bluuebunny/crossref_metadata_2025 huggingface dataset:
Short‐term interleukin‐37 treatment improves vascular endothelial function, endurance exercise capacity, and whole‐body glucose metabolism in old mice
Authors: Ballak Dov B. , Brunt Vienna E. , Sapinsley Zachary J. , Ziemba Brian P. , Richey James J. , Zigler Melanie C. , Johnson Lawrence C. , Gioscia‐Ryan Rachel A. , Culp‐Hill Rachel , Eisenmesser Elan Z. , D'Alessandro Angelo , Dinarello Charles A. , Seals Douglas R.
Published: November 2019

Aging is associated with vascular endothelial dysfunction, reduced exercise tolerance, and impaired whole‐body glucose metabolism. Interleukin‐37 (IL‐37), an anti‐inflammatory cytokine of the interleukin‐1 family, exerts salutary physiological effects in young mice independent of its inflammation‐suppressing properties. Here, we assess the efficacy of IL‐37 treatment for improving physiological function in older age. Old mice (26–28 months) received daily intraperitoneal injections of recombinant human IL‐37 (recIL‐37; 1 µg/200 ml PBS) or vehicle (200 ml PBS) for 10–14 days. Vascular endothelial function (ex vivo carotid artery dilation to increasing doses of acetylcholine, ACh) was enhanced in recIL‐37 vs. vehicle‐treated mice via increased nitric oxide (NO) bioavailability (all p < .05); this effect was accompanied by enhanced ACh‐stimulated NO production and reduced levels of reactive oxygen species in endothelial cells cultured with plasma from IL‐37‐treated animals (p < .05 vs. vehicle plasma). RecIL‐37 treatment increased endurance exercise capacity by 2.4‐fold, which was accompanied by a 2.9‐fold increase in the phosphorylated AMP‐activated kinase (AMPK) to AMPK ratio (i.e., AMPK activation) in quadriceps muscle. RecIL‐37 treatment also improved whole‐body insulin sensitivity and glucose tolerance (p < .05 vs. vehicle). Improvements in physiological function occurred without significant changes in plasma, aortic, and skeletal muscle pro‐inflammatory proteins (under resting conditions), whereas pro‐/anti‐inflammatory IL‐6 was greater in recIL‐37‐treated animals. Plasma metabolomics analysis revealed that recIL‐37 treatment altered metabolites related to pathways involved in NO synthesis (e.g., increased L‐arginine and citrulline/arginine ratio) and fatty acid metabolism (e.g., increased pantothenol and free fatty acids). Our findings provide experimental support for IL‐37 therapy as a novel strategy to improve diverse physiological functions in old age.
Molecular and geographical heterogeneity of hemoglobinopathy mutations in Azerbaijanian populations
Authors: Aliyeva Gunay , Asadov Chingiz , Mammadova Tahira , Gafarova Surmaya , Guliyeva Yegana , Abdulalimov Eldar
Published: November 2019

With the carrier rate of 4%–8.6%, β‐thalassemia is one of the most prevalent hereditary disorders in Azerbaijan. Taking into consideration the high frequency of β‐thalassemia as well as the occurrences of several other hemoglobinopathies, we conducted a large genotyping study to investigate the mutational background of common hemoglobinopathies in the country. Α‐ and β‐globin genes were evaluated in the carriers of mutations identified via hematological indices and hemoglobin fractions (n = 1,757). Genotyping of β‐thalassemia carriers identified through population screening revealed 32 mutations, with codon 8 [–AA]–34.96%, IVS‐II‐1 [G > A]–16.35%, and IVS‐I‐110 [G > A]–10.12% leading the spectrum. Analysis of associations of β‐thalassemia mutations with geographical regions of the country identified the strongest association between codon 8 [–AA] and Shaki‐Zaqatala, and codon 5 [–CT] in Mountainous Shirvan regions (ri > 6.00; p < 0.05). HbS, HbD‐Punjab, and HbE were the most prevalent among our variant hemoglobin cohort, commonly inherited in compounds with β‐thalassemia than in the homozygous state. We identified nine α‐thalassemia mutations, 20.5 kb and 3.7 kb deletions together accounting for 74% of the spectrum. Point mutations of α‐thalassemia were less common among our observations and were mainly inherited in compounds with deletions. Our results allow a better understanding of the wide spectrum of mutations in Azerbaijan and highlights the high heterogeneity of hemoglobinopathies in the local population.
Toll‐like receptor 4 polymorphisms were associated with low serum pro‐inflammatory cytokines in BCG osteitis survivors
Authors: Korppi Matti , Teräsjärvi Johanna , Lauhkonen Eero , Huhtala Heini , Nuolivirta Kirsi , He Qiushui
Published: November 2019

Aim

The aim of the study was to evaluate the association of Toll‐like receptor 4 (TLR4) gene variations with osteitis risk after Bacillus Calmette‐Guérin (BCG) vaccination given at birth and with serum cytokine levels measured in adulthood.

Methods

We determined the TLR4 rs4986790 single‐nucleotide polymorphism (SNP) in 132 study subjects with BCG osteitis in infancy and compared the genotype distributions and allele frequencies between them and population controls. Serum concentrations of 11 cytokines measured in adulthood were compared between study subjects with the wild vs variant TLR4 rs4986790 genotype.

Results

The genotypes and allele frequencies of the TLR4 rs4986790 SNP did not differ between BCG osteitis cases and population controls. Instead, subjects with the variant genotype presented with lower serum interleukin (IL) concentrations of the pro‐inflammatory IL‐6, IL‐17A and IL‐12 cytokines and with marginally lower interferon‐γ concentrations, but with higher serum anti‐inflammatory IL‐4 concentration. The results concern also the TLR4 rs4986791, since these two SNPs are co‐segregating in the Finnish population.

Conclusion

The findings suggest that TLR4 has no significant role in the emergence of osteitis after newborn BCG vaccination, but the variant genotypes of the TLR4 rs4986790 and rs4986791 may impair the production of pro‐inflammatory cytokines.
Discovery of N‐(2‐(Benzylamino)‐2‐oxoethyl)benzamide analogs as a novel scaffold of pancreatic β‐cell protective agents against endoplasmic reticulum stress
Authors: Eeda Venkateswararao , Herlea‐Pana Oana , Lim Hui‐Ying , Wang Weidong
Published: November 2019

Endoplasmic reticulum (ER) stress‐induced pancreatic β‐cell dysfunction and death play important roles in the development of diabetes. The 1,2,3‐triazole derivative 1 is one of only a few structures that have thus far been identified that protect β cells against ER stress. However, this compound has narrow activity range and limited aqueous solubility. To overcome these, we designed and synthesized a new scaffold in which the triazole pharmacophore was substituted with a glycine‐like amino acid. Structure–activity relationship studies on this scaffold identified a N‐(2‐(Benzylamino)‐2‐oxoethyl)benzamide analog WO5m that possesses β‐cell protective activity against ER stress with much improved potency (maximal activity at 100% with EC50 at 0.1 ± 0.01 µm) and water solubility. Identification of this novel β‐cell protective scaffold thus provides a new promising modality for the treatment of diabetes.
Treatment with a platelet‐activating factor receptor antagonist improves hemodynamics and reduces epinephrine requirements, in a lethal rodent model of anaphylactic shock
Authors: Tacquard Charles , Oulehri Walid , Collange Olivier , Garvey Lene H. , Nicoll Susan , Tuzin Nicolas , Geny Bernard , Mertes Paul M.
Published: November 2019

Background

In some cases, anaphylactic shock (AS) is still lethal, despite rapid use of epinephrine. High doses of epinephrine are associated with severe complications. Platelet‐activating factor (PAF) is secreted in massive amounts during AS, and a high plasma level is correlated with increased AS severity.

Objective

To assess the effect of ABT‐491, a PAF‐receptor antagonist and possible adjunct treatment, alone or in combination with epinephrine during AS.

Methods

AS was induced by intravenous injection of 1 mg ovalbumin into ovalbumin‐sensitized rats. Rats were then randomly assigned to 5 groups (n = 10 per group): SHAM (vehicle only), SHOCK (no treatment), ABT (ABT‐491 1 mg/kg), EPI (epinephrine 5 µg as a bolus then 10 µg kg−1 min−1 by continuous infusion, followed by a reducing protocol) and EPI‐ABT (both treatments).

Results

Ovalbumin injection resulted in a severe decrease in mean arterial pressure, left ventricular inotropy (max dP/dt) and left ventricular shortening fraction (LVSF). All rats from the ABT group survived until the end of the experiment. ABT‐491 prevented the LVSF decrease observed in the SHOCK group (at T15: ABT 50% ± 11% vs SHOCK 36% ± 9%, P = .01), significantly reduced the dose of epinephrine needed to treat anaphylactic shock (EPI‐ABT 314 ± 67 µg/kg vs EPI 475 ± 69 µg/kg, P < .001) and reduced the time to restore basal MAP (ABT 23 ± 7 minutes vs EPI‐ABT 13 ± 5 minutes, P < .01).

Conclusions and Clinical Relevance

AS was characterized by early cardiac dysfunction in our model. Treatment with ABT‐491 allowed survival until the end of the experiment and reduced cardiac dysfunction. Use of the PAF‐R antagonist had a synergistic effect with epinephrine and allowed a significant reduction in epinephrine consumption. Use of PAF‐R antagonists during AS could reduce epinephrine‐related complications and improve the treatment of epinephrine refractory cases.
Flapless immediate implant placement and provisionalization in periodontal patients: A retrospective consecutive case‐series study of single‐tooth sites with dehiscence‐type osseous defects
Authors: Sicilia‐Felechosa Alberto , Pereira‐Fernández Adolfo , García‐Lareu Javier , Bernardo‐González Julio , Sicilia‐Blanco Pelayo , Cuesta‐Fernández Isabel
Published: November 2019

Objective

To assess the clinical outcomes of flapless, immediate implant placement with simultaneous augmentation of dehiscence defects and immediate provisional restoration.

Materials and Methods

Retrospective evaluation of 40 periodontal patients who received a flapless immediate implant for single‐tooth replacement with simultaneous augmentation of dehiscence defects and immediate provisional restoration, at follow‐up periods ranging from 1 year minimum to 7 years maximum. Dehiscence defects were augmented using autogenous bone grafts and/or deproteinized bovine bone mineral, and autogenous or allogeneic connective tissue grafts. The following aspects were evaluated: clinical success (Clinical Oral Implants Research, 8, 1997, 161), crestal bone loss (calibrated digital periapical X‐rays) and aesthetics (Pink Esthetic Score, PES). Additionally, a questionnaire was devised to obtain patient's subjective evaluation.

Results

A 98.3% (95% CI: 91%–99%) success rate was observed. At 8 weeks, mean bone loss was 0.47 mm (n = 39); between 8 weeks and 1 year, this va lue attained 0.24 mm and between years 1 and 5 years 0.06 mm (n = 9). The evaluated PES in 37 single‐tooth implants was 12.4, with PES = 7 (aesthetic failures) in two cases, and aesthetic outcomes were excellent (PES ≥ 12) in 29 cases (78.4%). When compared with the contralateral tooth, a recession under 1 mm was observed in 78% of cases. The patient's subjective satisfaction value ranged from 98% to 100%.

Conclusion

This type of minimally invasive treatment of alveoli with buccal plate deficiencies delivers, in the hands of an experienced clinician, a high clinical and aesthetic success percentage being rated by patients as satisfactory. Clinicians should be aware that 1–2 mm comparative recession could be observed.
Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model
Authors: Jorwal Pooja , Sikdar Sujit Kumar
Published: November 2019

Objective

Much evidence suggests that the subiculum plays a significant role in the regulation of epileptic activity. Lactate acts as a neuroprotective agent against many conditions that cause brain damage. During epileptic seizures, lactate formation reaches up to ~6 mmol/L in the brain. We investigated the effect of lactate on subicular pyramidal neurons after induction of epileptiform activity using 4‐aminopyridine (4‐AP‐0Mg2+) in an in vitro epilepsy model in rats. The signaling mechanism associated with the suppression of epileptiform discharges by lactate was also investigated.

Methods

We used patch clamp electrophysiology recordings on rat subicular neurons of acute hippocampal slices. Immunohistochemistry was used for demonstrating the expression of hydroxycarboxylic acid receptor 1 (HCA1) in the subiculum.

Results

Our study showed that application of 6 mmol/L lactate after induction of epileptiform activity reduced spike frequency (control 2.5 ± 1.23 Hz vs lactate 1.01 ± 0.91 Hz,P = .049) and hyperpolarized the subicular neurons (control −51.8 ± 1.9 mV vs lactate −57.2 ± 3.56 mV,P = .002) in whole cell patch‐clamp experiments. After confirming the expression of HCA1 in subicular neurons, we demonstrated that lactate‐mediated effect occurs via HCA1 by using its specific agonist. All values are mean ±SD. Electrophysiological recordings revealed the involvement of Gβγ and intracellular cAMP in the lactate‐induced effect. Furthermore, current‐clamp and voltage‐clamp experiments showed that the G protein–coupled inwardly rectifying potassium (GIRK) channel blocker tertiapin‐Q, negated the lactate‐induced inhibitory effect, which confirmed that lactate application results in outward GIRK current.

Significance

Our finding points toward the potential role of lactate as an anticonvulsant by showing lactate‐induced suppression of epileptiform activity in subicular neurons. The study gives a different insight by suggesting importance of endogenous metabolite and associated signaling factors, which can aid in improving the present therapeutic approach for treating epilepsy.
Segregation of seizures and spreading depolarization across cortical layers
Authors: Zakharov Andrey , Chernova Kseniya , Burkhanova Gulshat , Holmes Gregory L. , Khazipov Roustem
Published: November 2019

Objective

Cortical spreading depolarization (SD) and seizures are often co‐occurring electrophysiological phenomena. However, the cross‐layer dynamics of SD during seizures and the effect of SD on epileptic activity across cortical layers remain largely unknown.

Methods

We explored the spatial‐temporal dynamics of SD and epileptic activity across layers of the rat barrel cortex using direct current silicone probe recordings during flurothyl‐induced seizures.

Results

SD occurred in half of the flurothyl‐evoked seizures. SD always started from the superficial layers and spread downward either through all cortical layers or stopping at the L4/L5 border. In cases without SD, seizures were characterized by synchronized population firing across all cortical layers throughout the entire seizure. However, when SD occurred, epileptic activity was transiently silenced in layers involved with SD but persisted in deeper layers. During partial SD, epileptiform activity persisted in deep layers throughout the entire seizure, with positive signals at the cortical surface reflecting passive sources of population spikes generated in deeper cortical layers. During full SD, the initial phase of SD propagation through the superficial layers was similar to partial SD, with suppression of activity at the superficial layers and segregation of seizures to deep layers. Further propagation of SD to deep layers resulted in a wave of transient suppression of epileptic activity through the entire cortical column. Thus, vertical propagation of SD through the cortical column creates dynamic network states during which epileptiform activity is restricted to layers without SD.

Significance

Our results point to the importance of vertical SD spread in the SD‐related depression of epileptiform activity across cortical layers.
Exploration of the effect of farm, breed, sex and animal on detailed mineral profile of beef and their latent explanatory factors
Authors: Patel Nageshvar , Bergamaschi Matteo , Cagnin Massimo , Bittante Giovanni
Published: November 2019

Minerals in meat vary with different extrinsic and intrinsic sources; therefore, we aimed to quantify different sources of variation in mineral profile of beef. Longissimus thoracis muscle (N.182) from young bulls and heifers was analysed using ICP‐OES for 6 macrominerals, 5 essential microminerals and 9 environmental microminerals. Results of mixed models show that breed and sex have little effect on mineral profile. Major sources of variation, such as farm, individual animal within farm and side/sample within animal, differed markedly from mineral to mineral, affecting reproducibility coefficients. Multivariate factor analysis revealed that five latent factors explained 69% of the co‐variance of 20 minerals. The first was a quantitative factor, followed by others based on Na‐Fe‐Cu, on K‐B‐Pb, on Fe‐Mn and on Zn content, respectively. In conclusion, minerals’ major source of variation depends on complex relationships between the animal’s genetics, physiology, farm environment, management and feeding, whose understanding is favoured by latent factor analyses.
Depletion of Foxp3+ regulatory T cells is accompanied by an increase in the relative abundance of Firmicutes in the murine gut microbiome
Authors: Kehrmann Jan , Effenberg Laura , Wilk Camilla , Schoemer Davina , Ngo Thi Phuong Nhi , Adamczyk Alexandra , Pastille Eva , Scholtysik René , Klein‐Hitpass Ludger , Klopfleisch Robert , Westendorf Astrid M. , Buer Jan
Published: November 2019

A reciprocal interaction exists between the gut microbiota and the immune system. Regulatory T (Treg) cells are important for controlling immune responses and for maintaining the intestinal homeostasis but their precise influence on the gut microbiota is unclear. We studied the effects of Treg cell depletion on inflammation of the intestinal mucosa and analysed the gut microbiota before and after depletion of Treg cells using the DEpletion of REGulatory T cells (DEREG) mouse model. DNA was extracted from stool samples of DEREG mice and wild‐type littermates at different time‐points before and after diphtheria toxin application to deplete Treg cells in DEREG mice. The V3/V4 region of the 16S rRNA gene was used for studying the gut microbiota with Illumina MiSeq paired ends sequencing. Multidimensional scaling separated the majority of gut microbiota samples from late time‐points after Treg cell depletion in DEREG mice from samples of early time‐points before Treg cell depletion in these mice and from gut microbiota samples of wild‐type mice. Treg cell depletion in DEREG mice was accompanied by an increase in the relative abundance of the phylum Firmicutes and by intestinal inflammation in DEREG mice 20 days after Treg cell depletion, indicating that Treg cells influence the gut microbiota composition. In addition, the variables cage, breeding and experiment number were associated with differences in the gut microbiota composition and these variables should be respected in murine studies.
The Great Crash of 1929: A Look Back After 90 Years
Authors: Bruner Robert F. , Miller Scott C.
Published: November 2019

The Great Crash of 1929 ranks among the climactic events of the last century, apparently heralding the beginning of the Great Depression. This event raises at least four questions that are relevant today:

Why did the “Roaring 20s” roar? Some prominent contemporaries held that the decade roared because of consumerism, credit growth, and the Jazz Age. However, recent research suggests an alternative explanation: a revolution in manufacturing and technology that amplified economic growth and volatility in markets.

Was the boom in equities a “bubble?” Both the authors’ research and other studies show surprisingly weak evidence of a bubble. The boom probably reflected the technology shock of the ‘20s. If there was a bubble, it was limited in time, breadth, and impact.

What caused the Crash? The onset of an ordinary recession, surprising changes in monetary policy by the Fed, growing regulation, and rising protectionism all help to explain a sharp and sudden change in investor sentiment.

Did the Crash cause the Great Depression, as popular opinion has long maintained? No. The cycle of economic contraction had begun well before the crash. Furthermore, the wealth effect of the Crash was limited. The pivot from recession into Great Depression reflected the abandonment of the Gold Exchange Standard, a wave of bank panics and collapse of credit, protectionism, and a number of maladroit public policies. But if the Crash did not cause the Depression, it probably amplified the effects of forces already at work.

Answers to these questions, illuminated by careful research, remind decision‐makers in business and government that the first explanations for historical events are not always the best, that complex systems have unintended consequences, and that gaps in information make the Great Crash a difficult standard by which to assess future events. The use of historical precedent warrants caution and great humility in the makers of public policy.
Two Modes of Investment Banking: Technocrats, Relationship Managers, and Conflict
Authors: Morrison Alan D. , Wilhelm William J.
Published: November 2019

Efficient capital allocation in a market economy depends on the exchange of reliable information between providers of capital and companies that seek to put capital to work. One challenge, however, is that information exchange is at most only partly subject to verification and contractual arrangements. Take the case of securities issuance, including IPOs; whereas issuers of the new securities have incentives to overstate their prospects to attract higher bids, prospective investors have incentives to understate their interest. In principle, the counterparties could enter into an agreement that would prevent or discourage misrepresentations by both sides, but failure to perform would be very costly, if not impossible, for a court to verify.

Investment banks have traditionally addressed this problem by creating extralegal markets for information whose functioning depends on the reputations of the banks for upholding the interests of both their corporate clients and the providers of capital. But committing to strike the right balance among all of the parties’ interests means that relational investment bankers inevitably face conflicts of interest. The authors of this article argue that such bankers exist to absorb and to manage conflicts of interest in financial markets—and that they do so by exercising judgment in ways that support their reputation for fair dealing.

Modern full‐service investment banks, when addressing such conflicts, combine, or braid, such relational functions with technocratic banking activities involving the use of technical skills with advanced information technology. In so doing, however, technocratic bankers substitute formal contracts for the informal judgment exercised by relational bankers; and as a result, they are less dependent on their banks’ reputations for fair dealing. Moreover, technocratic bankers often have powerful incentives to pursue a personal reputation by executing complex transactions that demonstrate their skill, even at the expense of their clients and the bank's reputation for fair dealing.

Well‐governed braided banks can benefit from complementarities between relational and technocratic skills. Nevertheless, full‐service banks continue to struggle with governance problems. The authors discuss several market responses to these struggles, such as the growing use of boutique banks offering “unconflicted” sell‐side advice in mergers and acquisitions and securities offerings. But the authors view such responses as at most a first step toward achieving a new understanding of the extent of the challenge facing today's investment banks in carrying out their economic function of bringing together and balancing the interests of companies and their investors.
Predominant colonization of Malesian mountains by Australian tree lineages
Authors: Brambach Fabian , Leuschner Christoph , Tjoa Aiyen , Culmsee Heike
Published: November 2019

Aim

Massive biota mixing due to plate‐tectonic movement has shaped the biogeography of Malesia and during the colonization process, Asian plant lineages have presumably been more successful than their Australian counterparts. We aim to gain a deeper understanding of this colonization asymmetry and its underlying mechanisms by analysing how species richness and abundance of Asian versus Australian tree lineages in three Malesian subregions change along environmental gradients. We hypothesize that differing environmental histories of Asia and Australia, and their relation to habitats in Malesia, have been important factors driving assembly patterns of the Malesian flora.

Location

Malesia, particularly Sundaland, the Philippines and Wallacea.

Taxon

Seed plants (trees).

Methods

We compiled plot‐level data of environmental variables and tree abundances from three Malesian subregions. For each species, we inferred its geographical ancestry (Asian or Australian) based on published phylogenetic studies and the fossil record. We used proportions of Australian versus Asian species and individuals per plot to test how they are related to environmental parameters and geographical position using logistic regression models.

Results

Proportionally more Australian (and fewer Asian) tree species and individuals occurred (a) at higher elevations, (b) on sites over ultramafic parent material and (c) closer to their source region Australia with a significant increase of Australian elements east of Wallace's line. The trend was stronger for individuals than for species.

Main conclusions

Long‐term environmental similarities between source and sink habitats have shaped the assembly of the Malesian flora: Tree lineages from tropical Southeast Asia predominantly colonized the Malesian lowlands and rich soils, whereas trees from montane refuges in Australia were more successful in the newly emerging Malesian mountains and on poorer soils. The biogeographical patterns caused by the Malesian Floristic Interchange point to the importance of phylogenetic biome conservatism in biotic interchanges and resemble those resulting from the Great American Biotic Interchange in the Neotropics.
Parallel loss of sweet and umami taste receptor function from phocids and otarioids suggests multiple colonizations of the marine realm by pinnipeds
Authors: Wolsan Mieczyslaw , Sato Jun J.
Published: November 2019

Aim

Pinnipeds are thought to have evolved from a North Pacific ancestor, although some fossil evidence suggests a nonmarine Arctic origin and separate invasions into the North Pacific and North Atlantic. We here set out to test differing hypotheses about the origin of pinnipeds through identification and age estimation of pinniped marine invasions.

Location

Arctic, North America, North Atlantic, North Pacific.

Taxon

Pinnipeds (seals, sea lions, walruses and their fossil relatives).

Methods

Because evidence indicates that taste loss in marine mammals and birds results from adaptation to the marine environment, we examined 16 representative pinnipeds for loss‐of‐function mutations in theTAS1R1,TAS1R2andTAS1R3genes encoding the sweet T1R2–T1R3 and umami (savory) T1R1–T1R3 receptors, and used the loss‐of‐function events of these receptors as indicators of marine invasion.

Results

Numerous loss‐of‐function mutations were found in each pinnipedTAS1R(22 inTAS1R1, 21 inTAS1R2and 42 inTAS1R3). Six mutations were shared by all phocids and six other mutations by all otarioids (otariids and odobenids), but none by all phocids and all otarioids. Selective pressures onTAS1R1,TAS1R2andTAS1R3were estimated to have been relaxed, respectively, 16.3, 20.1 and 19.8 million years ago (Myra) in phocids, and 12.1, 18.1 and 18.2 Myra in otarioids.

Main conclusions

AllTAS1Rs, T1R1–T1R3 and T1R2–T1R3 are nonfunctional in all extant pinnipeds. Both receptors lost their function approximately 20 Myra in the Phocidae lineage and approximately 18 Myra in the Otarioidea lineage. Both lineages have colonized the marine realm independently, which entails nonmarine origins of both Pinnipedia and its stem lineage. Combined with fossil evidence, molecular findings here suggest an Arctic centre of long‐lasting (approximately 38–18 Myra) nonmarine pinniped evolution and at least five separate marine invasions, with the extinct (enaliarctid, Desmatophocidae,Kolponomos) and Otarioidea lineages entering the North Pacific and the Phocidae lineage the North Atlantic.
Inhibition of cyclin‐dependent kinase 7 down‐regulates yes‐associated protein expression in mesothelioma cells
Authors: Miao Jinbai , Kyoyama Hiroyuki , Liu Luwei , Chan Geraldine , Wang Yucheng , Urisman Anatoly , Yang Yi‐Lin , Liu Shu , Xu Zhidong , Bin Hu , Li Hui , Jablons David M. , You Liang
Published: November 2019

Cyclin‐dependent kinase 7 (CDK7) is a protein kinase that plays a major role in transcription initiation. Yes‐associated protein (YAP) is a main effector of the Hippo/YAP signalling pathway. Here, we investigated the role of CDK7 on YAP regulation in human malignant pleural mesothelioma (MPM). We found that in microarray samples of human MPM tissue, immunohistochemistry staining showed correlation between the expression level of CDK7 and YAP (n = 70, r = .513). In MPM cells, CDK7 expression level was significantly correlated with GTIIC reporter activity (r = .886, P = .019). Inhibition of CDK7 by siRNA decreased the YAP protein level and the GTIIC reporter activity in the MPM cell lines 211H, H290 and H2052. Degradation of the YAP protein was accelerated after CDK7 knockdown in 211H, H290 and H2052 cells. Inhibition of CDK7 reduced tumour cell migration and invasion, as well as tumorsphere formation ability. Restoration of the CDK7 gene rescued the YAP protein level and GTIIC reporter activity after siRNA knockdown in 211H and H2052 cells. Finally, we performed a co‐immunoprecipitation analysis using an anti‐YAP antibody and captured the CDK7 protein in 211H cells. Our results suggest that CDK7 inhibition reduces the YAP protein level by promoting its degradation and suppresses the migration and invasion of MPM cells. Cyclin‐dependent kinase 7 may be a promising therapeutic target for MPM.
Statistical optimization for precipitation of bioactive compounds from extracted Centella asiatica using gas anti‐solvent technique
Authors: Charoenchaitrakool Manop , Niamnuy Chalida , Dittanet Peerapan , Chantes Ornkanit , Chuangyang Pattamaporn
Published: November 2019

Centella asiatica is a well‐known herbal medicine used for antioxidant and antibacterial purposes. Main compounds in the group of triterpene saponins, namely, asiaticoside, asiatic acid, madecassoside, and madecassic acid are considered as the active compounds. These active ingredients were extracted from C. asiatica dried powder by the maceration method. The extracted solution was then used as a starting solution for the gas anti‐solvent (GAS) precipitation. The effects of % ethanol in a mixed solvent of ethanol and methanol (0–100%), carbon dioxide flow rate (3–9 ml/min), and temperature (25–45°C) on the amount of precipitates were investigated using a Box–Behnken design of experiments. It was found that % ethanol in the mixed solvent was significant at 5% significance level on madecassoside, asiaticoside, and total triterpene saponins. Higher amounts of total triterpene saponins could be precipitated when using low % ethanol and low temperature. At the optimal conditions, the amount of madecassoside, asiaticoside, madecassic acid, and asiatic acid were found to be 5,733 ± 537, 2,948 ± 249, 1,678 ± 163, and 436 ± 17 μg/5 ml of extracted solution, respectively. In the antioxidant studies, the highest Trolox equivalent found in the GAS products using 2,2‐diphenyl‐1‐picrylhydrazyl and 2,2‐azion‐bis‐3‐ethylbenzothiazo line‐6‐sulphonic acid assays was 5,622 ± 336 and 10,729 ± 820 μg/5 ml of extracted solution.

Practical applications

The novelty of this work covers the feasibility of applying gas anti‐solvent (GAS) technique for precipitation of bioactive compounds from extracted Centella asiatica and a statistical optimization of the operating parameters on the highest amount of precipitates. This work is important for extraction and purification applications focused on obtaining high purity of bioactive compounds from crude extracts. The use of dense CO2 as an anti‐solvent not only requires mild operating conditions but also provides a solvent‐free product. Therefore, the application of the GAS process can then be extended to precipitate active ingredients from other herbal extracts.
Combination of antioxidants and NFAT (nuclear factor of activated T cells) inhibitor protects auditory hair cells from ototoxic insult
Authors: Sekulic‐Jablanovic Marijana , Voronkova Krystsina , Bodmer Daniel , Petkovic Vesna
Published: November 2019

Hair cell (HC) degeneration causes hearing loss in millions of people worldwide. Aminoglycoside exposure is one major cause of sensory HC damage. Aminoglycosides generate free radicals within the inner ear, permanently damaging sensory cells, and thus causing hearing loss. Hearing protection requires strategies to overcome the apparently irreversible loss of HCs in mammals. The nuclear factor of activated T cells (NFAT) inhibitor 11R‐VIVIT reportedly protects HCs from gentamicin toxicity. Here we investigated whether the combination of 11R‐VIVIT with the antioxidant L‐carnitine or N‐acetylcysteine could protect mouse cochlear HCs from gentamicin damage. Compared to single‐component treatment, combined treatment with 11R‐VIVIT plus L‐carnitine yielded significant protection from gentamicin, and 11R‐VIVIT plus N‐acetylcysteine provided almost complete protection of HCs from gentamicin. Caspase activity in organ of Corti was significantly reduced by combined treatment with 11R‐VIVIT + N‐acetylcysteine + gentamicin, compared to 11R‐VIVIT + gentamicin or gentamicin alone. Analysis of relative gene expression by qPCR revealed down‐regulation of the pro‐apoptotic genes Fasl and Casp9, and up‐regulation of the antioxidant genes Hmox1 and Nrf2 after treatment with 11R‐VIVIT + N‐acetylcysteine + gentamicin, compared to single‐compound treatment or gentamicin alone in cultures. Selective NFAT inhibition by 11R‐VIVIT may be a good strategy for preventing gentamicin‐induced HC damage. L‐carnitine and N‐acetylcysteine, with their ROS‐reducing properties, contribute to the synergistic effectiveness with 11R‐VIVIT by decreasing ROS‐induced NFAT translocation. Our data suggest that a combined approach of NFAT inhibition together with an antioxidant, like N‐acetylcysteine, could be useful for hearing loss treatment and/or prevention.

image

Cover Image for this issue: https://doi.org/10.1111/jnc.14759.
EFFECTS OF HIV/AIDS ON CHILDREN'S EDUCATIONAL ATTAINMENT: A SYSTEMATIC LITERATURE REVIEW
Authors: P. Zinyemba Tatenda , Pavlova Milena , Groot Wim
Published: November 2019

Over the last three decades, 35 million people have died of AIDS. As a result, HIV/AIDS has brought about a significant reduction in human capital, especially in sub‐Saharan Africa. Several studies have examined the effects of HIV/AIDS on human capital, in particular educational attainment. These studies have examined different countries, datasets, and educational outcomes. This systematic literature review provides a comprehensive up‐to‐date overview of peer‐reviewed papers published in English by focusing on the main mechanisms that influence the effects of HIV/AIDS on educational outcomes. These are sickness of the child, orphanhood, and sickness of parents. The results show that educational outcomes of HIV‐infected children, AIDS orphans, and children with HIV‐infected parents are affected differently. HIV‐infected children mainly miss school days due to illness and medical appointments, and orphans mainly face financial problems and lack motivation in their education, while children with HIV‐infected parents may have to take care of their sick parents or face financial problems that affect their education. Distinguishing these groups of children could help to formulate policies that adequately improve schooling outcomes of these vulnerable children.
The Differential Management of Financial Illegalisms: Assigning Responsibilities in the Libor Scandal
Authors: Angeletti Thomas
Published: November 2019

How, in a context of growing critiques of financialization, can law contribute to protecting the legitimacy of finance? This paper argues that the assignment of responsibilities between individuals and organizations plays a decisive role, using the recent Libor scandal as an empirical illustration. To do so, the paper offers a Foucauldian framework, the differential management of financial illegalisms, dedicated to the study of illegalities in financial capitalism. The comparison of the legal treatment of two manipulations of Libor, this key benchmark in financial markets, reveals how mid-level traders have been the object of criminal prosecution, while law undervalued the role of top managers and organizations. To capture how differential management is performed in practice, I analyze precisely how the conflict-resolution devices (criminal trial vs. settlement) and the social categorizations prevailing in the two manipulations of Libor favor different forms of responsibility, individual or organizational. I conclude by exploring the implications of law's relationship to financial legitimacy.
The constancy of galactic cosmic rays as recorded by cosmogenic nuclides in iron meteorites
Authors: Smith Thomas , Cook David L. , Merchel Silke , Pavetich Stefan , Rugel Georg , Scharf Andreas , Leya Ingo
Published: November 2019

We measured the He, Ne, and Ar isotopic concentrations and the 10Be, 26Al, 36Cl, and 41Ca concentrations in 56 iron meteorites of groups IIIAB, IIAB, IVA, IC, IIA, IIB, and one ungrouped. From 41Ca and 36Cl data, we calculated terrestrial ages indistinguishable from zero for six samples, indicating recent falls, up to 562 ± 86 ka. Three of the studied meteorites are falls. The data for the other 47 irons confirm that terrestrial ages for iron meteorites can be as long as a few hundred thousand years even in relatively humid conditions. The 36Cl‐36Ar cosmic ray exposure (CRE) ages range from 4.3 ± 0.4 Ma to 652 ± 99 Ma. By including literature data, we established a consistent and reliable CRE age database for 67 iron meteorites. The high quality of the CRE ages enables us to study structures in the CRE age histogram more reliably. At first sight, the CRE age histogram shows peaks at about 400 and 630 Ma. After correction for pairing, the updated CRE age histogram comprises 41 individual samples and shows no indications of temporal periodicity, especially not if one considers each iron meteorite group separately. Our study contradicts the hypothesis of periodic GCR intensity variations (Shaviv 2002, 2003), confirming other studies indicating that there are no periodic structures in the CRE age histogram (e.g., Rahmstorf et al. 2004; Jahnke 2005). The data contradict the hypothesis that periodic GCR intensity variations might have triggered periodic Earth climate changes. The 36Cl‐36Ar CRE ages are on average 40% lower than the 41K‐K CRE ages (e.g., Voshage 1967). This offset can either be due to an offset in the 41K‐K dating system or due to a significantly lower GCR intensity in the time interval 195–656 Ma compared to the recent past. A 40% lower GCR intensity, however, would have increased the Earth temperature by up to 2 °C, which seems unrealistic and leaves an ill‐defined 41K‐K CRE age system the most likely explanation. Finally, we present new 26Al/21Ne and 10Be/21Ne production rate ratios of 0.32 ± 0.01 and 0.44 ± 0.03, respectively.
Secreted protein with altered thrombospondin repeat (SPATR) is essential for asexual blood stages but not required for hepatocyte invasion by the malaria parasite Plasmodium berghei
Authors: Gupta Roshni , Mishra Akancha , Choudhary Hadi Hasan , Narwal Sunil Kumar , Nayak Bandita , Srivastava Pratik Narain , Mishra Satish
Published: November 2019

Upon entering its mammalian host, the malaria parasite productively invades two distinct cell types, that is, hepatocytes and erythrocytes during which several adhesins/invasins are thought to be involved. Many surface‐located proteins containing thrombospondin Type I repeat (TSR) which help establish host–parasite molecular crosstalk have been shown to be essential for mammalian infection. Previous reports indicated that antibodies produced against Plasmodium falciparum secreted protein with altered thrombospondin repeat (SPATR) block hepatocyte invasion by sporozoites but no genetic evidence of its contribution to invasion has been reported. After failing to generate Spatr knockout in Plasmodium berghei blood stages, a conditional mutagenesis system was employed. Here, we show that SPATR plays an essential role during parasite's blood stages. Mutant salivary gland sporozoites exhibit normal motility, hepatocyte invasion, liver stage development and rupture of the parasitophorous vacuole membrane resulting in merosome formation. But these mutant hepatic merozoites failed to establish a blood stage infection in vivo. We provide direct evidence that SPATR is not required for hepatocyte invasion but plays an essential role during the blood stages of P. berghei.
A case of multiple cerebral cavernomas associated with en coup de sabre scleroderma
Authors: Alwash Noor , Dinani Naila , Felton Jessie
Published: November 2019

Linear scleroderma is a form of localized scleroderma that presents as band‐like sclerotic lesions. When it occurs on the scalp or forehead, it is called “en coup de sabre scleroderma" (ECDS). Extracutaneous associations, mostly neurologic, have been described with ECDS. We report a patient with ECDS associated with multiple cerebral cavernomas. This serves to highlight the importance of neuroimaging and multidisciplinary team involvement in patients with ECDS.
Deep Learning Models for Health and Safety Risk Prediction in Power Infrastructure Projects
Authors: Ajayi Anuoluwapo , Oyedele Lukumon , Owolabi Hakeem , Akinade Olugbenga , Bilal Muhammad , Davila Delgado Juan Manuel , Akanbi Lukman
Published: November 2019

Inappropriate management of health and safety (H&S) risk in power infrastructure projects can result in occupational accidents and equipment damage. Accidents at work have detrimental effects on workers, company, and the general public. Despite the availability of H&S incident data, utilizing them to mitigate accident occurrence effectively is challenging due to inherent limitations of existing data logging methods. In this study, we used a text‐mining approach for retrieving meaningful terms from data and develop six deep learning (DL) models for H&S risks management in power infrastructure. The DL models include DNNclassify (risk or no risk), DNNreg1 (loss time), DNNreg2 (body injury), DNNreg3 (plant and fleet), DNNreg4 (equipment), and DNNreg5 (environment). An H&S risk database obtained from a leading UK power infrastructure construction company was used in developing the models using the H2O framework of the R language. Performances of DL models were assessed and benchmarked with existing models using test data and appropriate performance metrics. The overall accuracy of the classification model was 0.93. The average R2 value for the five regression models was 0.92, with mean absolute error between 0.91 and 0.94. The presented results, in addition to the developed user‐interface module, will help practitioners obtain a better understanding of H&S challenges, minimize project costs (such as third‐party insurance and equipment repairs), and offer effective strategies to mitigate H&S risk.
Effects of a heat and moisture exchanger on respiratory function and symptoms post–cold air exercise
Authors: Frischhut Clemens , Kennedy Michael D. , Niedermeier Martin , Faulhaber Martin
Published: November 2019

Purpose

Exercise at temperatures below −15°C induces drying and cooling of lung airways which causes exercise‐induced bronchoconstriction (EIB) and respiratory symptoms, especially in winter sport athletes. The objective of this study was to evaluate whether a heat and moisture exchanger (HME) worn during intense cold air exercise improves lung function and reduces respiratory symptoms in healthy winter sport athletes.

Methods

Seven active males and six active females (maximum oxygen uptake 61.9 ± 6.9 and 52.2 ± 5.3 mL/kg/min), all active or former winter sport athletes, completed running trials with and without HME in random order on 2 days in an environmental chamber (−20°C temperature, humidity 46.2%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced expiratory flow at 25%‐75% (FEF25%‐75%), and FEF at 50% (FEF50%) were measured pre‐ and post‐exercise (3, 6, 10, 15, and 20 minutes). Respiratory symptoms were reported after exercise.

Results

Significant interaction effects were observed for FEV1 and FEF25%‐75%. Mean decrease of FVC (−5.9%, P ≤ .001) and FEV1 (−4.2%, P = .003) was largest 3 minutes post‐exercise without HME. There was an increase of FEV1, FEF25%‐75%, and FEF50% post‐exercise compared to pre‐exercise with HME. More respiratory symptoms overall were reported without HME (P = .046).

Conclusion

Intense cold air exercise likely causes transient acute bronchoconstriction and symptoms of cough in individuals participating in winter sports. However, this study finds that the application of an HME during intense cold air exercise improves lung function and reduces prevalence of EIB‐associated symptoms compared to unprotected intense cold air exercise.
Improvement of exercise capacity following neonatal respiratory failure: A randomized controlled trial
Authors: Toussaint‐Duyster Leontien C. C. , van der Cammen‐van Zijp Monique H. M. , Takken Tim , Harmsen Wouter J. , Tibboel Dick , van Heijst Arno F. J. , de Blaauw Ivo , Wijnen Rene M. H. , van Rosmalen Joost , IJsselstijn Hanneke
Published: November 2019

Exercise capacity deteriorates in school‐aged children born with major anatomical foregut anomalies and/or treated with extracorporeal membrane oxygenation. The aim of the present study was to evaluate whether exercise capacity can be improved in the short term and long term in children born with anatomical foregut anomalies and/or treated with extracorporeal membrane oxygenation. Therefore, we evaluated two different interventions in this single‐blinded randomized controlled trial. Forty participants were randomly assigned to group A: standardized anaerobic high‐intensity interval training plus online lifestyle coaching program, B: online lifestyle coaching program only, or C: standard of care. Inclusion criteria were as follows: score ≤−1 standard deviation (SD) on the Bruce protocol. Exercise capacity was assessed at baseline (T0), after 3 months (T1), and after 12 months (T2). Exercise capacity improved over time: mean (SD) standard deviation score (SDS) endurance time: T0 −1.91 (0.73); T1 −1.35 (0.94); T2 −1.20 (1.03): both P < .001. No significant differences in maximal endurance time were found at T1 (group A‐C: estimated mean difference (SDS): 0.06 P = .802; group B‐C: −0.17 P = .733) or T2 (group A‐C: −0.13 P = .635; group B‐C: −0.18 P = .587). Exercise capacity improved significantly over time, irrespective of the study arm. Not only residual morbidities may be responsible for reduced exercise capacity. Parental awareness of reduced exercise capacity rather than specific interventions may have contributed. Monitoring of exercise tolerance and providing counseling on lifestyle factors that improve physical activity should be part of routine care, and aftercare should be offered on an individual basis.