bluuebunny/crossref_metadata_2025 huggingface dataset:
MODERN TARİHÇİLİĞİN ŞAFAĞINDA BİR TANZİMAT DEVRİ MÜNEVVERİ: ZİVER BEY VE RODOS TARİHİ
Authors: Nalezen Orçun
Published: November 2023

Ege Denizi’ndeki en stratejik adalardan biri olan Rodos’un hikâyesini anlatan Ziver Bey, bir tarihçiden çok edebiyat yazarıydı. Ziver Bey eserini Rodos’ta maarif müdürü olarak görev yaptığı sırada kaleme almıştı. Büyük ölçüde Batılı kaynaklardan istifade etse de iktibaslarını kişisel gözlemlerinden beslenerek desteklemişti. Eserini Rodoslular için kaleme aldığını söyleyen Ziver Bey’in kendisi de adalıydı. Bir başka ifadeyle Osmanlı adalarındaki toplumsal yapıya aşina olduğu gibi bizzat o yapının bir ürünüydü. Tarihini II. Abdulhamid Dönemi’nde yazan Ziver Bey, sürgün politikasının tesiriyle Rodos’ta yaşamaya zorlanan Osmanlı aydınlarının zenginleştirdiği fikrî bir ortamdan beslenmişti. Rodos Tarihi’ni henüz kariyer basamaklarını tırmanmakta olan bir memurken yazmıştı. Öte yandan entelektüel üretiminin kariyer yolculuğunda kendisine fayda sağlamasını ummuştu. Bu çalışma bir Tanzimat Dönemi entelektüelinin yazdığı tarihi merkeze alarak onun düşünsel mirasına, içinde bulunduğu entelektüel çevreye ve XIX. yüzyıl tarih yazım geleneğindeki yerine odaklanmaktadır. Son dönem Osmanlı tarihçilerinin eser üretme motivasyonunu taşradaki bir memurun hikâyesi üzerinden ele almaktadır. Bunların da ötesinde bir tarihçiden çok edebiyatçı olarak temayüz etmiş bir yazarın Osmanlı tarihçiliğine ne ölçüde metodolojik katkıda bulunduğu araştırılmaktadır.
How do weather risks in Canada and the United States affect global commodity prices? Implications for the decarbonisation process
Authors: Lau Chi Keung , Cai Yifei , Gozgor Giray
Published: November 2023

Given that the probability of extreme weather has been dramatically increasing, this study contributes to the existing literature by bridging the relation between weather risks and global commodity prices with a secondary dataset (e.g., weather risks of Canada and the United States, agricultural raw materials price, gold price, and crude oil price). The results from the vector autoregression model and impulse response functions show that rising weather risks increase the price of agricultural raw materials and gold. However, the negative impact of weather risks on the crude oil price is found. Finally, the paper discusses the findings' potential implications (e.g., developing decarbonised supply chains) for decreasing weather risks' effects on commodity market uncertainties.
Effect of Aromatic Rings in AESO-VDM Biopolymers on the Local Free Volume and Diffusion Properties of Polymer Matrix
Authors: Královič David Pavel , Cifraničová Katarína , Švajdlenková Helena , Tóthová Darina , Šauša Ondrej , Kalinay Pavol , Kavetskyy Taras , Ostrauskaite Jolita , Smutok Oleh , Gonchar Mykhailo , Soloviev Vladimir , Kiv Arnold
Published: November 2023

In this work, the influence of aromatic rings on the local free volume of cured mixtures of acrylate epoxidized soybean oil (AESO) and vanillin dimethacrylate (VDM) was investigated. Cross-linking took place under the influence of UV light in the presence or absence of a photoinitiator. The local free volume and its homogeneity were characterized using the Positron Annihilation Lifetime Spectroscopy (PALS) technique. It was found that increasing the content of VDM, which contains aromatic rings, caused a decrease in the local free volume of the cured polymer network, with consequences for the diffusion properties of the polymer, which were tested for the case of water. Another consequence of increasing the content of VDM was a decrease in the conversion of double bonds in the finally cured samples, characterized by near-infrared spectroscopy (NIR). This finding illustrates a case where the decrease in free volume is not necessarily related to an increase in the crosslinking density of the polymer, but is a consequence of the presence of an increase in the occupied volume of aromatic rings in the volume of the polymer.
Strictly positive definite non-isotropic kernels on two-point homogeneous manifolds: the asymptotic approach
Authors: Guella J. C. , Jäger J.
Published: November 2023

We present sufficient conditions for a family of positive definite kernels on a compact two-point homogeneous space to be strictly positive definite based on their expansion in eigenfunctions of the Laplace–Beltrami operator. We also present a characterisation of this kernel class. The family analyzed is a generalization of the isotropic kernels and the case of a real sphere is analyzed in details.
An investigation of the applicability of contact models to the normal load-deformation behaviour of artificially shaped granite
Authors: Altuhafi F. , Baudet B. A. , Coop M. R.
Published: November 2023

The validity of different available contact models is tested against experimental data for contact normal loading of artificially shaped granite stones. Three elastic models and two plastic models were tested with different combinations of contact shape (spherical, conical and flat) and roughnesses. It was found that the deviation from the Hertz model increased with surface roughness with a generally better representation of the data achieved by using models which consider surface roughness and the fractality of the surface. The validity of all these models seems to be limited to before excessive plastic deformations start taking place, after which the contact seems to deform under constant stiffness.
Impact of industrial robots on environmental pollution: evidence from China
Authors: Liu Yanfang
Published: November 2023

The application of industrial robots is considered a significant factor affecting environmental pollution. Selecting industrial wastewater discharge, industrial SO2 emissions and industrial soot emissions as the evaluation indicators of environmental pollution, this paper uses the panel data model and mediation effect model to empirically examine the impact of industrial robots on environmental pollution and its mechanisms. The conclusions are as follows: (1) Industrial robots can significantly reduce environmental pollution. (2) Industrial robots can reduce environmental pollution by improving the level of green technology innovation and optimizing the structure of employment skills. (3) With the increase in emissions of industrial wastewater, industrial SO2, and industrial dust, the impacts generated by industrial robots are exhibiting trends of a “W” shape, gradual intensification, and progressive weakening. (4) Regarding regional heterogeneity, industrial robots in the eastern region have the greatest negative impact on environmental pollution, followed by the central region, and the western region has the least negative impact on environmental pollution. Regarding time heterogeneity, the emission reduction effect of industrial robots after 2013 is greater than that before 2013. Based on the above conclusions, this paper suggests that the Chinese government and enterprises should increase investment in the robot industry. Using industrial robots to drive innovation in green technology and optimize employment skill structures, reducing environmental pollution.
FT-Raman data analyzed by multivariate and machine learning as a new methods for detection spectroscopy marker of platinum-resistant women suffering from ovarian cancer
Authors: Kluz-Barłowska Marta , Kluz Tomasz , Paja Wiesław , Sarzyński Jaromir , Łączyńska-Madera Monika , Odrzywolski Adrian , Król Paweł , Cebulski Józef , Depciuch Joanna
Published: November 2023

The phenomenon of platinum resistance is a very serious problem in the treatment of ovarian cancer. Unfortunately, no molecular, genetic marker that could be used in assigning women suffering from ovarian cancer to the platinum-resistant or platinum-sensitive group has been discovered so far. Therefore, in this study, for the first time, we used FT-Raman spectroscopy to determine chemical differences and chemical markers presented in serum, which could be used to differentiate platinum-resistant and platinum-sensitive women. The result obtained showed that in the serum collected from platinum-resistant women, a significant increase of chemical compounds was observed in comparison with the serum collected from platinum-sensitive woman. Moreover, a decrease in the ratio between amides vibrations and shifts of peaks, respectively, corresponding to C–C/C–N stretching vibrations from proteins, amide III, amide II, C = O and CH lipids vibrations suggested that in these compounds, structural changes occurred. The Principal Component Analysis (PCA) showed that using FT-Raman range, where the above-mentioned functional groups were present, it was possible to differentiate the serum collected from both analyzed groups. Moreover, C5.0 decision tree clearly showed that Raman shifts at 1224 cm−1 and 2713 cm−1 could be used as a marker of platinum resistance. Importantly, machine learning methods showed that the accuracy, sensitivity and specificity of the FT-Raman spectroscopy were from 95 to 100%.
Identifying phenotype-associated subpopulations through LP_SGL
Authors: Li Juntao , Zhang Hongmei , Mu Bingyu , Zuo Hongliang , Zhou Kanglei
Published: November 2023

Single-cell RNA sequencing (scRNA-seq) enables the resolution of cellular heterogeneity in diseases and facilitates the identification of novel cell types and subtypes. However, the grouping effects caused by cell–cell interactions are often overlooked in the development of tools for identifying subpopulations. We proposed LP_SGL which incorporates cell group structure to identify phenotype-associated subpopulations by integrating scRNA-seq, bulk expression and bulk phenotype data. Cell groups from scRNA-seq data were obtained by the Leiden algorithm, which facilitates the identification of subpopulations and improves model robustness. LP_SGL identified a higher percentage of cancer cells, T cells and tumor-associated cells than Scissor and scAB on lung adenocarcinoma diagnosis, melanoma drug response and liver cancer survival datasets, respectively. Biological analysis on three original datasets and four independent external validation sets demonstrated that the signaling genes of this cell subset can predict cancer, immunotherapy and survival.
Understandings of Happiness and Life Satisfaction Among Refugees in the UK
Authors: Pollenne Daisy
Published: November 2023

Both qualitative and quantitative research draw increasingly on measures of life satisfaction and happiness to evaluate how refugees are faring in countries where asylum is obtained. However, existing evidence is limited, in that these two subjective well-being (SWB) measures are included in research as either interchangeable or distinct components of SWB. After conducting in-depth interviews with refugees based in the UK, this article presents three important contributions. First, life satisfaction is considered by refugees as a global assessment of key domains in their lives. Second, refugees define happiness not only as an emotion but also as a personal disposition towards experiencing emotions positively. Third, there is a complex relational conditionality between these two components of SWB. While individual socio-demographics and experiences, including those of seeking asylum, bring nuances to the findings, these have significant implications for measuring refugees’ SWB in the UK and in post-displacement contexts more broadly.
Familial nonmedullary thyroid cancer: a case series in Iranian patients with a meta-review of case series
Authors: Mohammadi Zaniani Zohreh , Zeinalian Mehrdad , Tabatabaiefar Mohammad Amin
Published: November 2023

Background

Nonmedullary thyroid cancer (NMTC) comprises approximately 90% of all thyroid cancers, and about 3% to 9% of NMTC cases have a familial origin. Familial NMTC (FNMTC) in the absence of a documented familial cancer syndrome such as Cowden syndrome is characterized by the occurrence of thyroid cancer of follicular cell origin in 2 or more first-degree relatives.

Methods

Whole-exome sequencing (WES) was used to identify pathogenic genetic variants in 2 Persian families with FNMTC. The purpose of this work is to assess the pathogenic status of these variants as well as the cosegregation status of the variants observed in the examined families.

Results

By analyzing WES data in the first family, SRGAP1: NM_020762: exon16: c.C1849T was identified as a pathogenic variant. This variant was confirmed by Sanger sequencing. In the second family, the variant FOXE1: NM_004473: exon1: c.531_532insCGCGA was identified but was not confirmed by Sanger sequencing.

Conclusion

Based on the data, SRGAP1 can be a potential candidate gene for susceptibility to FNMTC in the first family. However, additional analyses like whole genome sequencing and copy number variations are required to ascertain the disease status in second family.
Dietary nitrate, nitrite, and nitrosamine in association with diabetes: a systematic review and meta-analysis
Authors: Nguyen Nam N , Tran Linh T D , Ho Ngan D K , Huynh Linh B P , Nguyen Hung S , Chen Yang-Ching
Published: November 2023

Context

Diabetes is a global health concern, and diet is a contributing factor to diabetes. Findings regarding the connection between nitrate, nitrite, and nitrosamine and diabetes risk are inconsistent.

Objective

The aim was to examine the effects of these dietary compounds on diabetes risk.

Data Sources

The data were sourced from PubMed, EMBASE, Scopus, and Web of Science until February 28, 2023. Studies that reported individual-level consumption of these compounds were included. Review articles or ecological studies were excluded.

Data Extraction

The number of events and total observations were recorded.

Data Analysis

The pooled odds ratio (OR) was calculated and displayed in a forest plot. Subgroup and sensitivity analyses were predefined. A dose–response meta-analysis was conducted to determine the exposure intervals that may increase the risk of disease. Six observational reports that met the inclusion criteria were included, involving 108 615 individuals. Participants in the highest quantile of nitrite intake had a greater risk of diabetes compared with those in the lowest quantile (OR, 1.61; 95% confidence interval [CI], 1.08–2.39; I2 = 74%, P = 0.02). Higher nitrosamine consumption tended to increase diabetes risk (OR, 1.52; 95% CI, 0.76–3.04; I2 = 76%; P = 0.24). The relationship was stronger for type 1 (OR, 1.79; 95% CI, 1.20–2.67; I2 = 58%; P < 0.01) than for type 2 diabetes (OR, 1.42; 95% CI, 0.86–2.37; I2 = 71%; P = 0.17). Additionally, nitrite consumption had a dose-dependent association with both phenotypes. No association was found between diabetes risk and high nitrate intake (OR, 1.01; 95% CI, 0.87–1.18; I2 = 28%; P = 0.87).

Conclusion

Attention should be paid to the consumption of nitrite-containing foods.

Systematic Review Registration

PROSPERO registration no. CRD42023394462 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=394462).
Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance
Authors: Sone Daichi , Young Alexandra , Shinagawa Shunichiro , Tsugawa Sakiko , Iwata Yusuke , Tarumi Ryosuke , Ogyu Kamiyu , Honda Shiori , Ochi Ryo , Matsushita Karin , Ueno Fumihiko , Hondo Nobuaki , Koreki Akihiro , Torres-Carmona Edgardo , Mar Wanna , Chan Nathan , Koizumi Teruki , Kato Hideo , Kusudo Keisuke , de Luca Vincenzo , Gerretsen Philip , Remington Gary , Onaya Mitsumoto , Noda Yoshihiro , Uchida Hiroyuki , Mimura Masaru , Shigeta Masahiro , Graff-Guerrero Ariel , Nakajima Shinichiro
Published: November 2023

Background and Hypothesis

Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance.

Study Design

In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis.

Study Results

SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009).

Conclusions

The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.
Collaboration Between Basic Scientists and Clinicians: An Opportunity to Develop a Microanatomy Curriculum to Integrate Curricular Content and Encourage Student Interaction
Authors: McBride Jennifer M
Published: November 2023

Many microanatomy courses still maintain a traditional approach to student instruction. This consists of a didactic presentation followed by a laboratory session, which uses specimens either on glass slides, specimens viewed virtually or a combination of the two. Maintaining the time required to conduct these two separate sessions within an educational climate that promotes independent student study time and integration of course information, is problematic.

In an effort to encourage student interaction, basic scientists and clinicians at the Cleveland Clinic collaborated to create a case‐based microanatomy curriculum facilitated with the aid of a virtual microscopy system. They then identified time points, in each of the organ system courses, where microanatomy seminars would appropriately integrate with other course content and problem based learning cases. Student preparation for these seminars requires that they review the cases and examine virtual microscopy images. To encourage student participation during the seminar, the faculty member facilitates discussion of these cases with guiding questions and image review.

Evaluation of students in this program occurs through a competency based portfolio system rather than graded quizzes or exams, thus numerical course data over time are not available. Other metrics that are available include; end of course reports, graduation questionnaire ratings and USMLE Step 1 scores. Overall student feedback regarding the end of course reports indicate that they feel there is “Appropriate Coverage” of histology content. In addition, graduation questionnaires indicate that the majority of students felt their study of microanatomy/histology was “Good” or “Excellent”, which helped them prepare for clinical clerkships and electives. Finally, students have consistently performed above or significantly above the national average for Histology/Cell Biology on USMLE Step 1.

This approach to microanatomy instruction successfully addresses the desire to shorten student class time, integrate curricular content and encourage student interaction.
Sex dependent effects of prenatal infection on adult cardiovascular health: are females at greater risk for cardiovascular disease?
Authors: Hayward Linda , Watkins Jaqueline , Von Chamier Maria , Reyes Leticia , Brown Mary
Published: November 2023

Prenatal infection (INF) has been linked to an increased risk for psychiatric disorders such as schizophrenia. Emerging evidence suggests that a common cause of death among schizophrenics is cardiovascular disease. This study's aim was to investigate the link between INF and the risk for cardiovascular disease later in life. A rodent model of INF was used where Mycoplasma pulmonis or vehicle (SHAM) was given intravenously on gestational day 14. Following birth, litters were culled to 8, cross‐fostered, weaned and pair housed until adulthood. At 12 weeks of age (n=4–6/group), sex dependent differences in weight were identified: INF females weighed 17.8% more than SHAMs (P<0.05) while INF males weighed only 4.2% more than SHAMs (P>0.05). Resting mean arterial pressure (MAP) was not significantly different between groups, however in response to angiotensin II (10 μg/kg, subcutaneous) both INF males and females had a significantly greater rise in MAP (+31 and +19 mmHg, respectively; P<0.05) when compared to the sex‐matched SHAMs. In response to acute nicotine (0.37 mg/kg, subcutaneous) however only INF females demonstrated a greater increase in MAP (+ 5mmHg; P<0.02) when compared to sex‐matched SHAMs. These results suggest that offspring exposed to infection in utero are likely to have a greater risk for development of cardiovascular disease in adulthood, with females potentially having the greatest risk.

Support or Funding Information

Florida Department of Health‐James and Esther King 4KB11
Inhibition of Glial Metabolism Decreases Intestinal Afferent Nerve Activity
Authors: Miranda‐Morales Marcela , Ochoa‐Cortes Fernando , Christofi Fievos L , Villalobos‐Hernandez Egina C , Barajas‐Lopez Carlos
Published: November 2023

The enteric nervous system is embedded in the walls of the gastrointestinal tract and regulates among other functions: digestion, secretion and motility in synchrony with the central nervous system. The enteric ganglia consist of neurons and glial cells; these outnumber neurons and appear to participate in maintaining their homeostasis.

A lot is ignored about the physiological role of glial cells in the enteric nervous system. Recent experimental data indicates that inhibition of the functions of glial cells, decrease the gastrointestinal transit and contraction in response to field stimulation in mice. However, there are not reports on their role in the mesenteric afferent nerve functions.

The objective of this work was to investigate the role of enteric glia in the multiunit afferent activity in mesenteric nerves, both spontaneous and induced by increasing intraluminal intestinal pressure.

Multiunit afferent nerve activity from a segment of jejunum from C57BL/6 mice were recorded, a nerve was dissected from the mesenteric border. We recorded the spontaneous action potentials in response to the application of intraluminal pressure. Extraluminal application fluoroacetate (5 mM during 10 min) decreases afferent response to intraluminal pressure progressively. The maximum effect is observed around 50 minutes, time in which the response of the high threshold fibers is almost inhibited and the low threshold fibers decrease to one third of the control value. In addition multiunit basal activity remains unchanged.

Our results suggest a relevant role of enteric glia in mesenteric afferent nerve activity. The fact that the spontaneous activity is unchanged suggests that participation would be on sensory mechanisms that detect the tension of the intestinal wall.

Support or Funding Information

This work was supported by Fiscal Funds. Scholarships of EC‐VH was supported by CONACYT.
Organophosphorus Pesticides Stimulate Macrophages to Release Factors That Modulate M2 Muscarinic Receptors
Authors: Proskocil Becky , Lein Pamela , Jacoby David , Fryer Allison
Published: November 2023

BACKGROUND

The organophosphorus pesticides (OP) parathion, chlorpyrifos, and diazinon are widely used agricultural pesticides. We found that OPs cause airway hyperreactivity via dysfunction of autoinhibitory M2 muscarinic receptor expressed by parasympathetic nerves in the airways of guinea pigs. OP‐induced airway hyperreactivity occurs at concentrations below currently recommended exposure limits. OP‐induced effects are prevented by depleting alveolar macrophages or blocking tumor necrosis factor α (TNFα).

OBJECTIVE

To determine if OPs and/or their oxon metabolites directly stimulate human macrophages to increase the expression of cytokines and growth factors known to modulate M2 receptors. Since OPs interact with nicotinic and muscarinic receptors, which are expressed on macrophages, and since OPs are a potent acetylcholinesterase (AChE) inhibitor, we also evaluated whether OP stimulation of macrophages is mediated by AChE inhibition and/or modulation of nicotinic or muscarinic receptor activity.

METHODS

THP1 cells, a human monocyte cell line differentiated into macrophages, were treated with 1–100 μM parathion, chlorpyrifos, or diazinon or 1 nM – 100 μM paraoxon, chlorpyrifos oxon, or diazoxon for 24 hr. Some THP1 cells were pretreated with 100 μM mecamylamine (nicotinic antagonist) or 100 μM atropine (muscarinic antagonist) 1 hr prior to addition of the OPs. Other cells were treated with 100 μM eserine (AChE inhibitor). Cells were harvested for RT‐PCR and supernatants were collected for ELISA.

RESULTS

Parathion, chlorpyrifos, and diazinon increased mRNA expression of TNFα, IL‐1β, platelet derived growth factor (PDGF), and transforming growth factor β (TGFβ) in a concentration‐dependent manner. TNFα protein was significantly increased at 100 μM, however IL‐1β and PDGF proteins were not increased and fibroblast growth factor (FGF) and TGFβ proteins were undetectable. No oxon metabolite increased mRNA or protein levels of these factors. Inhibiting nicotinic or muscarinic receptors did not prevent OP‐induced increase in IL‐1β, TNFα, PDGF, and TGFβ mRNA or secreted TNFα protein. Blocking AChE with eserine did not increase cytokine or growth factor expression.

CONCLUSIONS

Parent OP compounds, but not their metabolites, stimulate macrophages to express cytokines and growth factors that have previously been shown to modulate parasympathetic M2 muscarinic receptor function. Macrophage stimulation occurs via a non‐muscarinic, non‐nicotinic pathway and independent of AChE inhibition. Characterizing this pathway is important for determining biological effects of OPs and treatment following OP exposure.

Support or Funding Information

This work was supported by NIH grants ES017592, ES014521, ES014601, HL124165, HL113023, and AR061567.
Exaggerated blood pressure and sympathetic reactivity in patients with Type 2 Diabetes
Authors: Vranish Jennifer R , Holwerda Seth W , Keller David M , Fadel Paul J
Published: November 2023

Although greater blood pressure (BP) responses to exercise have been observed in Type 2 Diabetes (T2D) patients, our understanding of the time course and mechanisms involved remains limited. Herein, we focused on the immediate onset of isometric handgrip (i.e., first 30 seconds) and tested the hypothesis that T2D patients would exhibit an augmented increase in BP and muscle sympathetic nerve activity (MSNA) relative to age and bodyweight‐matched, healthy controls. T2D patients (n=14) and controls (n=8) performed isometric handgrip at 40% of maximal voluntary contraction while BP, MSNA, and heart rate (HR) were continuously recorded. A cold pressor test (CPT) was also performed as a generalized, central sympatho‐excitatory stimulus. Data were averaged over 10s intervals for the initial 30s of handgrip and CPT. HR increased at exercise onset (first 10s; P < 0.001) with no differences between groups (8±1.9 vs. 11±1.7; P = 0.655). However, mean BP (9±1.2 vs. 4±1.9 mmHg; P = 0.019) and systolic BP (12±1.7 vs. 3±2.5 mmHg; P = 0.003) were significantly greater for the first 10s of handgrip in T2D patients than controls. These differences were maintained over the entire 30s onset of exercise. Likewise, MSNA was also greater for T2D patients (10±2.1 vs. 1±2.6 bursts per minute; P = 0.031) at the onset of exercise. Interestingly, T2D patients also exhibited a greater mean BP (11±2.4 vs. 3±1.4 mmHg; P = 0.013) and MSNA (17±3.6 vs. 7±2.4 bursts per minute; P = 0.042) response to the first 30s of CPT. Collectively, these data suggest that T2D patients exhibit heightened pressor and sympathetic responsiveness at the onset of isometric handgrip that may be mediated by greater central reactivity, although a role for the muscle mechanoreflex also warrants consideration.

Support or Funding Information

Supported by AHA‐20160072 (P.J.F.).
The Effect of Stimulation of β2 Adrenergic Receptor on Glucose Uptake in Skeletal Muscles
Authors: Gao Hongbo
Published: November 2023

Background and Hypothesis

Skeletal muscles are innervated with sympathetic nervous systems. β2 adrenergic receptor (β2AR) is predominantly expressed in skeletal muscles. Activation of β2AR has been shown to improve glucose uptake in skeletal muscles. However, the underlying mechanisms remain to be fully understood.

Methods and Results

In this study, adult healthy female mice were pretreated with β2AR selective agonist formoterol (Fm) for 15min prior to insulin tolerance test (ITT), or glucose tolerance test (GTT). The ITT displayed that the blood glucose level, while was restored at 60 min in controls, remained a continual low level throughout the 120 min test period in Fm treated group. In GTT, the magnitude of blood glucose in mice pretreated with Fm was significantly blunted at 15 and 30 min compared to the control group. We further assessed the effect of Fm on insulin receptor β (IRβ)/AKT2/AS160 pathway in extensor digitorum longus (EDL) and soleus dissected from mice at 90 min of insulin stimulation with or without Fm pretreatment. Results showed that phosphorylation of AS160 was comparably increased among groups treated with Fm only, insulin only, and Fm and insulin combined in EDL. Interestingly, the phosphorylation of AKT2, the upstream kinase of AS160, was unfailingly enhanced in EDL and soleus from the group co‐treated with Fm and insulin as compared with those from other groups. Consistently, phosphorylation of IRβ, the onset of insulin signal transduction remained at a significantly higher level in the groups co‐treated with Fm and insulin compared to other groups in EDL.

Conclusion

β2AR might be involved in the enhancement of insulin‐induced glucose uptake in skeletal muscles via prolonging insulin signal transduction.

Support or Funding Information

This work was partially supported by NIH grant No. 1R15HL118696 and SSOM BBS bridge grant.
Role of renal nerves in cardiovascular nuclei and kidneys in renovascular hypertensive rats
Authors: Nishi Erika E , Gomes Guiomar N , Perry Juliana C , Simões Alex Y , Bergamaschi Cassia T , Campos Ruy R
Published: November 2023

Our aim was to investigate whether renal nerves play a role in the renal injury process and modulation of AngII receptors expression in the central nuclei and kidneys in renovascular hypertension. Denervation of clipped kidney (RD: visible bundles were dissected + 10% phenol) was performed in Wistar male rats (n=5/group) 4–5 weeks after clip implantation (gap width: 0.2mm). Ten days after RD, blood pressure (BP) was significantly reduced in the 2K‐1C rats. Gene expression of upregulated AT1R and AT2R within the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN) in the 2K‐1C group was normalized after RD. Following RD, there was no change in plasma renin activity in control and 2K‐1C rats. In order to distinguish the effects of RD from the reduction in BP, 2K‐1C rats were treated orally with hydralazine (25mg/kg/day for seven consecutive days). Hydralazine significantly reduced BP and AT1R and AT2R within the RVLM and PVN in the 2K‐1C rats. Renal injury was observed in both ischemic and contralateral kidneys of 2K‐1C rats. Following RD, renal injury was attenuated in both kidneys of hypertensive rats, however, hydralazine improved injury only in the contralateral kidney. These results demonstrate that the renal nerves contribute to AngII receptors changes within the cardiovascular nuclei and renal injury in the ischemic kidney independent of plasma renin activity in the 2K‐1C model of arterial hypertension.

Support or Funding Information

Supported by FAPESP and CNPq.
Effect of B‐type natriuretic peptide and phosphodiesterase 2A is coupled to neurotransmitter release in pro‐hypertensive rats
Authors: LIU KUN , Woodward Lavinia , Ioannides Demetris , Lu Chieh‐Ju , Li Dan , Paterson David
Published: November 2023

Background

B‐type natriuretic peptide (BNP) decreases cardiac sympathetic neurotransmission by attenuating activation of neuronal calcium channels and the intracellular calcium transient via a cGMP‐protein kinase G (PKG) pathway. Elevated levels of BNP are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. Emerging evidence suggests that phosphodiesterase 2A (PDE2A) is upregulated in heart failure. Therefore we tested whether PDE2A was directly involved in modulating cardiac neurotransmitter release and Ca2+ handling from young (pre‐hypertensive) spontaneously hypertensive rats (SHRs) that show an enhanced Ca2+ phenotype.

Methods and Results

Four week old SHRs and the normotensive Wistar‐Kyoto (WKY) rats were humanely killed by an approved Home Office (UK) schedule 1 method. Intracellular free Ca2+ concentration ([Ca2+]i) was measured by ratiometric fluorescence imaging using fura‐2AM in cultured cardiac sympathetic neurons. The evoked [Ca2+]i transient was evaluated following 30 sec exposure to 50 mM KCL in the Tyrode solution. [3H] labelled noradrenaline (NE) release was measured from isolated spontaneously beating atrial in response to 5Hz field stimulation for 1 minute at the 16th (S1, control) and 40th (S2, with BNP) minutes. BNP significantly reduced the magnitude of the calcium transients in WKY rats, but not in SHR. PDE2A protein and activity levels from the stellate ganglia were greater in SHRs (n=8) compared with WKY rats (n=8). PDE2 inhibitor Bay60‐7550 restored the capacity of BNP to reduce [Ca2+]i in the SHR. Overexpression of dnPDE2A (a catalytically‐dead mutant of PDE2A) using a viral vector (Ad.CMVmCherry. dnPDE2A) also rescued the BNP inhibition of the calcium transients from the SHR. Functionally, BNP significantly reduced [3H]‐NE release in the WKY, whereas it failed in the SHR. Overexpression of dnPDE2A recovered the BNP inhibition of the NE release in the SHR.

Conclusion

These data support the hypothesis that higher PDE2A expression in the SHR abolishes the capacity of BNP to reduce neurotransmitters release. They also suggest that inhibiting neuronal PDE2 may be important in restoring the efficacy of BNP to decrease sympathetic neurotransmission in cases of dysautonomia.

Support or Funding Information

Supported by the British Heart Foundation
The Central Deacetylase Sirtuin1 Decreases Sympathetic Hyperactivity by Anti‐oxidative Stress in Hypertensive Rats
Authors: Wang Weizhong , Wu Zhaotang , Ren Changzhen , Wang Yangkai
Published: November 2023

Hypertension is characterized by sympathetic hyperactivity, which is associated with pathophysiological progressing of hypertension. The rostral ventral lateral medulla (RVLM) plays a vital role of the sympathetic activity and blood pressure regulation. The NAD‐dependent deacetylase Sirtuin1 (Sirt1) plays an organ protective role by regulating the transcription of its target genes. Sirt1 is reported to show a protective effect in circulation system such as heart and blood vessel. However, it is not clear if Sirt1 in the RVLM is involved in modulating the central control of cardiovascular activity in hypertension. In our research work, Sirt1 was detected to be expressed in the catecholaminergic neurons in the RVLM, and Sirt1 was downregulated in the RVLM of the spontaneous hypertensive rats (SHR) compared with normotensive WKY rats. Chronic central administration of resveratrol (a specific agonist of Sirt1, 4 weeks) or injection of lentivirus containing Sirt1 gene in the RVLM produced a significant decrease in blood pressure, heart rate and renal sympathetic nerve activity in SHR but not in WKY rats. Furthermore, high level of reactive oxygen species in the RVLM was significantly reduced in SHR treated with over‐expression of Sirt1 gene in the RVLM. In summary, the present data suggest that Sirt1 in the RVLM exerts an anti‐hypertensive effect, which is associated with anti‐oxidative stress.

Support or Funding Information

This work was supported by NSCF (81570385 and 31500933)
Maximum Blood Lactate Responses Acutely and After Two Weeks of Moderate Altitude Exposure in a Large Multi‐year Study
Authors: Davis John
Published: November 2023

There has been a great deal of controversy associated with the Lactate Paradox since Edwards in 1936 proposed that maximum blood lactate responses are reduced after altitude acclimatization. Conversely, with acute ascent to altitude there are many reports that maximum blood lactate responses are unchanged. To our knowledge, no studies with a large subject pool have looked at maximum blood lactate after acute exposure, acclimatization and upon return to sea level in the same study.

Purpose

Therefore, the purpose of these studies was to determine the effect of moderate altitude exposure on maximum blood lactate acutely, after acclimatization, and upon return to sea level.

Methods

Over the course of a 6‐year period, thirty nine, active subjects (age = 23.3 ± 3.5 yrs, weight = 80.1 ± 17.5 kg, VO2max = 44.9 ± ml/kg/min) completed a graded‐exercise test to exhaustion on a cycle ergometer at sea level (SL1), upon acute exposure to 3400 m (ALT1), two weeks following acclimatization at 3400 m (ALT2), and upon return to sea level (SL2). Workloads were increased every two minutes following a two‐minute warmup until volitional fatigue. A venous blood sample was taken via an in‐dwelling catheter without stasis for subsequent lactate determination. Lactate was measured every 2 minutes during the exercise and then every 2 minutes after for 10 minutes.

Results

Maximum blood lactate was unchanged from SL1 to ALT 1 (11.87 ±2.17 vs. 11.28 ±2.33 mmol/l). However, ALT2 (9.82±1.70 mmol/l ) was significantly lower than both SL1 and ALT1. Maximum blood lactate returned to SL1 values upon return to sea level (SL2 = 11.30±2.77mmol/l).

Conclusions

These data suggest that acute altitude exposure does not result in a reduction in maximum blood lactate. However, after two weeks of acclimatization maximum blood lactate is reduced and returns to pre‐sea level values upon return to sea level.
Highland Andean Populations Show Reduced Variation in the Hypoxic Ventilatory Response
Authors: Heinrich Erica C. , Gaio Eduardo , Powell Frank L. , Macarlupú José Luis , Anza‐Ramirez Cecilia , Corante Noemi , Vizcardo‐Galindo Gustavo , Villafuerte Francisco C. , Simonson Tatum S.
Published: November 2023

Multiple adaptive phenotypes for high‐altitude and hypoxic stress have developed by distinct evolutionary trajectories in highland populations. For example, considerable variation is observed in the hypoxic ventilatory response (HVR) of Tibetans, while high altitude Andean populations show blunted responses and low variation in this trait. Evidence suggests that genetic background plays a major role in these adaptations as native highlanders exhibit adaptive signals in genomic regions containing genes related to the hypoxic response. In some cases these signals are associated with physiological differences, such as hemoglobin concentration in Tibetans, which is relatively lower than levels observed in Andeans. Few adaptive signals have been reported in more than one highland population. This suggests distinct genetic contributions to different adaptive processes in these groups. We aim to link additional hypoxia‐related phenotypes to their underlying genetic basis in order to understand how different populations have adapted to life at high altitude. The present studies examine how ventilatory control and oxygen delivery differ in high altitude Andean populations compared to lowlanders. We measured the HVR in 50 lifelong male residents of Cerro de Pasco (CDP) (4,330 m) and compared to 15 sea‐level residents tested at UC San Diego (SL) and after acclimatization at 3,800 m (HA). Andean hemoglobin values ranged from 15.2 to 27.5 g/dL (20.1 ± 2.9 g/dL, M ± SD). Consistent with previous reports, CDP residents have similar ventilation in normoxia compared to HA (CDP: 0.21 ± 0.06, HA: 0.19 ± 0.08 L·min−1·kg−1, t(62)=1.54, p=0.22) CDP residents also demonstrate a blunted HVR with less variability than observed in SL or HA (CDP: 0.002 ± 0.005, SL: 0.008 ± 0.009, HA: 0.020 ±0.013 L·min−1·kg−1·%−1, F(2, 77)=33.256, p<<0.001). Although CDP showed essentially no increase in ventilation in acute hypoxia, it is possible that oxygen delivery may increase with cardiac output, as evidenced by the expected increase in heart rate in isocapnic hypoxia (F(5,290) = 12.54, p << 0.001). CDP also consistently maintain lower end‐tidal CO2 values (26.93 ± 4.13 torr) compared to SL (34.99 ± 2.25 torr), as expected for acclimatization to high altitude, and also lower than HA (30.07 ± 2.58 torr) (F(2, 77)=29.68, p<<0.001), as expected for acclimatization to a lower altitude. Using DNA samples collected from CDP, we will test if allelic variation in candidate genes previously identified to be involved in the hypoxic response (and under selection in high‐altitude populations) explains any of the variation in these physiological variables.

Support or Funding Information

This work was supported by NIH grant T32HL098062 to FLP.
Novel Insight Regarding the Trajectory and Time‐course of Immobilisation Induced Impairment of Limb Glucose Uptake in Healthy Volunteers
Authors: Burns Aisling , Nixon Aline , Stephens Francis , Francis Susan , Gowland Penny , Greenhaff Paul
Published: November 2023

Immobilisation impairs muscle glucose uptake, which is local to the affected limb. The trajectory and time‐course of this effect in man is unknown, but is central to understanding the mechanistic basis of immobilisation induced insulin resistance and therefore was the focus of this study.

Ten healthy, young men (age 24.8±1.9 yr, body mass 72.0±8.2kg, body mass index 23.6±2.6kg/m2) completed an oral glucose tolerance test (OGTT, 75g dextrose) before (0) and at 24, 48 and 72 hr after immobilisation of the non‐dominant arm (IMM) in a cast and having subjects wear an arm support sling. On each visit, brachial artery blood flow (BAF) was measured throughout the OGTT using Doppler ultrasound and forearm glucose uptake (FGU), calculated as a function of BAF and the difference in forearm arterialised venous to venous blood glucose concentration (AV‐V), was determined at baseline and at 10 min intervals for the initial 120 min following glucose ingestion and every 15 min for 60 min thereafter. Arterialised‐venous serum insulin concentration was determined at baseline and at 20 min intervals after glucose ingestion for 120 min and every 30 min thereafter. The same measurements were also made in the non‐immobilised arm (NIMM) at 0 and 72 hr thereby establishing a control intervention. Area under the curve (AUC) for the total 180 min was calculated for FGU, BAF and serum insulin, and time (immobilised limb) and treatment (0 and 72 hr both limbs) effects were determined using repeated measures one‐way ANOVA with Tukey post‐hoc and two‐way ANOVA with Sidak post hoc analysis, respectively. Values represent mean ± SEM and statistical significance was set at p<0.05. The University of Nottingham Medical School Ethics Committee approved the study.

Forearm glucose uptake was not different between limbs at baseline (9.5±2.2 and 8.7±1.8 mmol.180min−1 in NIM and IMM, respectively), and was not reduced from baseline at 72 hr in the NIM limb (12.7±3.0 mmol.180min−1). However, FGU was less than at baseline in the IMM limb at 24 hr (38%; 5.4±1.1 mmol.180min−1, p<0.05), 48 hr (67%; 3.8±0.5 mmol.180min−1, p=0.01) and 72 hr (46%; 4.7±0.7 mmol.180min−1, p=0.06), and was also less than in NIM at 72 hr (p<0.01).

Brachial artery blood flow and arterialised‐venous serum insulin responses during the OGTT were generally unaffected by immobilisation and no different between limbs (data not shown). This study confirms the inhibitory effect of immobilisation on glucose uptake is local to the affected limb. The novel insight generated is that this effect is marked, rapid (38% within 24 hr) and sustained, and appears to be overtly muscle centric. The mechanistic basis of this precipitous induction of insulin resistance and its significance to inactivity induced impairment of metabolic health warrant further investigation.

Support or Funding Information

Arthritis Research United Kingdom
Beta‐aminoisobutyrate, a circulating metabolite which regulates beta‐cell insulin secretory function
Authors: Solomon Thomas P , Gillum Matthew
Published: November 2023

Glucose‐stimulated insulin secretion and insulin‐stimulated glucose disposal (insulin sensitivity) are related by an inverse function. A reduction in insulin sensitivity promotes increased insulin secretion in order to compensate. The mechanism for this is unknown. The objective of this work was to identify a circulating metabolite that may explain this regulation between the insulin sensitive tissue and the endocrine pancreas.

By elevating plasma glucose to ~11 mM for 24 hours we experimentally‐induced a diabetic‐like state of hyperglycemia in healthy human subjects. This caused insulin resistance and compensatory hyperinsulinemia. Using metabolomics (LC and GC‐MS) we measured 358 metabolites in plasma samples collected at baseline and after 24 hours of hyperglycemia. We then identified a short‐list of circulating metabolites which were associated with hyperglycemia‐induced changes in insulin secretory compensation.

We then measured the same 358 metabolites in the plasma of patients with type 2 diabetes. Some of these compounds were also differentially‐regulated in plasma between healthy subjects and patients with type 2 diabetes, a disease where insulin secretory function is impaired. The shortlist of compounds which correlated with group differences (i.e. healthy vs. diabetic) and hyperglycemic‐induced changes in insulin secretion were then used to incubate rat islets in culture experiments.

We identified beta‐aminoisobutyrate as a metabolite that suppressed glucose‐stimulated insulin secretion from rat islets in a dose‐response fashion. Interestingly, beta‐aminoisobutyrate is a metabolite that has been demonstrated in mice to be secreted from skeletal muscle, thus identifying it as a potential muscle‐derived regulator of beta‐cell insulin secretion. Ongoing work is determining the in vivo effect of beta‐aminoisobutyrate on insulin secretory function and determining whether it is secreted from skeletal muscle in humans.

Support or Funding Information

This work was primarily funded by the Novo Nordisk Foundation (TS).