Froudist-Walsh Seán , Margulies Daniel S. , Schroeder Charlie E. , Fair Damien A. , Milham Michael P.
Published: January 2019

Background

Nonhuman primate models (NHP) are commonly used to advance our understanding of brain function and organization. However, to date, they have offered few insights into individual differences among NHPs. In large part, this is due to the logistical challenges of NHP research, which limit most studies to five subjects or fewer.

Methods

We leveraged the availability of a large-scale open NHP imaging resource to provide an initial examination of individual differences in the functional organization of the nonhuman primate brain. Specifically, we selected one awake fMRI dataset (Newcastle: n = 10) and two anesthetized fMRI data sets (Oxford: n = 19; UC-Davis: n = 19) to examine individual differences in functional connectivity characteristics across the cortex, as well as potential state dependencies.

Results

We noted significant individual variations of functional connectivity across the macaque cortex. Similar to the findings in human, during the awake state, the primary sensory and motor cortices showed lower variability than the high-order association regions. This variability pattern was significantly correlated with T1w/T2w map, the degree of long-distance connectivity, but not short-distance connectivity. However, the inter-individual variability under anesthesia exhibited a very distinct pattern, with lower variability in medial frontal cortex, precuneus and somatomotor regions and higher variability in the lateral ventral frontal and insular cortices.

Conclusions

This work has implications for our understanding of the evolutionary origins of individual variation in the human brain, as well as methodological implications that must be considered in any pursuit to study individual variation in NHP models.
Dissociation of broadband high-frequency activity and neuronal firing in the neocortex
Authors: Leszczynski Marcin , Barczak Annamaria , Kajikawa Yoshinao , Ulbert Istvan , Falchier Arnaud , Tal Idan , Haegens Saskia , Melloni Lucia , Knight Robert , Schroeder Charles
Published: January 2019

Broadband High-frequency Activity (BHA; 70-150 Hz), also known as "high gamma," a key analytic signal in human intracranial recordings is often assumed to reflect local neural firing (multiunit activity; MUA). Accordingly, BHA has been used to study neuronal population responses in auditory (1,2), visual (3,4), language (5), mnemonic processes (6-9) and cognitive control (10,11). BHA is arguably the electrophysiological measure best correlated with the Blood Oxygenation Level Dependent (BOLD) signal in fMRI (12-13). However, beyond the fact that BHA correlates with neuronal spiking (12, 14-16), the neuronal populations and physiological processes generating BHA are not precisely defined. Although critical for interpreting intracranial signals in human and non-human primates, the precise physiology of BHA remains unknown. Here, we show that BHA dissociates from MUA in primary visual and auditory cortex. Using laminar multielectrode data in monkeys, we found a bimodal distribution of stimulus-evoked BHA across depth of a cortical column: an early-deep, followed by a later-superficial layer response. Only, the early-deep layer BHA had a clear local MUA correlate, while the more prominent superficial layer BHA had a weak or undetectable MUA correlate. In many cases, particularly in V1 (70%), supragranular sites showed strong BHA in lieu of any detectable increase in MUA. Due to volume conduction, BHA from both the early-deep and the later-supragranular generators contribute to the field potential at the pial surface, though the contribution may be weighted towards the late-supragranular BHA. Our results demonstrate that the strongest generators of BHA are in the superficial cortical layers and show that the origins of BHA include a mixture of the neuronal action potential firing and dendritic processes separable from this firing. It is likely that the typically-recorded BHA signal emphasizes the latter processes to a greater extent than previously recognized.
Distribution Pattern and Diversity Maintenance Mechanism of the Denitrifier Community in Alkaline Copper Mine Drainage
Authors: Liu Jinxian , Li Cui , Luo Zhengming , Wang Xue , Bao Jiabing , Chai Baofeng
Published: January 2019

Denitrifiers have been shown to vary in abundance and diversity across the environmental gradients; however, the factors that determine the type and magnitude of the response of the denitrifier communities remain unclear. In order to reveal the effects of alkaline mine drainage (AlkMD) on the denitrifier community composition and diversity maintenance mechanism in a tailings reservoir, we examined the diversity patterns and adaptation mechanisms of different denitrifier communities in Shibahe copper tailings water in Zhongtiaoshan, China. The results showed that the α-diversity of Proteobacteria and the nosZI-bearing denitrifier community in downstream seeping water (SDSW) were the highest, while those in the upstream tailings water (STW1) were the lowest. The highest nirS and nirK-bearing denitrifier community α-diversity were measured in STW1, and the lowest in STW3. The community dissimilarity of the denitrifier communities was strongly correlated with environment parameters, but the factors varied in different groups. The Proteobacteria community was correlated strongly with nitrate (NO3-); the nirS and nirK-bearing denitrifier communities were correlated strongly with pH, total carbon (TC), NO3- and ammonia nitrogen (NH4+), and the nosZI-bearing denitrifier community was correlated strongly with total organic carbon (TOC), dissolved oxygen (DO), NO3-, electroconductibility (EC) and spatial distance (PCNM1). Our results indicated that environmental changes were valuable index reflecting variations in denitrifier community composition in AlkMD. Additionally, the findings in this study are helpful in understanding the relationship between the microbial community composition changes and functional adaptation in different ecosystems.

IMPORTANCE

Metal mine tailings pond is an important site polluted by heavy metals and nitrogen, and excess nitrogen is mainly removed by microorganisms through denitrification. Although many studies have reported that Proteobacteria is the main denitrifying bacteria, and nirS, nirK and nosZ-bearing denitrifiers are three key functional groups in denitrification process. However, less is known of their response to discharge of alkaline copper tailings wastewater (AlkMD). AlkMD exerts an adverse impact on composition and structure of denitrifying bacteria community. The change of nitrogen and carbon concentration along the flow direction of wastewater resulted in the change of denitrifying bacteria community diversity pattern, that is to say, environmental filtering force drove the denitrifier community structure in this highly polluted ecosystem.
Lineage tracing analysis of cone photoreceptor-associated cis-regulatory elements in the developing chicken retina
Authors: Schick Estie , McCaffery Sean D. , Keblish Erin E. , Thakurdin Cassandra , Emerson Mark M.
Published: January 2019

During vertebrate retinal development, transient populations of retinal progenitor cells with restricted cell fate choices are formed. One of these progenitor populations expresses the Thrb gene and can be identified with the ThrbCRM1 cis-regulatory element. Short-term assays have concluded that these cells preferentially generate cone photoreceptors and horizontal cells, however developmental timing has precluded an extensive cell type characterization of their progeny. Here we describe the development and validation of a recombinase-based lineage tracing system for the chicken embryo to further characterize the lineage of these cells. The ThrbCRM1 element was found to preferentially form photoreceptors and horizontal cells, as well as a small number of retinal ganglion cells. The photoreceptor cell progeny are exclusively cone photoreceptors and not rod photoreceptors, confirming that ThrbCRM1-progenitor cells are restricted from the rod fate. In addition, specific subtypes of horizontal cells and retinal ganglion cells were overrepresented, suggesting that ThrbCRM1 progenitor cells are not only restricted for cell type, but for cell subtype as well.
ATAC-seq signal processing and recurrent neural networks can identify RNA polymerase activity
Authors: Tripodi Ignacio J. , Chowdhury Murad , Dowell Robin
Published: January 2019

Nascent transcription assays are the current gold standard for identifying regions of active transcription, including markers for functional transcription factor (TF) binding. Here we present a signal processing-based model to determine regions of active transcription genome-wide using the simpler assay for transposase-accessible chromatin, followed by high-throughput sequencing (ATAC-seq). The focus of this study is twofold: First, we perform a frequency space analysis of the “signal” generated from ATAC-seq experiments’ short reads, at a single-nucleotide resolution, using a discrete wavelet transform. Second, we explore different uses of neural networks to combine this signal with its underlying genome sequence in order to classify ATAC-seq peaks on the presence or absence of bidirectional transcription. We analyze the performance of different data encoding schemes and machine learning architectures, and show how a hybrid signal/sequence representation classified using recurrent neural networks (RNNs) yields the best performance across different cell types.

Contact

robin.dowell@colorado.edu
Obesity is a significant risk factor for ileostomy site incisional hernia following reversal
Authors: De Robles Marie Shella , Bakhtiar Arsalan , Young Christopher J.
Published: January 2019

Background

Incisional hernia following ileostomy reversal can cause significant morbidity, impaired quality of life, and burden on the healthcare system. This study aimed to determine the prevalence of ileostomy site incisional hernia following reversal and to identify possible risk factors for its development.

Methods

This was a retrospective cohort study involving consecutive patients who underwent ileostomy reversal between November 1999 to February 2015 by a single surgeon. Primary outcome analysed was incisional hernia occurrence at the previous stoma site.

Results

Two hundred and twenty‐four ileostomy reversals were identified. The most common indication for ileostomy construction was colorectal cancer, followed by inflammatory bowel disease and diverticulosis. The stomas were either a loop (75%), end‐loop (24%) or end ileostomy (1%). The mean time interval from the stoma creation to reversal was 6.1 months (range 2–69, SD 7.1). After a mean follow‐up of 30.7 months (range 10–89, SD 15.1), 12 patients (5%) developed a hernia at the previous stoma. The mean time for hernia occurrence was 25.2 months (range 3–126, SD 32). Patients who developed ileostomy site incisional hernia were more likely to have a higher body mass index (28.1 versus 26.3, P = 0.007).

Conclusion

Although we found a lower rate of incisional hernias after reversal of ileostomies than reported elsewhere in the literature, it remains a significant clinical problem. Obesity is a significant risk factor for ileostomy‐site incisional hernia.
Expanding the clinical spectrum associated with PACS2 mutations
Authors: Dentici Maria L. , Barresi Sabina , Niceta Marcello , Ciolfi Andrea , Trivisano Marina , Bartuli Andrea , Digilio Maria C. , Specchio Nicola , Dallapiccola Bruno , Tartaglia Marco
Published: January 2019

Whole exome sequencing (WES) has led to the understanding of the molecular events affecting neurodevelopment in an extremely diverse clinical context, including diseases with intellectual disability (ID) associated with variable central nervous system (CNS) malformations, and developmental and epileptic encephalopathies (DEEs). Recently, PACS2 mutations have been causally linked to a DEE with cerebellar dysgenesis and facial dysmorphism. All known patients presented with a recurrent de novo missense mutation, c.625G>A (p.Glu209Lys). Here, we report on a 7‐year‐old boy with DEE, cerebellar dysgenesis, facial dysmorphism and postnatal growth delay, apparently not fitting with any recognized disorder. WES disclosed a de novo novel missense PACS2 variant, c.631G>A (p.Glu211Lys), as the molecular cause of this complex phenotype. We provide a detailed clinical characterization of this patient, and analyse the available clinical data of individuals with PACS2 mutations to delineate more accurately the clinical spectrum associated with this recently described syndrome. Our study expands the clinical and molecular spectrum of PACS2 mutations. Overview of the available clinical data allow to delineate the condition associated with PACS2 mutations as a variable trait, in which the key features are represented by moderate to severe ID, cerebellar dysgenesis and other CNS malformations, reduced growth, and facial dysmorphism.
Factors controlling the variation in organic carbon stocks in agricultural soils of Germany
Authors: Vos Cora , Don Axel , Hobley Eleanor U. , Prietz Roland , Heidkamp Arne , Freibauer Annette
Published: January 2019

This study gives an overview of soil organic carbon (SOC) stocks in Germany's agricultural soils, and quantifies and explains the influence of explanatory variables such as land use and management, soil type and climate. Over 2500 agricultural sites were sampled and their SOC stocks determined, together with other soil properties. Machine‐learning algorithms were used to identify the most important variables. Land use, land‐use history, clay content and electrical conductivity were the main predictors in the topsoil, whereas bedrock material, relief and electrical conductivity governed the variation in subsoil carbon stocks. We found that 32% of all soil profiles were anthropogenically transformed. The influence of climate variables was surprisingly small, whereas site variables, in particular in the subsoil, explained a large proportion of the variation in soil carbon. The understanding of SOC dynamics at the regional scale requires a thorough description of the spatial variation in soil properties. The effect of agronomic management on SOC stocks was important near the soil surface, but was mainly attributable to land use (grassland or arable and not to other management factors.

Highlights

Factors affecting spatial variation of soil organic carbon stocks are largely unknown.

More than 200 possible predictors for this variation were assessed for over 2500 sites.

Land use (history), texture, electrical conductivity, bedrock and relief were main controlling factors of carbon stock variation.

Aggregation and carbon storage capacity of soil determine much of the spatial variation in carbon stocks.
Socially controlled male‐to‐female sex reversal in the protogynous orange‐spotted grouper, Epinephelus coioides
Authors: Chen Jiaxing , Xiao Ling , Peng Cheng , Ye Zhifeng , Wang Dengdong , Yang Yuqing , Zhang Haifa , Zhao Mi , Li Shuisheng , Lin Haoran , Zhang Yong
Published: January 2019

Socially controlled sex change in teleosts is a dramatic example of adaptive reproductive plasticity. In many cases, the occurrence of sex change is triggered by a change in the social context, such as the disappearance of the dominant individual. The orange‐spotted grouper Epinephelus coioides is a typical protogynous hermaphrodite fish that changes sex from female to male and remains male throughout its life span. In this study, male‐to‐female sex reversal in male Epinephelus coioides was successfully induced by social isolation. The body length and mass, gonadal change, serum sex steroid hormone levels and sex‐related gene expression patterns during the process of socially controlled male‐to‐female sex reversal in E. coioides were systematically examined. This report investigates the physiological mechanisms of the socially controlled male‐to‐female sex reversal process in a protogynous hermaphrodite grouper species. The results enable us to study the physiological control of sex change, not only from female to male, but also from male to female.
Price–quality competition in a mixed duopoly
Authors: Klumpp Tilman , Su Xuejuan
Published: January 2019

We examine competition between a private and a public provider in markets for merit goods, such as education, healthcare, housing, recreation, or culture. The private firm provides a high‐price/high‐quality variety of the good and serves richer individuals, whereas the public firm provides a low‐price/low‐quality variety and serves poorer individuals. We first characterize the private competitor’s best response to changes in the public firm’s price and quality. This enables us to examine the distributional effects of policies that affect the price or quality of the public firm’s product. We then numerically characterize the public firm’s optimal provision policy, taking the private response into consideration. Our results have implications for the financing of publicly provided goods, and for whether additional resources, if available, should be spent on reducing the price or enhancing the quality of these goods.
Impulse balance and framing effects in threshold public good games
Authors: Cartwright Edward , Stepanova Anna , Xue Lian
Published: January 2019

In this paper, we revisit the evidence for framing effects in threshold public good games. Our particular focus is on why the probability of providing the public good appears to be higher in positive, give frames compared with negative, take frames. We show that the impulse balance theory can explain this effect. We also report a new experiment designed to test the predictions of the impulse balance theory. The results of the experiment fit well, both in quantitative and qualitative terms, with our predictions.
Canine sterile steroid‐responsive lymphadenitis in 49 dogs
Authors: Ribas Latre A. , McPartland A. , Cain D. , Walker D. , Black V. , Van Den Steen N. , Warman S. , Battersby I. , Murtagh K. , Silvestrini P. , Batchelor D. , Tappin S. W.
Published: January 2019

Objectives

To report clinical and laboratory features, treatment responses and outcome in dogs diagnosed with sterile steroid‐responsive lymphadenitis in the United Kingdom.

Materials and Methods

Medical records of dogs diagnosed with sterile steroid‐responsive lymphadenitis from 2009 to 2016 at six specialist referral centres were evaluated retrospectively.

Results

The study included 49 dogs. Springer spaniels appeared to be over‐represented (16 of 49 dogs). Young dogs (median age: 3 years and 9 months) and females (31 of 49) were frequently affected. Clinical presentation was variable, with pyrexia (39 of 49), lethargy (35 of 49) and anorexia (21 of 49) the most commonly reported clinical signs. Lymph node cytology or histopathology demonstrated neutrophilic, pyogranulomatous, granulomatous or necrotising lymphadenitis without a detectable underlying cause in all cases. Because a sterile immune‐mediated aetiology was suspected, all dogs received prednisolone, which was followed by rapid resolution of clinical signs and lymphadenopathy in most cases.

Clinical Significance

Sterile steroid‐responsive lymphadenitis should be considered in dogs with pyrexia of unknown origin with inflammatory lymphadenopathy if no underlying cause can be found and often responds well to immunosuppressive corticosteroid therapy.
Insight into the impact of vitamin D on cardiovascular outcomes in chronic kidney disease
Authors: Junarta Joey , Jha Vivekanand , Banerjee Debasish
Published: January 2019

Patients with chronic kidney disease (CKD) experience excess cardiovascular morbidity and mortality that is unexplained by traditional cardiovascular risk factors. Vitamin D deficiency is highly prevalent in CKD and is associated with increased cardiovascular mortality in both the general population and in CKD patients. Vitamin D supplementation is a reasonably safe and simple intervention and meta‐analyses of observational studies have suggested that vitamin D supplementation in CKD improves cardiovascular mortality. However, randomized controlled trials examining the impact of vitamin D supplementation in improving surrogate markers of cardiovascular structure and function remain inconclusive. This review investigates the impact of vitamin D supplementation on surrogate end‐points and cardiovascular events from trials in CKD; and discusses why results have been heterogenous, particularly critiquing the effect of different dosing regimens and the failure to take into account the implications of vitamin D supplementation in study participants with differing vitamin D binding protein genotypes.
Multiple principals, multiple problems: Implications for effective governance and a research agenda for joint service delivery
Authors: Voorn Bart , van Genugten Marieke , van Thiel Sandra
Published: January 2019

The multiple principal problem refers to multiple collective action problems that organizations face when they must balance (competing) interests of multiple stakeholders under joint service delivery. It negatively affects different types of organization, yet we know little about how organizations (can) mitigate it. We expand a framework based on principal–agent theory, review the literature, and consider implications for effective governance of joint service delivery in the public sector. We observe that joint service delivery can lead to free‐riding and duplication in monitoring, lobbying by principals, and increased autonomy for agents, leading to inefficiency. We build a research agenda and tentatively suggest, based on the literature, that an interface approach, where an elected unitary actor is placed in a middle tier between politics and service delivery, might best mitigate the multiple principal problem, which is currently not dealt with effectively in public management.
Bananas tackling drought and heat – with DREBs and more
Authors: Baral Anirban
Published: January 2019

With the changing climate, crops are facing mounting threats from multiple abiotic stresses, and studies that assess the response of plants to combinations, rather than to individual, abiotic stresses are becoming increasingly relevant. Bananas are one of the most globally important and popular food crops and their production is threatened by increasing heat and diminishing rainfall in tropical and subtropical regions. In pursuit of effective stress management strategies, Jangale et al. (2019) look into the physiological and molecular responses of banana plants to combined heat and drought stresses.
Comparative physiological and biochemical evaluation of salt and nickel tolerance mechanisms in two contrasting tomato genotypes
Authors: Amjad Muhammad , Ameen Nuzhat , Murtaza Behzad , Imran Muhammad , Shahid Muhammad , Abbas Ghulam , Naeem Muhammad A. , Jacobsen Sven‐Erik
Published: January 2019

Plant tolerance against a combination of abiotic stresses is a complex phenomenon, which involves various mechanisms. Physiological and biochemical analyses of salinity (NaCl) and nickel (Ni) tolerance in two contrasting tomato genotypes were performed in a hydroponics experiment. The tomato genotypes selected were proved to be tolerant (Naqeeb) and sensitive (Nadir) to both salinity and Ni stress in our previous experiment. The tomato genotypes were exposed to combinations of NaCl (0, 75 and 150 mM) and Ni (0, 15, and 20 mg l−1) for 28 days. The results revealed that the tolerant and sensitive tomato genotypes showed similar response to NaCl and Ni stress; however, the level of response was significantly different in both genotypes. The tolerant tomato genotype showed less reduction in growth than the sensitive genotype against both NaCl and Ni stress. Root and shoot ionic analysis showed a decrease in Na and increase in K concentration by increasing Ni levels in the growth medium. Moreover, accumulation of Na and Ni in tissues showed a decrease in membrane stability index and an increase in malondialdehyde contents. The activity of superoxide dismutase, catalase, peroxidase and glutathione reductase under NaCl and Ni stress was significantly higher in the tolerant compared to the sensitive genotype. Enhanced activity of many antioxidant enzymes in Naqeeb under stress conditions is among the other mechanisms that enabled the genotype to better detoxify reactive oxygen species and therefore Naqeeb tolerated the stresses better than Nadir.
Identification of a novel HLA‐C allele, HLA‐C*16:123N, in an Emirati blood donor
Authors: Al Yafei Zain , Alvares Marion S. , Alkatheeri Layla M. , Al Mahri Ayeda , ElGhazali Gehad
Published: January 2019

The novel allele HLA‐C*16:123N has a single nucleotide difference with HLA‐C*01:02:01:01 in exon 2.
Differentially expressed microRNAs, including a large microRNA cluster on chromosome 24, are associated with equine sarcoid and squamous cell carcinoma
Authors: Bogedale Kirsten , Jagannathan Vidhya , Gerber Vinzenz , Unger Lucia
Published: January 2019

The aim of this study was to investigate microRNA (miRNA) differential expression in the two most common equine skin tumours, equine sarcoid (ES) and squamous cell carcinoma (SCC), and its potential influence on the tumour microenvironment at post‐transcriptional level. We investigated miRNA fingerprints in four subgroups: mild (ESM) and aggressive (ESA) ES and ocular SCC (oSCC) and genital SCC (gSCC). Three tumours and three control samples were included in each of the four subgroups. Following next generation sequencing, miRNA differential expression analysis using DESeq2 was carried out. Pathways associated with the human mature homologues of identified dysregulated miRNAs were predicted using DIANA‐ miRPath v3.0. When comparing tumour vs control tissue, 57 miRNAs in ESM, six in ESA, 47 in oSCC and zero in gSCC were found to be differentially expressed and may thus serve as potential diagnostic tissue biomarkers. Whereas, ES lesions in general were associated with downregulation of the miR‐200 family, which may trigger epithelial‐mesenchymal transition, ESM lesions were associated with upregulation of the proposed tumour‐suppressive miRNA cluster on equine chromosome 24. In contrast, the oSCC tumours showed downregulation of this cluster as well as downregulation of the miR‐34 family, which may favour oSCC tumour cell metabolism. To further validate the proposed diagnostic miRNA fingerprints and their suggested biological effects, further miRNA studies need to be carried out in larger study cohorts.
Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma
Authors: Withers Sita S. , York Daniel , Choi Jin W. , Woolard Kevin D. , Laufer‐Amorim Renee , Sparger Ellen E. , Burton Jenna H. , McSorley Stephen J. , Monjazeb Arta M. , Murphy William J. , Canter Robert J. , Rebhun Robert B.
Published: January 2019

Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limited the identification of potential immunotherapeutic targets. In particular, our ability to utilize readily available tissue from a dog's primary tumour to predict the type and extent of immune response in their pulmonary metastatic lesions is unknown. We, therefore, collected 21 matched pairs of primary tumours and pulmonary metastatic lesions from dogs with OSA and performed immunohistochemistry to quantify T‐lymphocyte (CD3), FOXP3+ cell, B‐lymphocyte (Pax‐5), and CD204+ macrophage infiltration. We found that T‐lymphocytes and FOXP3+ infiltrates in primary tumours positively correlated with that of metastatic lesions (ρ= 0.512,P= 0.038 andρ= 0.698,P= 0.007, respectively), while a strong trend existed for CD204+ infiltrates (ρ = 0.404,P= 0.087). We also observed T‐ and B‐lymphocytes, and CD204+ macrophages to be significantly higher in a dog's pulmonary metastasis compared to their primary tumour (P= 0.018,P= 0.018,P= 0.016, respectively), while FOXP3+ cells were only significantly higher in metastases when all primary tumour and metastasis lesions were compared without pairing (P= 0.036). Together, these findings suggest that the metastatic immune microenvironment may be influenced by that of the primary cOSA, and that primary tumour immune biomarkers could potentially be applied to predict immunotherapeutic responses in gross metastatic disease. We, therefore, provide a rationale for the treatment of cOSA pulmonary metastases with immunotherapeutics that enhance the anti‐tumour activity of these immune cells, particularly in dogs with moderate to high immune cell infiltration in their primary tumours.
Clinical features and outcome of dermal squamous cell carcinoma in 193 dogs (1987‐2017)
Authors: Willcox Jennifer L. , Marks Stanley L. , Ueda Yu , Skorupski Katherine A.
Published: January 2019

Squamous cell carcinoma (SCC) is a frequently recognized dermal tumour in dogs and has been described as a common pathology induced by solar ultraviolet radiation exposure. Little has been published about this neoplasm with regard to clinical features and outcome in dogs. This retrospective study included 193 dogs from a single institution histopathologically diagnosed with SCC of the dermis. Thirty‐eight percent of all dogs had documented histopathologic actinic change. The overall median survival time was 1004 days, with the population demonstrating actinic change associated with a significantly longer survival time (median 1359 days, range 16‐3530 days) compared to dogs without actinic change (median 680 days, range 16‐3066 days) and this achieved significance on multivariate analysis (hazard ratio 0.42, 95% confidence interval 0.193‐0.930,P= 0.032). These data demonstrate increased survival of dogs with SCC demonstrating actinic change over those with non‐actinic SCCs, and purports long‐term survival for these animals. Dogs received a variety of treatment approaches as a retrospective study, and future prospective studies will be necessary to investigate whether adjunct therapies such as radiation or chemotherapy offer improvement in survival for dermal SCC in the dog.
Effect of Sampling Frequency on Isometric Midthigh-Pull Kinetics
Authors: Dos’Santos Thomas , Jones Paul A. , Kelly Jonathan , McMahon John J. , Comfort Paul , Thomas Christopher
Published: January 2019

Purpose: Skeletal-muscle function can be evaluated using force-times curves generated via the isometric midthigh pull (IMTP). Various sampling frequencies (500–1000 Hz) have been used for IMTP assessments; however, no research has investigated the influence of sampling frequency on IMTP kinetics. Therefore, the purpose of this study was to investigate the influence of sampling frequency on kinetic variables during the IMTP, including peak force, time-specific force values (100, 150, and 200 ms), and rate of force development (RFD) at 3 time bands (0–100, 0–150, 0–200 ms). Methods: Academy rugby league players (n = 30, age 17.5 ± 1.1 y, height 1.80 ± 0.06 m, mass 85.4 ± 10.3 kg) performed 3 IMTP trials on a force platform sampling at 2000 Hz, which was subsequently down-sampled to 1500, 1000, and 500 Hz for analysis. Results: Intraclass correlation coefficients (ICC) and coefficients of variation (CV) demonstrated high within-session reliability for all force and RFD variables across all sampling frequencies (ICC ≥ .80, CV ≤ 14.4%) except RFD 0–100 and 0–150, which demonstrated slightly greater levels of variance (CV = 18.0–24.1%). Repeated-measures analysis of variance revealed no significant differences (P > .05, Cohen d ≤ 0.0171) in kinetic variables between sampling frequencies. Overall, high reliability was observed across all sampling frequencies for peak force, time-specific force, and RFD 0- to 200-ms variables, with no significant differences (P > .05) for each kinetic variable across sampling frequencies. Conclusions: Practitioners and scientists may consider sampling as low as 500 Hz when measuring peak force, time-specific force values, and RFD at predetermined time bands during the IMTP for accurate and reliable data.
The existence and impact of persistent ferroelectric domains in MAPbI
3
Authors: Garten Lauren M. , Moore David T. , Nanayakkara Sanjini U. , Dwaraknath Shyam , Schulz Philip , Wands Jake , Rockett Angus , Newell Brian , Persson Kristin A. , Trolier-McKinstry Susan , Ginley David S.
Published: January 2019

We demonstrate a ferroelectric response in MAPbI
3
single crystals that can modulate the electronic response and increase stability.
Waterproof, electronics-enabled, epidermal microfluidic devices for sweat collection, biomarker analysis, and thermography in aquatic settings
Authors: Reeder Jonathan T. , Choi Jungil , Xue Yeguang , Gutruf Philipp , Hanson Justin , Liu Mark , Ray Tyler , Bandodkar Amay J. , Avila Raudel , Xia Wei , Krishnan Siddharth , Xu Shuai , Barnes Kelly , Pahnke Matthew , Ghaffari Roozbeh , Huang Yonggang , Rogers John A.
Published: January 2019

Waterproof epidermal microfluidics enable collection and analysis of sweat during aquatic exercise.
Quantum generative adversarial learning in a superconducting quantum circuit
Authors: Hu Ling , Wu Shu-Hao , Cai Weizhou , Ma Yuwei , Mu Xianghao , Xu Yuan , Wang Haiyan , Song Yipu , Deng Dong-Ling , Zou Chang-Ling , Sun Luyan
Published: January 2019

A quantum version of generative adversarial learning is experimentally demonstrated with a superconducting circuit.
Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8
+
T cells
Authors: Gemta Lelisa F. , Siska Peter J. , Nelson Marin E. , Gao Xia , Liu Xiaojing , Locasale Jason W. , Yagita Hideo , Slingluff Craig L. , Hoehn Kyle L. , Rathmell Jeffrey C. , Bullock Timothy N. J.
Published: January 2019

Impaired activity of enolase 1 limits glycolysis and effector function of tumor-infiltrating CD8
+
T cells.
Interleukin 6: The biology behind the therapy
Authors: Jones Simon A , Takeuchi Tsutomu , Aletaha Daniel , Smolen Josef , Choy Ernest H , McInnes Iain
Published: January 2019

The cytokine interleukin (IL)−6 performs a diverse portfolio of functions in normal physiology and disease. These functions extend beyond the typical role for an inflammatory cytokine, and IL-6 often displays hormone-like properties that affect metabolic processes associated with lipid metabolism, insulin resistance, and the neuroendocrine system. Consequently, the biology of IL-6 is complex. Recent advances in the field have led to novel interpretations of how IL-6 delivers immune homeostasis in health and yet drives disease pathology during infection, autoimmunity, and cancer. Various biological drugs that target IL-6 are in clinical practice or emerging in clinical trials and pre-clinical development programmes. The challenge is knowing how and when to apply these therapies. In this review, we will explore the biology behind IL-6 directed therapies and identify some key hurdles for future investigation.
Impact of chronic headache on workdays, unemployment and disutility in the general population
Authors: Kristoffersen Espen Saxhaug , Stavem Knut , Lundqvist Christofer , Russell Michael Bjørn
Published: January 2019

Background

Data on the socioeconomic burden of chronic headache (≥15 days/last month or>180 days/year) is lacking. This study investigated the impact of chronic headache on sickness absence, unemployment and disutility in the general population in Norway.

Methods

30 000 persons aged 30–44 from the general population were screened for chronic headache by a screening questionnaire. The responder rate was 71%. The International Classification of Headache Disorders was used. We analysed the association of chronic headache with lost workdays, days with ≥50% reduced productivity, sick leave, unemployment and disutility, as assessed with the Short-Form Six-Dimension (SF-6D) in separate regression analyses.

Results

Eighty-three per cent (427/516, 79% women) of the eligible participants completed the data on workdays and utility. They reported a mean of 9.7 (SD 24.8) workdays lost over the last 3 months, because of headache. The mean disutility score (1-SF-6D score) was 0.41. Thirty-three per cent were on long-term (>1 year) sick leave. The OR for being on sick leave was 1.9 (95% CI 1.1 to 3.2, p=0.017) for those with secondary compared with primary chronic headache. Similarly, the OR for increased number of workdays lost to headache was 3.5 (95% CI 1.8 to 6.5, p<0.001) and for unemployment 1.7 (95% CI 1.0 to 2.9, p=0.07), for those with secondary compared with primary chronic headache. Secondary chronic headache, high headache frequency and high psychological distress were significantly associated with higher disutility score.

Conclusions

The burden of chronic headache in the general population is substantial with high rates of lost workdays and disutility.
Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis
Authors: Manjaly Zina-Mary , Harrison Neil A , Critchley Hugo D , Do Cao Tri , Stefanics Gabor , Wenderoth Nicole , Lutterotti Andreas , Müller Alfred , Stephan Klaas Enno
Published: January 2019

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients’ quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.