bluuebunny/crossref_metadata_2025 huggingface dataset:
Strongyloides stercoralis Coinfection Is Associated With Greater Disease Severity, Higher Bacterial Burden, and Elevated Plasma Matrix Metalloproteinases in Pulmonary Tuberculosis
Authors: Kumar Nathella P , Kathamuthu Gokul R , Moideen Kadar , Banurekha Vaithilingam V , Nair Dina , Fay Michael P , Nutman Thomas B , Babu Subash
Published: April 2020

Background

Helminths and tuberculosis (TB) largely overlap at the population level. Whether helminth infections influence disease severity and bacterial burdens in TB is not well understood.

Methods

This study was conducted to examine the disease severity in a cohort of pulmonary TB (PTB) individuals with (Ss+) or without (Ss−) seropositivity for Strongyloides stercoralis infection.

Results

Ss+ was associated with increased risk of cavitation (odds ratio [OR], 4.54; 95% confidence interval [CI], 2.33–9.04; P < .0001) and bilateral lung involvement (OR, 5.97; 95% CI, 3.03–12.09; P < .0001) in PTB individuals. Ss+ was also associated with higher bacterial burdens (OR, 7.57; 95% CI, 4.18–14.05; P < .0001) in PTB individuals. After multivariate analysis adjusting for covariates, Ss+ was still associated with greater risk of cavitation (adjusted OR [aOR], 3.99; 95% CI, 1.73–9.19; P = .0014), bilateral lung involvement (aOR, 4.09; 95% CI, 1.78–9.41; P = .0011), and higher bacterial burden (aOR, 9.32; 95% CI, 6.30–13.96; P < .0001). Finally, Ss+ was also associated with higher plasma levels of matrix metalloproteinases ([MMP]-1, -2, -7, -8, and -9) in PTB individuals.

Conclusions

Therefore, our data demonstrate that coexistent Ss infection is associated with greater disease severity and higher bacterial burden in PTB. Our data also demonstrate enhanced plasma levels of MMPs in coinfected individuals, suggesting a plausible biological mechanism for these effects.
Real-Time Monitoring of Beer Parameters Using Infrared Spectroscopy—A Process Analytical Technology Approach
Authors: Estevão Simone Tessarini , Lourenço Felipe Rebello
Published: April 2020

Background

Quality assessment of a finished beer product is usually performed by determining whether a sample from the batch conforms to the specifications and industry standards. However, if one or more quality parameters do not meet specifications, the batch must be reprocessed or even disposed of entirely.

Objective

The aim of this work was to propose real-time monitoring of beer parameters using infrared spectroscopy, according to the process analytical technology (PAT) approach.

Method

Sixteen formulations of beer containing barley malt, rice, maize, and/or oat malt were manufactured and analyzed, using an off-line infrared spectrometer and a beer analyzer, for alcohol content and density. All formulations were also subjected to color analysis, pH measurements, and sensory analysis.

Results

Partial least square regression models achieved coefficients of determination and prediction of 95.4% and 76.1% for the alcohol content, 90.9% and 69.2% for the density, 93.6% and 85.7% for the pH, and 98.1% and 94.8% for color, respectively. An infrared spectrometric method was used in the real-time monitoring of alcohol content, density, pH, and color of optimized (55% barley malt, 42% oat malt, and 3% maize) and standard (100% barley malt) formulations.

Conclusions

No statistical differences were observed between the results of the alcoholic content, density, pH, and color predicted by the partial least square regression and those obtained experimentally in the optimized and standard formulations.

Highlights

The application of the PAT tool is particularly useful for long manufacturing processes and can be applied in the development of food products.
A Little Piece of Me: When Mortality Reminders Lead to Giving to Others
Authors: Dunn Lea , White Katherine , Dahl Darren W
Published: April 2020

Past research demonstrates that reminders of one’s own mortality can lead to materialistic and self-serving consumer behaviors. In contrast, across five studies, we explore a condition under which mortality salience (MS) leads to increased tendency to give away one’s possessions—when the donation act is high in transcendence potential. We propose and find that consumers are more likely to donate their possessions to charity under MS (vs. comparison conditions) when the product is considered highly (vs. not highly) connected to the self. Moreover, we demonstrate that this tendency manifests only when transcendence is attainable through donation. In support of the proposition of transcendence as the underlying mechanism, the observed effects are attenuated under conditions where: (1) transcendence has already been satiated via alternative means or (2) the donated possession will not transcend the self (i.e., its physical integrity is lost by being broken down and recycled). The theoretical and practical implications of the work are discussed.
Should I Touch the Customer? Rethinking Interpersonal Touch Effects from the Perspective of the Touch Initiator
Authors: Luangrath Andrea Webb , Peck Joann , Gustafsson Anders
Published: April 2020

Previous research has highlighted the effects of receiving interpersonal touch on persuasion. In contrast, we examine initiating touch. Individuals instructed to touch engage in egocentric projection in which they project their own affective reaction onto their expectations for how the recipient will feel (i.e., empathic forecast), how they appear to the recipient (i.e., metaperception), and the evaluation of the interaction itself (i.e., interaction awkwardness). Touch initiators expect that recipients will feel worse with touch, express concern for how they, themselves, will be perceived, and think that interactions are more awkward. Interestingly, touch recipients do not evaluate these interactions more negatively and leave higher tips after having been touched; touch initiators do not expect this to be the case. As a result, instructed touch initiators (vs. volitional touch initiators) are less (more) likely to engage in subsequent interactions with customers, potentially undermining future service provided to customers. Across five studies, four of which involve actual dyadic interactions, we test the consequences of initiating touch with an inquiry into the effects of interpersonal touch on the initiator. We discuss theoretical and managerial implications.
RUNX1-205, a novel splice variant of the human RUNX1 gene, has blockage effect on mesoderm–hemogenesis transition and promotion effect during the late stage of hematopoiesis
Authors: Sun Wencui , Zeng Jiahui , Chang Jing , Xue Yuan , Zhang Yonggang , Pan Xu , Zhou Ya , Lai Mowen , Bian Guohui , Zhou Qiongxiu , Liu Jiaxing , Chen Bo , Ma Feng
Published: April 2020

Runt-related transcription factor 1 (RUNX1) is required for definitive hematopoiesis; however, the functions of most human RUNX1 isoforms are unclear. In particular, the effects of RUNX1-205 (a novel splice variant that lacks exon 6 in comparison with RUNX1b) on human hematopoiesis are not clear. In this study, a human embryonic stem cell (hESC) line with inducible RUNX1-205 overexpression was established. Analyses of these cells revealed that induction of RUNX1-205 overexpression at early stage did not influence the induction of mesoderm but blocked the emergence of CD34+ cells, and the production of hematopoietic stem/progenitor cells was significantly reduced. In addition, the expression of hematopoiesis-related factors was downregulated. However, these effects were abolished when RUNX1-205 overexpression was induced after Day 6 in co-cultures of hESCs and AGM-S3 cells, indicating that the inhibitory effect occurred prior to generation of hemogenic endothelial cells, while the promotive effect could be observed during the late stage of hematopoiesis. This is very similar to that of RUNX1b. Interestingly, the mRNA expression profile of RUNX1-205 during hematopoiesis was distinct from that of RUNX1b, and the protein stability of RUNX1-205 was much higher than that of RUNX1b. Thus, the function of RUNX1-205 in normal and diseased models should be further explored.
Skin and Nerve Neovascularization in POEMS Syndrome: Insights From a Small Cohort
Authors: Guibert Camille , Richard Laurence , Durand Stéphanie , Maquin Fanny , Demiot Claire , Vallat Jean-Michel , Jaccard Arnaud , Magy Laurent , Duchesne Mathilde
Published: April 2020

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome is a rare systemic disorder linked to plasma cell dyscrasia and is related to elevation of vascular endothelial growth factor (VEGF). Diagnosis is still challenging and pathophysiology unclear. Because VEGF drives neovascularization, we investigated skin and nerve vascularization in 6 patients with POEMS syndrome compared with 5 control groups of polyneuropathies and healthy subjects (n = 104) from the University Hospital of Limoges between 2009 and 2018. We evaluated loss of small and large fibers in these patients. Skin and nerve vascularization were quantified manually on immunofluorescence using vessel staining (anti-α-SMA antibody). Dermal vascularization was significantly higher in POEMS syndrome than in other groups, but unrelated to loss of small fibers and VEGF. Perineurial vascularization was higher in POEMS syndrome than in healthy controls, and was related to loss of large fibers and VEGF level. Our study highlights the existence of neovascularization in skin of patients with this rare disorder. These data suggest that skin neovascularization could be an additional biomarker to help in the diagnosis and understanding of POEMS syndrome. Moreover, nerve neovascularization, driven by VEGF overexpression, may play a role in the pathophysiology of large fiber loss in this condition.
Extensive subdural spread of a glioblastoma associated with subdural hygroma: case report
Authors: Mikhalkova Agdaliya , Hoffermann Markus
Published: April 2020

Despite its highly malignant behaviour, glioblastoma very rarely spread beside the arachnoid layer. We describe a very rare case of a 67-year-old patient with glioblastoma, who developed a recurrent subdural hygroma associated with the subdural spread of the glioblastoma, which was confirmed histologically. Possible predisposing factors and management suggestions are discussed.
Modelling a bright z = 6 galaxy at the faint end of the AGN luminosity function
Authors: Trebitsch Maxime , Volonteri Marta , Dubois Yohan
Published: April 2020

Recent deep surveys have unravelled a population of faint active galactic nuclei (AGNs) in the high-redshift Universe, leading to various discussions on their nature and their role during the Epoch of Reionization. We use cosmological radiation hydrodynamics simulations of a bright galaxy at z ∼ 6 (${M_\star } \gtrsim 10^{10}\, {\rm M}_{\odot }$) hosting an actively growing supermassive black hole to study the properties of these objects. In particular, we study how the black hole and the galaxy coevolve and what is the relative contribution of the AGNs and of the stellar populations to the luminosity budget of the system. We find that the feedback from the AGN has no strong effect on the properties of the galaxy, and does not increase the total ionizing luminosity of the host. The average escape fraction of our galaxy is around $f_{\rm esc} \sim 5{{\ \rm per\ cent}}$. While our galaxy would be selected as an AGN in deep X-ray surveys, most of the ultraviolet (UV) luminosity is originating from stellar populations. This confirms that there is a transition in the galaxy population from star-forming galaxies to quasar hosts, with bright Lyman-break galaxies with MUV around −22 falling in the overlap region. Our results also suggest that faint AGNs do not contribute significantly to reionizing the Universe.
H i absorption towards radio active galactic nuclei of different accretion modes
Authors: Chandola Yogesh , Saikia D J , Li Di
Published: April 2020

We present results of H i absorption experiment done using the Giant Metrewave Radio Telescope (GMRT) towards 27 low- and intermediate-luminosity ($P_{\rm 1.4 GHz}\, \sim 10^{23}$-1026 W Hz−1) radio active galactic nuclei (AGNs), classified as either low excitation radio galaxies (LERGs) or high excitation radio galaxies (HERGs) and with WISE colour W2[4.6 μm]−W3[12  μm]> 2. We report H i absorption detection towards seven radio AGNs, six of which are new. Combined with other sources from literature classified as LERGs or HERGs, we confirm our earlier result that compact radio AGNs with WISE colour W2−W3 > 2 have higher detection rates compared to those with W2−W3 < 2. We find that H i absorption detection rate is higher for HERGs (37.0$^{+15.8}_{-11.5}$ per cent) compared to LERGs (22.0$^{+3.9}_{-3.4}$ per cent), mainly due to a larger fraction of HERGs being gas and dust rich with a younger stellar population compared to LERGs. However, for similar compact radio structures and host galaxies with WISE colours W2−W3 > 2, we don’t find any significant difference in detection rates of two types of AGNs implying detection of H i gas may not necessarily mean high excitation mode AGN. We further analysed the kinematics towards these sources. We find that while LERGs show a wide range in the shift of centroid velocities ($\sim \, -$479 to +356 km s−1) relative to the optical systemic velocity, most of the HERGs have centroid velocity shift less than 200 km s−1, possibly due to differences in jet-interstellar medium interaction.
Ancient Genomes Reveal the Evolutionary History and Origin of Cashmere-Producing Goats in China
Authors: Cai Yudong , Fu Weiwei , Cai Dawei , Heller Rasmus , Zheng Zhuqing , Wen Jia , Li Hui , Wang Xiaolong , Alshawi Akil , Sun Zhouyong , Zhu Siqi , Wang Juan , Yang Miaomiao , Hu Songmei , Li Yan , Yang Zhirui , Gong Mian , Hou Yunan , Lan Tianming , Wu Kui , Chen Yulin , Jiang Yu , Wang Xihong
Published: April 2020

Goats are one of the most widespread farmed animals across the world; however, their migration route to East Asia and local evolutionary history remain poorly understood. Here, we sequenced 27 ancient Chinese goat genomes dating from the Late Neolithic period to the Iron Age. We found close genetic affinities between ancient and modern Chinese goats, demonstrating their genetic continuity. We found that Chinese goats originated from the eastern regions around the Fertile Crescent, and we estimated that the ancestors of Chinese goats diverged from this population in the Chalcolithic period. Modern Chinese goats were divided into a northern and a southern group, coinciding with the most prominent climatic division in China, and two genes related to hair follicle development, FGF5 and EDA2R, were highly divergent between these populations. We identified a likely causal de novo deletion near FGF5 in northern Chinese goats that increased to high frequency over time, whereas EDA2R harbored standing variation dating to the Neolithic. Our findings add to our understanding of the genetic composition and local evolutionary process of Chinese goats.
Defending Comprehensive Tobacco Control Policy Implementation in Nepal From Tobacco Industry Interference (2011–2018)
Authors: Bhatta Dharma N , Crosbie Eric , Bialous Stella A , Glantz Stanton
Published: April 2020

Introduction

Nepal passed a comprehensive tobacco control law in 2011. Tobacco control advocates successfully countered tobacco industry (TI) interference to force implementation of law.

Aims and Methods

Policy documents, news stories, and key informant interviews were triangulated and interpreted using the Policy Dystopia Model (PDM).

Results

The TI tried to block and weaken the law after Parliament passed it. Tobacco control advocates used litigation to force implementation of the law while the TI used litigation in an effort to block implementation. The TI argued that tobacco was socially and economically important, and used front groups to weaken the law. Tobacco control advocates mobilized the media, launched public awareness campaigns, educated the legislature, utilized lawsuits, and monitored TI activities to successfully counter TI opposition.

Conclusions

Both tobacco control advocates and the industry used the discursive and instrumental strategies described in the PDM. The model was helpful for understanding TI activities in Nepal and could be applied to other low- and middle-income countries. Civil society, with the help of international health groups, should continue to track TI interference and learn the lessons from other countries to proactively to counter it.

Implications

The PDM provides an effective framework to understand battles over implementation of a strong tobacco control law in Nepal, a low- and middle-income country. The TI applied discursive and instrumental strategies in Nepal in its efforts to weaken and delay the implementation of the law at every stage of implementation. It is important to continuously monitor TI activities and learn lessons from other countries, as the industry often employ the same strategies globally. Tobacco control advocates utilized domestic litigation, media advocacy, and engaged with legislators, politicians, and other stakeholders to implement a strong tobacco control law. Other low- and middle-income countries can adapt these lessons from Nepal to achieve effective implementation of their laws.
Far Lateral Craniotomy and Occlusion In Situ of a Lateral Medullary Arteriovenous Malformation: 2-Dimensional Operative Video
Authors: Gandhi Sirin , Mascitelli Justin R , Cavallo Claudio , Tayebi Meybodi Ali , Lawton Michael T
Published: April 2020

Lateral medullary arteriovenous malformations (AVMs) are located in the pia on the lateral medullary surface.
1
They are supplied by arterial feeders from the V4 segment of the vertebral artery or posterior inferior cerebellar artery. A 64-yr-old man presented with leg spasms and progressively worsening gait. Angiography demonstrated a lateral medullary AVM. Patient consent was obtained for the surgical treatment of this lesion. Owing to its eloquent location, an occlusion in situ was performed without resection.
1,2
This technique relies on the interruption of the arterial blood supply and occlusion of the draining vein to occlude the AVM. Intraoperative neurophysiological monitoring of motor and somatosensory evoked potentials was used, and the elimination of arteriovenous shunt flow was confirmed using indocyanine green videoangiography. Occlusion in situ preserves the flow to the delicate brainstem perforators and is safer than resection in selected cases like this one. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.
Exploring the views of planners and public health practitioners on integrating health evidence into spatial planning in England: a mixed-methods study
Authors: Ige-Elegbede Janet , Pilkington Paul , Bird Emma L , Gray Selena , Mindell Jennifer S , Chang Michael , Stimpson Aimee , Gallagher Dominic , Petrokofsky Carl
Published: April 2020

Background

This study explored barriers and facilitators to integrating health evidence into spatial planning at local authority levels and examined the awareness and use of the Public Health England ‘Spatial Planning for Health’ resource.

Methods

A sequential exploratory mixed-methods design utilized in-depth semi-structured interviews followed by an online survey of public health, planning and other built environment professionals in England.

Results

Views from 19 individuals and 162 survey responses revealed high awareness and use of the Spatial Planning for Health resource, although public health professionals reported greater awareness and use than other professionals. Key barriers to evidence implementation included differences in interpretation and the use of ‘evidence’ between public health and planning professionals, lack of practical evidence to apply locally and lack of resource and staff capacity in local authorities. Key facilitators included integrating health into the design of local plans, articulating wider benefits to multiple stakeholders and simplifying presenting evidence (regarding language and accessibility).

Conclusion

The Spatial Planning for Health resource is a useful resource at local authority level. Further work is needed to maximize its use by built environment professionals. Public health teams need support, capacity and skills to ensure that local health and well-being priorities are integrated into local planning documents and decisions.
Development and validation of an alternative ankylosing spondylitis disease activity score when patient global assessment is unavailable
Authors: Ortolan Augusta , Ramiro Sofia , van Gaalen Floris , Kvien Tore K , Landewe Robert B M , Machado Pedro M , Ruyssen-Witrand Adeline , van Tubergen Astrid , Bastiaenen Caroline , van der Heijde Désirée
Published: April 2020

Objective

To develop an alternative Ankylosing Spondylitis Disease Activity Score (ASDAS) to be used in research settings in axial SpA (axSpA) when Patient Global Assessment (PGA) is unavailable in databases.

Methods

Longitudinal data from four axSpA cohorts and two randomized controlled trials were combined. Observations were randomly split in a development (N = 1026) and a validation cohort (N = 1059). Substitutes of PGA by BASDAI total score, single or combined individual BASDAI questions, and a constant value, were established in the development cohort. Conversion factors for each substitute were defined by Generalized Estimating Equations, obtaining seven ‘alternative’ formulae. Validation was performed in the validation cohort according to the OMERACT filter, taking into consideration: (i) truth (agreement with original-ASDAS in the continuous score, by intraclass correlation coefficient and in disease activity states, by weighted kappa); (ii) discrimination [standardized mean difference of ASDAS scores between high/low disease activity states defined by external anchors, e.g. Patient Acceptable Symptom State; agreement (kappa) in the percentage of patients reaching ASDAS improvement criteria according to alternative vs original formulae]; and (iii) feasibility.

Results

Comparing various options, alternative-ASDAS using BASDAI total as PGA replacement proved to be: truthful (intraclass correlation coefficient = 0.98, kappa = 0.90), discriminative [ASDAS scores between Patient Acceptable Symptom State no/yes: standardized mean difference = 1.37 (original-ASDAS standardized mean difference = 1.43); agreement with original-ASDAS in major improvement/clinically important improvement criteria: kappa = 0.93/0.88] and feasible (BASDAI total often available, as questions required for the ASDAS; conversion coefficient ≈ 1).

Conclusion

Alternative-ASDAS using BASDAI total score as PGA replacement is the most truthful, discriminative and feasible instrument.
Topical Application of the Antimicrobial Agent Triclosan Induces NLRP3 Inflammasome Activation and Mitochondrial Dysfunction
Authors: Weatherly Lisa M , Shane Hillary L , Friend Sherri A , Lukomska Ewa , Baur Rachel , Anderson Stacey E
Published: April 2020

5-Chloro-2-(2,4-dichlorophenoxy)phenol (triclosan) is an antimicrobial chemical widely used in consumer household and clinical healthcare products. Human and animal studies have associated triclosan exposure with allergic disease. Mechanistic studies have identified triclosan as a mitochondrial uncoupler; recent studies suggest that mitochondria play an important role in immune cell function and are involved in activation of the NLRP3 inflammasome. In this study, early immunological effects were evaluated via NLRP3 activation following dermal triclosan application in a BALB/c murine model. These investigations revealed rapid caspase-1 activation and mature IL-1β secretion in the skin and draining lymph nodes (dLNs) after 1.5% and 3% triclosan exposure. Correspondingly, pro-Il-1b and S100a8 gene expression increased along with extracellular ATP in the skin. Peak gene expression of chemokines associated with caspase-1 activation occurred after 2 days of exposure in both skin tissue and dLNs. Phenotypic analysis showed an increase in neutrophils and macrophages in the dLN and myeloid and inflammatory monocytes in the skin tissue. Triclosan also caused mitochondrial dysfunction shown through effects on mitochondrial reactive oxygen species, mass, mitochondrial membrane potential, and mitochondrial morphology. These results indicate that following triclosan exposure, activation of the NLRP3 inflammasome occurs in both the skin tissue and dLNs, providing a possible mechanism for triclosan’s effects on allergic disease and further support a connection between mitochondrial involvements in immunological responses.
Upregulation of Prokineticin 2 and Prokineticin Receptor 1 in low shear stress‐induced vascular remodeling in mice
Authors: Jiang Zhilong , Huang Qi , Jiang Yue , Liao Qingchuan , Zhang Youzhi
Published: April 2020

Low shear stress induced vascular remodeling emerging atherosclerosis. Prokineticin 2 (PK2) via prokineticin receptor 1(PKR1), is an angiogenic factor. However, little is known about the effect of the low shear stress on PK2/PKR1 signaling in vascular remodeling. The present study aimed that the PK2/PKR1 signaling was involved in low shear stress‐induced vascular remodeling in vivo. Higher protein expression of PK2 and PKR1 was examined in the aortic arch exerting low shear stress in physiological conditions. Further, in pathological conditions, murine model of partial carotid ligation exerted low shear stress, which induced neointima formation with media and adventitia growth, emerging vascular remodeling. It was worth noting that positive staining of PK2 distributed more in neointima area in ligated mice. Lastly, ligated carotid arteries also exerted higher protein expression of PK2 and PKR1. Thus, PK2/PKR1 signaling was involved in the low shear stress‐ induced vascular remodeling in physiological curvature of aortic arch and pathological ligation, which attempted to analyze a potential role of PK2/PKR1 signaling in vascular remodeling associated with atherosclerosis.

Support or Funding Information

The National Natural Science Foundation of China (NO. 81603110).
Mitochondrial Dysfunction Contributes to Germ Cell Apoptosis via the JNK/p53/ survivin Pathway
Authors: Al-Maghrebi May , Fadel Fatemah , Al-Kandari Nora , Khashab Farah , Al-Saleh Farah
Published: April 2020

The aim is to show whether the c‐Jun N‐terminal kinases (JNK) signaling is a regulator of oxidative DNA damage, germ cell apoptosis (GCA) and mitochondrial dysfunction during testicular ischemia reperfusion injury (tIRI) using the JNK inhibitor SP600125. Male Sprague‐Dawley rats (n=36) were equally divided into 3 groups: sham, tIRI only and tIRI + SP600125 (15 mg/Kg, i.p.). Testicular ischemia was induced for 1 hour followed by 4 hours reperfusion prior to animal sacrifice. Spermatogenesis was evaluated by light microscopy using the Johnsen’s scoring system. Expression of oxidative stress and GCA genes and proteins were evaluated by real‐time PCR and colorimetric assays, respectively. Activation of the JNK/p53/survivin signaling pathway was detected by immunofluorescence (IF) staining. Indicators of mitochondrial dysfunction were examined by Western blot and colorimetric assays. In comparison to sham group, the tIRI testes showed a significant decrease in the antioxidant activity of superoxide dismutase, which was associated with increased lipid and protein oxidation products. Oxidative DNA damage was reflected by a significant increase in the number of single and double DNA strand breaks and increased concentration of 8‐OHdG DNA adducts. Spermatogenic damage was associated with the activation of caspases 9 and 3 and an elevated Bax to Bcl2 ratio. This was also accompanied by a significantly heightened IF expression of the phosphorylated forms of JNK and p53 paralleled with the down‐regulation of survivin. Mitochondrial dysfunction was reflected by NADH depletion, overexpression of uncoupling protein 2 and increased levels of cytochrome c protein. Such tIRI‐induced modulations were all attenuated by SP600125 treatment prior to reperfusion. In conclusion, mitochondrial dysfunction could contribute to GCA during tIRI under the control of the JNK/p53/survivin signaling pathway.

Support or Funding Information

This study was supported by Kuwait University Grants YM 15/17 (College of Graduate Studies ) and SRU02/13 (Research Administration).
Exo1‐independent MMR at euchromatin is error‐prone and involves Pol ζ and Rev1
Authors: Gujar Vaibhavi V. , Dahal Basanta K. , Kadyrova Lyudmila K. , Kadyrov Farid
Published: April 2020

Genomes are under a constant attack by exogenous and endogenous agents that cause various forms of DNA damage. If the DNA damage is left unrepaired, it leads to a mutation. The mutation might alter the cell’s phenotype and trigger a disease. DNA repair processes and the high‐fidelity DNA replication play an important role in maintaining genome integrity. DNA mismatch repair (MMR) is a key DNA repair process that corrects DNA replication errors that have escaped proofreading. MMR can occur in an error‐free and error‐prone manner. Both error‐free and error‐prone MMR mechanisms have a strong impact on human health. Previous research has established that the exonuclease Exo1 is a non‐essential MMR factor that participates in MMR by removing the DNA mismatch in a 5′→3′ hydrolytic reaction. We have found that the Exo1‐independent MMR at euchromatin is error prone and occurs in a DNA polymerase (Pol) ζ‐ and DNA polymerase Rev1‐dependent manner. Surprisingly, the Pol ζ‐ and Rev1‐dependent error‐prone MMR does not involve PCNA K164 residue and ubiquitin ligase Siz1, factors that cooperate with Pol ζ in other DNA transactions. Our results have suggested that a novel error prone MMR mechanism is activated in response to the loss of a non‐essential MMR factor.

Support or Funding Information

National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM095758

Spontaneous CAN1 mutation rates in euchromatic CAN1 gene

Genotype

CAN1 mutation rate

Absolute rate (×10−8)

95% CI (×10−8)

Relative rate

Wild‐type

19

16–24

1

exo1Δ

120n,q

100–190

6

pol30‐K164R

24

18–31

1

msh2Δ

600p

450–800

32

pol30‐K164R msh2Δ

550p

400–650

29

pol30‐K164R exo1Δ

120q

100–190

6

siz1Δ

29

17–42

1.5

exo1Δ siz1Δ

120n

73–160

6

The mutant strains are isogenic to E134 (wild type). CI represents 95% confidence interval. The mutation rates marked n,p,q do not statistically differ from each other. p=0.5, 0.06, 0.1 respectively.
Anti‐adipogenic Effects of Anthocyanin‐enriched Riceberry Rice Extract (Oryza sativa L.) in 3T3‐L1 Preadipocytes
Authors: Kongthitilerd Phutthida , Cheng Henrique , Suantawee Tanyawan , Adisakwattana Sirichai
Published: April 2020

Riceberry rice containing anthocyanins is a new pigmented variety of rice from Thailand with various biological activities such as antioxidant, anti‐inflammatory, anti‐hyperglycemia, and anti‐cancer. The present study aimed to investigate the effects of Riceberry rice extract (RBE) on adipogenic differentiation in mice 3T3‐L1 cells. RBE was obtained using water followed by freeze dryer lyophilization. Then, total phenolic compounds, total anthocyanin contents, and major anthocyanins in RBE were analyzed. The 3T3‐L1 preadipocytes were cultured in differentiation media and supplemented with RBE 1, 10, 20 and 50 μg/ml concentrations. After 8 days of incubation, cell viability, mature adipocyte number, triglyceride levels, and glucose uptake were determined. The mRNA expression of transcription factors and adipogenic genes including PPARγ, C/EBPα, FasN, ACC, aP2, AdipoQ, Leptin, Resistin, InsR, and Glut4 were also examined. The results revealed that RBE contained total phenolic compounds (63.33±2.4 mg gallic acid equivalent/g extract) and total anthocyanin (10.13±0.14 mg cyanidin‐3‐glucoside/g extract). The anthocyanins detected were cyanidin‐3‐glucoside and peonidin‐3‐glucoside. In 3T3‐L1 cells, RBE significantly reduced the number of mature adipocytes and triglyceride accumulation in a concentration‐dependent manner. In addition, the treatment of 3T3‐L1 cells with the various RBE concentrations did not cause cytotoxicity. Furthermore, the mRNA expression of major transcription factors, PPARγ and C/EBPα were significantly downregulated by RBE (20 and 50 μg/ml) in both early phase (day 3) and late phase (day 8) of adipogenesis. At 50 μg/ml RBE, there was a significant reduction in mRNA expression levels of all adipogenic genes. Interestingly, RBE (10, 20 and 50 μg/ml) significantly reduced glucose uptake into adipocytes via downregulated InsR and Glut4 mRNA expression. These findings suggest that RBE could potentially be used as an anti‐obesity agent by inhibiting adipogenesis and reducing glucose uptake in adipocytes.

Support or Funding Information

Dutsadi Phiphat Scholarship from Chulalongkorn University, LSU‐SVM CORP
Teacher Knows Best: Student‐requested YouTube‐based Pre‐matriculation Resources do not Alleviate Student Anxiety in Anatomy
Authors: Attardi Stefanie M. , Gould Douglas J. , Pratt Rebecca L. , Roach Victoria A.
Published: April 2020

Rationale

Emerging trends in the literature report student preference for and dependence on video‐based resources. These sentiments were echoed by students at Oakland University William Beaumont School of Medicine (OUWB) through focus groups and course evaluations. These data supported the creation of a series of YouTube videos, to deliver introductory information (such as the structure of the anatomy curriculum, facilities, and resources) to students prior to their matriculation. The aim of this investigation was to assess if anatomy pre‐matriculation videos would affect students’ anatomy specific state anxiety levels.

Methods

Two professionally‐produced YouTube videos covering introductory topics, were distributed to 2019 matriculants. These videos were designed according to Meyer’s 12 Principles of Multimedia Learning, and in‐line with Cognitive Load Theory. To evaluate the longitudinal impact of the videos, students completed the State‐Trait Anxiety Inventory and a demographic questionnaire in 2018 (n=120; 94% response rate) and 2019 (n=118; 95% response rate), with the 2018 cohort serving as a historical control for comparison.

Results

These data confirmed equivalence between the two groups in terms of general trait anxiety between 2018 and 2019 (Independent Samples Mann‐Whitney U; p = 0.854). Equivalence was observed between the two cohorts in terms of anatomy specific state anxiety, even when student video exposure was controlled for (Independent Samples Kruskall‐Wallace; p = 0.495). These data did confirm a long‐held suspicion among educators, revealing that anatomy specific state anxiety is significantly lower in those students with prior anatomy exposure (Independent Samples Mann‐Whitney U; p=0.006). Further inquiry into students’ prior anatomy experience identified that individuals with post‐secondary dissection experience are significantly less anxious than their peers without anatomical experience (Independent Samples Kruskall‐Wallace, with Bonferroni correction; p=0.023).

Conclusions

These results may serve as a cautionary tale to educators who are considering curricular reform in anatomy with the intention of reducing student anxiety. While student preference for video‐based instructional materials may be prevalent, videos fail to prepare students for the psychological impact of the dissection experience.

Support or Funding Information

Department of Foundational Medical Studies at Oakland University William Beaumont School of Medicine
A Comparison of the Effects of Several Agents Found in Common Foodstuffs on Cholecystokinin‐induced Tension in Guinea Pig Gallbladder Strips
Authors: Kline Loren
Published: April 2020

17beta‐estradiol (E2) has an inhibitory effect on the contractility of gastrointestinal smooth muscle, including the gallbladder. The inhibition of extracellular Ca2+ entry mediated E2‐induced relaxation of either CCK‐ or KCl‐induced tension in male and female guinea pig gallbladder strips. Chrysin, an endocrine disrupter, and luteolin are flavones. Resveratrol is a non‐flavonoid phytoestrogen, quercetin a phytoestrogen, and curcumin a diarylheptanoid. All are natural constituents of common foodstuffs. All relaxed CCK‐induced tension in male guinea pig gallbladder strips. Luteolin, quercetin, curcumin, resveratrol, and chrysin relaxed the CCK‐induced tension in the gallbladder strips by blocking extracellular Ca2+ entry and intracellular Ca2+ release. The effect of luteolin was also mediated by the PKA/cAMP system while quercetin also involved NO. In addition to the Ca2+ effects, the effects of curcumin and chrysin involved the PKC system. The purpose of this study was to determine which of these agents was most potent in relaxing the CCK‐induced tension in gallbladder strips. Luteolin was the most potent (98.2±2.0%), chrysin (45.4±3.7%), resveratrol (41.1±4.0%), quercetin (42.9±3.0%), curcumin (39.4±4.0%), and E2 (64.5±2.3%) when using 50 mM of each agent. Luteolin had the largest effect at all the other concentrations used (10, 25, 50, and 100 mM) in relaxing CCK‐induced tension. Curcumin was the least potent. There was no significant difference in the amount of relaxation induced by chrysin, resveratrol, and quercetin were compared. The effect of E2 was second only to luteolin.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
Emerging role of the unfolded protein response in ER membrane homeostasis
Authors: Ernst Robert
Published: April 2020

All cells must balance the production of proteins and lipids to maintain membrane functions. Imbalances in protein folding and lipid metabolism cause endoplasmic reticulum (ER) stress, which is associated with a wide range of complex diseases including diabetes and neurodegeneration. The central homeostatic program of the ER is the unfolded protein response (UPR), which senses accumulating unfolded proteins to control global protein synthesis, chaperone abundance, and lipid metabolism. Through these mechanisms, the UPR centrally controls decisions between cell survival, adaptation, and apoptosis. We have shown that perturbations of the cellular lipidome, referred to as lipid bilayer stress, are equally potent as unfolded proteins in activating the UPR. Using an interdisciplinary platform to study highly flexible membrane property sensors, we could show that an aberrant stiffening of the ER membrane is sufficient to activate the UPR by driving the sensor protein Ire1 into oligomers via a hydrophobic mismatch‐based mechanism. We show in vitro that the binding of soluble, unfolded proteins to Ire1 is dramatically affected by the composition of the lipid environment. Furthermore, we show that chronic ER stress is initiated and maintained by a membrane‐based mechanism: Ire1 perpetuates a vicious cycle, which leads to an accumulation of saturated lipids, massive changes of ER morphology, and dramatically increased rates of cell death. This vicious cycle can be interrupted by a single point mutation in the transmembrane domain of Ire1 thereby restoring ER morphology and cellular fitness. Together, we provide a radically new, membrane‐based perspective on the role of the UPR in acute and chronic ER stress.

Support or Funding Information

Our work is supported by the DFG (SFB894) and the VW foundation (Life?, #93089).
The Role of Metabolism in Modulating Radiation Fibrosis & Lymphedema
Authors: Liu Fei-Fei
Published: April 2020

With the improvements in cancer diagnosis and therapy, clinical outcome has increased substantially, to the extent that by 2026, there will be >20M cancer survivors in the United States alone. The majority of survivors fare well; however, there is a significant proportion of patients who continue to experience the aftermath of their treatments such as radiation fibrosis (RF) or lymphedema. Until recently, there has been little understanding of the biological basis of RF, which is defined by the aberrant accumulation of extracellular matrix (ECM), leading to reduced tissue elasticity, and potential loss of organ function. The regulation of ECM production and degradation is a complex process, mediated through the production of a myriad of cytokines such as TGFB, and environmental conditions such as hypoxia. We have recently identified that metabolic dysregulation, and in particular, downregulation of fatty acid oxidation (FAO) is a key pathway driving the production and reducing the degradation of collagen, the predominant component of the ECM. Conversely, upregulation of PPAR signaling, a major mediator of FAO, reduced transcription of key ECM genes; whilst increasing internalization and degradation of extracellular collagen. Furthermore, CD36, a membrane transporter of long chain fatty acids, was discovered to play a critical role in regulating the trafficking of collagen and lysosomal degradation. Finally, using a pharmacogenomics approach, caffeic acid was identified to be a compound which can be systemically administered, and reduced RF in pre‐clinical models.

These data, along with other reports in the literature, strongly point towards the use of metabolic drugs as a therapeutic strategy by which we can mitigate the deleterious effects of RF on cancer patients. More recently, we have also uncovered that metabolic dysregulation likely plays a similar role in the development of lymphedema, a common long‐term toxicity in women after breast cancer therapy. Finally, these findings have broad application to the increasing burden of fibrosis beyond cancer, wherein end‐stage renal, liver, cardiac, and pulmonary fibrosis accounts for up to 1/3 of the deaths around the world.

Support or Funding Information

The work is funded in part by the Canadian Institutes of Health Research, Genome Canada, the Canadian Cancer Society Research Institute, the Physicians Services Incorporated Foundation, the Harry Barberian Research Scholarship, the Mariano Elia Chair in Head and Neck Cancer Research, the Peter and Shelagh Godsoe Chair in Radiation Medicine, the Princess Margaret Cancer Centre Head and Neck Translational Program, the Princess Margaret Cancer Centre Radiation Medicine Program and the Ottawa Heart Institute Research Corporation, as well by philanthropic funding from the Jesse Rasch Foundation, the Wharton family, Joe’s Team and the Ministry of Health and Long‐Term Care.
Cellular Machineries Devoted to Rubisco – the Most Abundant Enzyme
Authors: Hayer-Hartl Manajit
Published: April 2020

Photosynthesis is a fundamental process in biology as it converts solar energy into chemical energy and thus, directly or indirectly, fuels all life on earth. The chemical energy is used to fix atmospheric CO2 and produce reduced carbon compounds in the Calvin‐Benson‐Bassham cycle. The key enzyme for this process in all photosynthetic organisms is ribulose‐1,5‐bisphosphate carboxylase/oxygenase (Rubisco), which is responsible for the conversion of an estimated amount of ~1011 tons of CO2 per annum into organic material. Rubisco is the most abundant enzyme in nature, owing in part to its low catalytic turnover rate and limited specificity for CO2 versus O2.

Recent forecasts suggest that global food production will need to rise more than 25 % by 2050 to meet the ever increasing demand. Engineering a catalytically more efficient Rubisco enzyme and/or compartmentalizing Rubisco in higher plants could contribute to reaching that goal. However, the complex nature of Rubisco’s folding and assembly pathway has made these efforts exceedingly challenging. In my talk I will review recent progress in understanding the complex chaperone machineries that are necessary for the efficient biogenesis of this most abundant enzyme.
BSCL2/Seipin in Lipid Catabolism and Lipodystrophy
Authors: Chen Weiqin
Published: April 2020

Adipose tissue is the body’s largest endocrine organ that plays a major role in systemic energy homeostasis and thermoregulation. Mutations in BSCL2 (a.k.a. Seipin) gene underlie human type 2 Berardinelli‐Seip Congenital Lipodystrophy (BSCL2) disease with near absence of adipose tissue at birth and severe metabolic diseases. Global Bscl2−/− mice largely recapitulate human BSCL2 lipodystrophy with severe insulin resistance and organomegly. Seipin is known for its critical role in controlling lipid droplet (LD) assembly at the LD‐forming subdomain of the endoplasmic reticulum (ER), but its exact functional role has been enigmatic. Our laboratory has focused on elucidating the mechanisms through which Seipin regulates adipocyte differentiation thus lipodystrophy and its associated metabolic diseases. This presentation will focus on the role of Seipin in mediating cAMP/PKA signaling to regulate lipid catabolism in mature white adipose tissue (WAT) and during perinatal brown adipose tissue (BAT) development which exert profound effect on metabolic homeostasis and thermogenesis. We will also explore the role of Seipin as a key node that links ATGL‐mediated lipolysis to govern mitochondrial dynamics and function in WAT, BAT and heart. These findings will highlight novel roles for Seipin in cellular and organismal biology and its importance in human health.

Support or Funding Information

This work was supported by NIH grant 1R01HL132182‐01.
SPTLC1 Mutations Associated with Early Onset Amyotrophic Lateral Sclerosis
Authors: Dunn-Giroux Teresa , Gable Kenneth , Gupta Sita D. , Mohassel Payam , Nalls Matthew , Donkervoort Sandra , Piccus Zoe , Majumder Saurav , Proia Richard L. , Le Pichon Claire E. , Bönnemann Carsten G. ,   SPTLC1-related ALS Study Group
Published: April 2020

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of lower and upper motor neurons leading to progressive muscle weakness, swallowing difficulties, and respiratory insufficiency that ultimately causes death usually within 2–5 years of diagnosis. The majority of ALS cases occur sporadically, but a significant number (>10%) display Mendelian inheritance. Very recently, four unique de novo or dominantly inherited SPTLC1 mutations associated with early childhood‐onset ALS without clinical sensory involvement have been identified in eight independent families. SPTLC1 encodes a subunit of serine palmitoyltransferase (SPT), the committed and rate‐limiting enzyme of sphingolipid synthesis. The ALS mutations flank the first membrane spanning domain of SPTLC1, which is not required for ER targeting, association with the SPTLC2 and ssSPT subunits, or enzymatic activity. Rather, this domain is critical for binding of the ORMDL proteins that negatively regulate SPT. This suggested that the SPTLC1 mutations might interfere with homeostatic regulation of SPT and that elevated de novo sphingolipid synthesis could underlie the ALS disease pathology. Our studies reveal that these highly penetrant SPTLC1 mutations do indeed abrogate negative regulation of SPT by the ORMDL proteins and result in elevated levels of sphingolipids. Using cultured cells, patient fibroblasts, iPSC‐induced MNs, and mouse models, we are investigating the importance of ORMDL regulation in the maintenance of sphingolipid homeostasis and the mechanisms responsible for sphingolipid mediated motor neuron death. Significantly, the ALS SPTLC1 mutations confer disease pathology by a distinctly different mechanism than the previously characterized SPTLC1 and SPTLC2 mutations associated with hereditary sensory and autonomic neuropathy type 1 (HSAN1). Whereas the ALS mutations result in elevated levels of canonical sphingolipids, the HSAN1 mutations, which compromise amino acid substrate selectivity of SPT, cause accumulation of atypical deoxy‐sphingoid bases that are implicated in neuronal cell death.