bluuebunny/crossref_metadata_2025 huggingface dataset:
Arresting calcium-regulated sperm metabolic dynamics enables prolonged fertility in poultry liquid semen storage
Authors: Sushadi Pangda Sopha , Kuwabara Maiko , Maung Ei Ei Win , Mohamad Mohtar Mohamad Shuib , Sakamoto Kouyo , Selvaraj Vimal , Asano Atsushi
Published: December 2023

The preservation of liquid semen is pivotal for both industrial livestock production and genetic management/conservation of species with sperm that are not highly cryo-tolerant. Nevertheless, with regard to poultry semen, even brief in vitro storage periods can lead to a notable decline in fertility, despite the in vivo capacity to maintain fertility for several weeks when within the hen’s sperm storage tubules. For fertility in sperm, intracellular calcium ions ([Ca2+]i) play a key role in signaling towards modifying energy metabolism. While reducing [Ca2+]i has been found to enhance the preservation of sperm fertility in some mammals, the connection between semen fertility and calcium availability in avian sperm has received limited attention. In this study, we demonstrate that the use of extracellular and intracellular calcium chelators in liquid semen extenders, specifically EGTA and EGTA-AM, has distinct effects on prolonging the fertility of chicken sperm. These results were validated through in vivo fertility tests. Mechanistically, the effects observed were linked to coordination of mitochondrial metabolism and ATP catabolism. Despite both calcium chelators inducing hypoxia, they differentially regulated mitochondrial respiration and ATP accumulation. This regulation was closely linked to a bimodal control of dynein ATPase activity; a direct initial activation with reduction in [Ca2+]i, and subsequent suppression by cytoplasmic acidification caused by lactic acid. These findings not only contribute to advancing poultry liquid semen preservation techniques, but also elucidates biologically relevant mechanisms that may underlie storage within the female reproductive tract in birds.
Automatic GAN-based MRI volume synthesis from US volumes: a proof of concept investigation
Authors: Vukovic Damjan , Ruvinov Igor , Antico Maria , Steffens Marian , Fontanarosa Davide
Published: December 2023

Usually, a baseline image, either through magnetic resonance imaging (MRI) or computed tomography (CT), is captured as a reference before medical procedures such as respiratory interventions like Thoracentesis. In these procedures, ultrasound (US) imaging is often employed for guiding needle placement during Thoracentesis or providing image guidance in MISS procedures within the thoracic region. Following the procedure, a post-procedure image is acquired to monitor and evaluate the patient’s progress. Currently, there are no real-time guidance and tracking capabilities that allow a surgeon to perform their procedure using the familiarity of the reference imaging modality. In this work, we propose a real-time volumetric indirect registration using a deep learning approach where the fusion of multi-imaging modalities will allow for guidance and tracking of surgical procedures using US while displaying the resultant changes in a clinically friendly reference imaging modality (MRI). The deep learning method employs a series of generative adversarial networks (GANs), specifically CycleGAN, to conduct an unsupervised image-to-image translation. This process produces spatially aligned US and MRI volumes corresponding to their respective input volumes (MRI and US) of the thoracic spine anatomical region. In this preliminary proof-of-concept study, the focus was on the T9 vertebrae. A clinical expert performs anatomical validation of randomly selected real and generated volumes of the T9 thoracic vertebrae and gives a score of 0 (conclusive anatomical structures present) or 1 (inconclusive anatomical structures present) to each volume to check if the volumes are anatomically accurate. The Dice and Overlap metrics show how accurate the shape of T9 is when compared to real volumes and how consistent the shape of T9 is when compared to other generated volumes. The average Dice, Overlap and Accuracy to clearly label all the anatomical structures of the T9 vertebrae are approximately 80% across the board.
Inflammatory burden, lifestyle and atherosclerotic cardiovascular disease: insights from a population based cohort study
Authors: Bay Benjamin , Blaum Christopher , Kellner Caroline , Bei der Kellen Ramona , Ojeda Francisco , Waibel Julia , Arnold Natalie , Behrendt Christian-A. , Rimmele David L. , Thomalla Goetz , Twerenbold Raphael , Blankenberg Stefan , Zyriax Birgit , Brunner Fabian J. , Waldeyer Christoph
Published: December 2023

The inflammatory burden as measured by high-sensitivity C-reactive Protein (hsCRP) is recognized as a cardiovascular risk factor, which can however be affected by lifestyle-related risk factors (LRF). Up-to-date the interplay between hsCRP, LRF and presence and extent of atherosclerotic disease is still largely unknown, which we therefore sought to investigate in a contemporary population-based cohort. We included participants from the cross-sectional population-based Hamburg City Health Study. Affected vascular beds were defined as coronary, peripheral, and cerebrovascular arteries. LRF considered were lack of physical activity, overweight, active smoking and poor adherence to a Mediterranean diet. We computed multivariable analyses with hsCRP as the dependent variable and LRF as covariates according to the number of vascular beds affected. In the 6765 individuals available for analysis, we found a stepwise increase of hsCRP concentration both according to the number of LRF present as well as the number of vascular beds affected. Adjusted regression analyses showed an independent association between increasing numbers of LRF with hsCRP levels across the extent of atherosclerosis. We demonstrate increasing hsCRP concentrations according to both the number of LRF as well as the extent of atherosclerosis, emphasizing the necessity of lifestyle-related risk factor optimization.
A structural approach to detecting opinion leaders in Twitter by random matrix theory
Authors: Mohammadi Saeedeh , Moradi Parham , Trufanov Andrey , Jafari G. Reza
Published: December 2023

This paper presents a novel approach leveraging Random Matrix Theory (RMT) to identify influential users and uncover the underlying dynamics within social media discourse networks. Focusing on the retweet network associated with the 2021 Iranian presidential election, our study reveals intriguing findings. RMT analysis unveils that power dynamics within both poles of the network do not conform to a “one-to-many” pattern, highlighting a select group of users wielding significant influence within their clusters and across the entire network. By harnessing Random Matrix Theory (RMT) and complementary methodologies, we gain a profound understanding of the network’s structure and, in turn, unveil the intricate dynamics of the discussion extending beyond mere structural analysis. In sum, our findings underscore the potential of RMT as a tool to gain deeper insights into network dynamics, particularly within popular discussions. This approach holds promise for investigating opinion leaders in diverse political and non-political dialogues.
Doctors’ perceptions of using their digital twins in patient care
Authors: Zalake Mohan
Published: December 2023

Recent Artificial Intelligence (AI) advancements have facilitated tools capable of generating digital twins of real human faces and voices for interactive communication. In this research, we explore utilizing Digital Twins of Doctors (DTDs) in healthcare because using a doctor’s identity can provide benefits like enhancing the credibility of the health information delivered using computers. DTDs are computer-controlled AI-generated digital replicas of doctors that closely resemble their characteristics. However, there exist limitations, including the social implications of using a doctor’s identity, potential negative impacts on doctor–patient communication, and liability concerns. To ensure a comprehensive understanding of DTD usage in healthcare before widespread adoption, systematic research is essential. As a step towards this direction, in this qualitative research, we report findings from 13 semi-structured interviews with doctors. Our findings indicate that doctors believe DTDs offer benefits by saving doctors’ time through the efficient delivery of repetitive information and personalizing patient care. Moreover, while using a doctor’s identity can enhance credibility, it also raises concerns about using a doctor’s identity to spread potential misinformation. These findings contribute by informing future researchers about doctors’ perspectives on utilizing DTDs in healthcare, guiding the development of effective implementation strategies for responsible DTD integration into healthcare.
Effect of screw angulation on the bending performance of polyaxial locking interfaces: a micro-CT evaluation
Authors: Glowacki Jakub , Bartkowiak Tomasz , Paczos Piotr , Gapinski Bartosz , Mietlinski Patryk , Zawadzki Pawel , Weiss Weronika , Lapaj Lukasz
Published: December 2023

Polyaxial locking plates rely on a specific thread-to-thread interface of the screw head and the plate hole. The objective of this study was to evaluate the mechanical performance of single screw interfaces when inserted off-axis and to establish correlations between those parameters and the engagement of the screw head and the plate hole thread. Three polyaxial locking screw systems were inserted into the corresponding plates at various angles (0°, 5°, 10°, and 15° off-axis). The screws were tested until failure. A micro-CT was performed to examine the interface between the plate hole and the screw head. The standard insertion at 0° sustained the greatest maximum bending strength without relocation in the screw hole. Screws inserted at 15° showed a significant reduction in force of up to 44%, 55% and 57%, respectively. Micro-CT analysis of the interface showed a significant loss of thread engagement for off-axis insertion. Polyaxial plates offer additional advantages for off-axis placement of screws. However, this flexibility is related to a significant decrease in both thread engagement and bending strength compared to monoaxial insertion. Regardless the insertion angle, the loss of stability is comparable when screws are placed off-axis. Surgeons are advised to consider off-axis insertion as a salvage option, providing access to better bone stock.
Effect of alkali metals on physical and spectroscopic properties of cellulose
Authors: Refaat Ahmed , Elhaes Hanan , Ibrahim Medhat A.
Published: December 2023

A 3-unit cellulose model molecule was built and optimized using DFT B3LYP/6-31G(d,p). The electronic properties of the optimized structure of cellulose were investigated in terms of total dipole moment (TDM), HOMO–LUMO band gap (ΔE), and molecular electrostatic potential (MESP). Cellulose demonstrated a TDM of 9.106 Debye and ΔE of 7.647 eV. The hydrogen atom of the hydroxyl group of the CH2OH group of each cellulose unit was replaced by an alkali metal atom (X) such that the 3-unit cellulose once had 1X atom, then 2X, then 3X atoms, where X = Li, Na or K, both without and with 2, 4 and 6 water molecules (W), respectively, to study also the effect of hydration. Without hydration, the values of TDM decreased for all of the proposed interaction, but increased with hydration, while ΔE decreased in all interactions, confirming that interaction cellulose-alkali metal interaction, especially with hydration, resulted in more reactive structures. Mapping of HOMO–LUMO and MESP indicated significant change in the electron density distribution around cellulose under the effect of interaction with the alkali metals, both with and without hydration. The plots of projected density of states also clearly demonstrated the contribution of each alkali metal as well as water in the molecular orbitals, reflecting their effect on the electronic properties of cellulose and cellulose-alkali metals composites. The theoretical calculations were experimentally verified using FTIR and FT-Raman spectroscopy.
Ternary nanocomposite comprising MnO2, GQDs, and PANI as a potential structure for humidity sensing applications
Authors: Morsy Mohamed , Gomaa Islam , Abd Elhamid Abd Elhamid M. , Shawkey Heba , Aly Mohamed Aly Saad , Elzwawy Amir
Published: December 2023

Humidity sensing has been offering a noticeable contribution in different industrial, medical, and agricultural activities. Here, graphene quantum dots doped with polyaniline (PANI) and MnO2 were successfully prepared. The synthesized system is exposed to a set of structural, morphological, and optical investigations. The apparent crystallite size is less than 30 nm, reflecting the nanoscale of the structure, and thus validating the preparation route as evident on XRD pattern. SEM images show a fibrous structure where polyaniline dominates and covers most of the structure’s surface. The evident bands of the FTIR spectrum are designated to the component used in synthesis confirming the chemical structure of the fabricated system. The humidity sensing study of the synthesized structure is carried out through a wide range of relative humidity (RH) levels range of 11–97%. The response and recovery times of the fabricated structure are found to be around 120 and 220s, respectively.
Cucumber grafting on indigenous cucurbit landraces confers salt tolerance and improves fruit yield by enhancing morpho-physio-biochemical and ionic attributes
Authors: Abbas Fazal , Faried Hafiz Nazar , Akhtar Gulzar , Ullah Sami , Javed Talha , Shehzad Muhammad Asif , Ziaf Khurram , Razzaq Kashif , Amin Muhammad , Wattoo Fahad Masoud , Hafeez Aqsa , Rahimi Mehdi , Abeed Amany H. A.
Published: December 2023

Pakistan is the 8th most climate-affected country in the globe along with a semi-arid to arid climate, thereby the crops require higher irrigation from underground water. Moreover,  ~ 70% of pumped groundwater in irrigated agriculture is brackish and a major cause of secondary salinization. Cucumber (Cucumis sativus L.) is an important vegetable crop with an annual growth rate of about 3.3% in Pakistan. However, it is a relatively salt-sensitive crop. Therefore, a dire need for an alternate environment-friendly technology like grafting for managing salinity stress in cucumber by utilizing the indigenous cucurbit landraces. In this regard, a non-perforated pot-based study was carried out in a lath house to explore indigenous cucurbit landraces; bottle gourd (Lagenaria siceraria) (cv. Faisalabad Round), pumpkin (Cucurbit pepo. L) (cv. Local Desi Special), sponge gourd (Luffa aegyptiaca) (cv. Local) and ridge gourd (Luffa acutangula) (cv. Desi Special) as rootstocks for inducing salinity tolerance in cucumber (cv. Yahla F1). Four different salts (NaCl) treatments; T0 Control (2.4 dSm–1), T1 (4 dSm–1), T2 (6 dSm–1) and T3 (8 dSm–1) were applied. The grafted cucumber plants were transplanted into the already-induced salinity pots (12-inch). Different morpho-physio-biochemical, antioxidants, ionic, and yield attributes were recorded. The results illustrate that increasing salinity negatively affected the growing cucumber plants. However, grafted cucumber plants showed higher salt tolerance relative to non-grafted ones. Indigenous bottle gourd landrace (cv. Faisalabad Round) exhibited higher salt tolerance compared to non-grafted cucumber plants due to higher up-regulation of morpho-physio-biochemical, ionic, and yield attributes that was also confirmed by principal component analysis (PCA). Shoot and root biomass, chlorophylls contents (a and b), activities of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POX) enzymes, antioxidants scavenging activity (ASA), ionic (↑ K and Ca, ↓ Na), and yield-related attributes were found maximum in cucumber plants grafted onto indigenous bottle gourd landrace. Hence, the indigenous bottle gourd landrace ‘cv. Faisalabad round’ may be utilized as a rootstock for cucumber under a mild pot-based saline environment. However, indigenous bottle gourd landrace ‘cv. Faisalabad round’ may further be evaluated as rootstocks in moderate saline field conditions for possible developing hybrid rootstock and, subsequently, sustainable cucumber production.
Exposure of the US population to extreme precipitation risk has increased due to climate change
Authors: Kim Jungho , Porter Jeremy , Kearns Edward J.
Published: December 2023

The magnitude and frequency of extreme precipitation events in the early twenty-first century have already proven to be increasing at a rate more quickly than previously anticipated. Currently, the biggest consequence of the change in extreme precipitation is the lack of a climate-adjusted national standard taking into account these recent increases that could be used to prevent life and property loss from catastrophic precipitation-driven floods. Here, we address how severe the change in extreme precipitation compares against the current national standard for precipitation climatology (NOAA Atlas 14) and how much of the population is affected by the underestimation of this risk in the contiguous United States (CONUS). As a result, extreme precipitation in the early twenty-first century has outpaced our current national standard in half of CONUS, and the heavy precipitation events experienced recently are quickly becoming a “new normal”, which will increase in severity and frequency in a continually changing climate. Over three-quarters of the U.S. population will likely experience this new normal occurrence of extreme precipitation. As much as one-third of the population is expected to experience the current definition of a 1-in-100-year storm as often as three times in their lifetime. Additionally, the current precipitation standards for designing transportation infrastructure and urban stormwater drainage systems that are built upon Atlas 14 may be insufficient to protect the public's safety and personal/community property from severe flooding. Areas where flood risk is mitigated by operating hydraulic and adaptation structures urgently need to assess the impact of the increased-hourly extreme precipitation and reevaluate their applicable operation rules. Understanding and predicting patterns and the likelihood of short-duration heavy precipitation would be beneficial in preparing for severe precipitation-driven disasters, such as flash floods and landslides, which would happen more frequently in a changing climate. Following the results of this analysis, accelerating the development and dissemination of the next generation of the national standard that has been climatically adjusted to adapt to the new normal is strongly recommended.
Machine-learning guided Venom Induced Dermonecrosis Analysis tooL: VIDAL
Authors: Laprade William , Bartlett Keirah E. , Christensen Charlotte R. , Kazandjian Taline D. , Patel Rohit N. , Crittenden Edouard , Dawson Charlotte A. , Mansourvar Marjan , Wolff Darian S. , Fryer Thomas , Laustsen Andreas H. , Casewell Nicholas R. , Gutiérrez José María , Hall Steven R. , Jenkins Timothy P.
Published: December 2023

Snakebite envenoming is a global public health issue that causes significant morbidity and mortality, particularly in low-income regions of the world. The clinical manifestations of envenomings vary depending on the snake's venom, with paralysis, haemorrhage, and necrosis being the most common and medically relevant effects. To assess the efficacy of antivenoms against dermonecrosis, a preclinical testing approach involves in vivo mouse models that mimic local tissue effects of cytotoxic snakebites in humans. However, current methods for assessing necrosis severity are time-consuming and susceptible to human error. To address this, we present the Venom Induced Dermonecrosis Analysis tooL (VIDAL), a machine-learning-guided image-based solution that can automatically identify dermonecrotic lesions in mice, adjust for lighting biases, scale the image, extract lesion area and discolouration, and calculate the severity of dermonecrosis. We also introduce a new unit, the dermonecrotic unit (DnU), to better capture the complexity of dermonecrosis severity. Our tool is comparable to the performance of state-of-the-art histopathological analysis, making it an accessible, accurate, and reproducible method for assessing dermonecrosis in mice. Given the urgent need to address the neglected tropical disease that is snakebite, high-throughput technologies such as VIDAL are crucial in developing and validating new and existing therapeutics for this debilitating disease.
Decreased expression of TFF2 and decreased αGlcNAc glycosylation are malignant biomarkers of pyloric gland adenoma of the duodenum
Authors: Yamanoi Kazuhiro , Fujii Chifumi , Nakayama Atsushi , Matsuura Noriko , Takatori Yusaku , Kato Motohiko , Yahagi Naohisa , Nakayama Jun
Published: December 2023

Pyloric gland adenoma (PGA) is a duodenal neoplasm expressing MUC6 and is often associated with high-grade dysplasia and adenocarcinoma. MUC6 secreted from the pyloric gland cells carries unique O-glycans exhibiting terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). The small peptide trefoil factor 2 (TFF2) is also secreted from pyloric gland cells and binds to αGlcNAc. We recently demonstrated that αGlcNAc serves as a tumor suppressor for gastric neoplasm including PGA, but the significance of TFF2 expression remains unknown. We examined 20 lesions representing low- and high-grade PGA in 22 cases by immunohistochemistry for αGlcNAc, TFF2, MUC6, MUC5AC, MUC2 and p53. αGlcNAc, TFF2 and MUC6 were co-expressed on the cell surface and a dot-like pattern in the cytosol in low-grade PGA lesions. High-grade PGA also expressed MUC6, but reduced αGlcNAc and TFF2 expression. The ratios of αGlcNAc or TFF2 to MUC6 score in high-grade PGA were significantly lower than low-grade PGA (P < 0.001). Co-expression of αGlcNAc-glycosylated MUC6 and TFF2 in PGA suggests the existence of αGlcNAc/TFF2 form complex in PGA cells, a finding consistent with our observations in non-neoplastic Brunner’s gland cells. The decreased αGlcNAc and TFF2 expression are associated with high grade atypical cells, indicative of the malignant potential of PGA.
Domoic acid affects brain morphology and causes behavioral alterations in two fish species
Authors: Beltrán-Solís Kassandra , García-Mendoza Ernesto , Sánchez-Serrano Samuel , López Lus M.
Published: December 2023

Domoic acid (DA) produces neurotoxic damage in seabirds and marine mammals when they are exposed to this potent neurotoxin. Other vertebrates are also susceptible to DA intoxication including humans. However, neurobehavioral affectations have not been detected in fish when naturally exposed to DA but only when it is administered intraperitoneally. Therefore, the current idea is that fish are less sensitive to DA acquired under ecologically relevant routes of exposure. Here, we show that oral consumption of DA induces neurobehavioral and histopathological alterations in the brain and heart of totoaba (Totoaba macdonaldi) and striped bass (Morone saxatilis). Lesions were found in both species in the optic tectum and cerebellum after exposure for 7 days to a diet containing 0.776 µgDA g−1. The affectations prevailed chronically. Also, we found that cardiac tissue exhibits lesions and focal atrium melanism. Although affectations of the brain and heart tissue were evident, excitotoxic signs like those described for other vertebrates were not observed. However, the use of standardized behavioral tests (dark/light and antipredator avoidance tests) permitted the detection of behavioral impairment of fish after DA exposure. Pathological and associated behavioral alterations produced by DA can have relevant physiological consequences but also important ecological implications.
Longitudinal changes and variation in human DNA methylation analysed with the Illumina MethylationEPIC BeadChip assay and their implications on forensic age prediction
Authors: Refn Mie Rath , Andersen Mikkel Meyer , Kampmann Marie-Louise , Tfelt-Hansen Jacob , Sørensen Erik , Larsen Margit Hørup , Morling Niels , Børsting Claus , Pereira Vania
Published: December 2023

DNA methylation, a pivotal epigenetic modification, plays a crucial role in regulating gene expression and is known to undergo dynamic changes with age. The present study investigated epigenome-wide methylation profiles in 64 individuals over two time points, 15 years apart, using the Illumina EPIC850k arrays. A mixed-effects model identified 2821 age-associated differentially methylated CpG positions (aDMPs) with a median rate of change of 0.18% per year, consistent with a 10–15% change during a human lifespan. Significant variation in the baseline DNA methylation levels between individuals of similar ages as well as inconsistent direction of change with time across individuals were observed for all the aDMPs. Twenty-three of the 2821 aDMPs were previously incorporated into forensic age prediction models. These markers displayed larger changes in DNA methylation with age compared to all the aDMPs and less variation among individuals. Nevertheless, the forensic aDMPs also showed inter-individual variations in the direction of DNA methylation changes. Only cg16867657 in ELOVL2 exhibited a uniform direction of the age-related change among the investigated individuals, which supports the current knowledge that CpG sites in ELOVL2 are the best markers for age prediction.
Noninvasive tracking of mixed venous oxygen saturation via near-infrared spectroscopy cerebral oximetry: a retrospective observational study
Authors: Oh Chahyun , Baek Sujin , Lee Soomin , Shim Man-Shik , Han Sung Joon , Kim Yoon-Hee , Lee Jeong Yeon , Ku Yunseo , Hong Boohwi
Published: December 2023

Although previous studies have shown correlation between regional cerebral oxygen saturation (rScO2) and mixed venous oxygen saturation (SvO2), there is a lack of pragmatic information on the clinical applicability of these findings, such as tracking ability. We retrospectively analyzed continuous intraoperative recordings of rScO2 and SvO2 obtained from a pulmonary artery catheter and either of two near-infrared spectroscopy (NIRS) devices (INVOS 5100C, Medtronic; O3, Masimo) during off-pump cardiopulmonary bypass (OPCAB) surgery in adult patients. The ability of rScO2 to track SvO2 was quantitatively evaluated with 5 min interval changes transformed into relative values. The analysis included 176 h of data acquired from 48 subjects (26 and 22 subjects for INVOS and O3 dataset, respectively). The area under ROC of the left-rScO2 for detecting change of SvO2 ≥ 10% in INVOS and O3 datasets were 0.919 (95% CI 0.903–0.936) and 0.852 (95% CI 0.818–0.885). The concordance rates between the interval changes of left-rScO2 and SvO2 in INVOS and O3 datasets were 90.6% and 91.9% with 10% exclusion zone. rScO2 can serve as a noninvasive tool for detecting changes in SvO2 levels, a critical hemodynamic measurement.
Prevalence of thyroid dysfunction among Iranian older adults: a cross-sectional study
Authors: Mirahmad Maryam , Mansour Asieh , Moodi Mitra , Safkhani Elaheh , Haghpanah Vahid , Asili Pooria , Fakhrzadeh Hossein , Payab Moloud , Ebrahimpur Mahbube , Khorashadi Masoumeh , Khodabakhshi Huriye , Esmaeili Ali Akbar , Sharifzadeh Gholamreza , Zarban Asghar , Sharifi Farshad , Sajjadi-Jazi Sayed Mahmoud
Published: December 2023

There is limited data on the prevalence of thyroid dysfunction in the older population. This study aimed to determine the prevalence of thyroid dysfunction among a sample of Iranian older adults. A cross-sectional analysis of older adults who aged 60 years and over was conducted. A total of 363 subjects were randomly selected from Birjand longitudinal aging study (BLAS) cohort study. Serum thyroid-stimulating hormone (TSH) level, total thyroxine (T4) and total triiodothyronine (T3) were measured by the enzyme-linked immunosorbent assay (ELISA). Based on thyroid function tests and history of taking medicines used to treat thyroid disorders, participants were classified into the following groups: euthyroid, overt/subclinical hypothyroidism, and overt/subclinical hyperthyroidism. Subsequently, the crude and World Health Organization (WHO) age-standardized prevalence were estimated for different thyroid function categories. A total of 171 men and 192 women, aged 60–94 years, were randomly selected. The crude prevalence of total hypothyroidism was 22.31% (subclinical [18.46%], overt [3.86%]), and that of hyperthyroidism was 1.66% (subclinical [1.38%], overt [0.28%]). The crude prevalence of total thyroid dysfunction was, therefore, 23.97%. A female preponderance was noticed in both total (P-value = 0.035) and overt (P-value = 0.035) hypothyroidism. An increasing trend with age was noticed in the prevalence of total hypothyroidism (P-value = 0.049). Age-standardized prevalence of total hypothyroidism and hyperthyroidism was 26.63% (95% confidence interval [CI] 20.58–33.69%) and 1.11% (95% CI 0.49–2.51%), respectively. A considerable proportion of our study population demonstrated evidence of thyroid dysfunction, particularly subclinical hypothyroidism. Our findings highlight the importance of further investigation of thyroid disorders among older Iranian adults.
The optimal puncture time point of prolonged occlusion flow-mediated dilatation in radial artery catheterization: a prospective observational study
Authors: Qi Wensheng , Ma Haichun , Wu Xuehan , Wei Kun , Li Yanhui
Published: December 2023

Previous studies have demonstrated prolonged occlusion flow-mediated dilatation (PO-FMD) could reduce cannulation failure rates and decrease radial artery pulsation loss during trans-radial coronary angiography. However, the time and degree of radial artery dilatation induced after PO-FMD were unclear. This study aimed to evaluate the degree and duration of the radial artery dilation after PO-FMD, and the time point at which the radial artery diameter is expanded to the maximum. This was a prospective observational study. According to the Chinese guideline on the primary prevention of cardiovascular diseases, 142 patients awaking from general anesthesia were divided into two groups: low-risk (LR) group and high-risk (HR) group. Firstly, the baseline radial artery diameter was measured on the left wrist using ultrasound in both groups. Subsequently, the radial artery diameters were obtained continuously at the same location for 5 min after PO-FMD. The baseline radial artery diameter, the maximum radial artery diameter, and the duration of radial artery dilation in the two groups were recorded. The time point at which the radial artery diameter is expanded to the maximum in the LR group and HR group was 26.49 ± 11.69 s and 46.27 ± 12.03 s, respectively (P < 0.01). The time of radial artery dilation and the percentage changes in arterial diameter in HR group were significantly lower than LR group (duration time: mean [mean ± standard]: 136.65 ± 31.55 s vs. 168.98 ± 33.27 s; percentage changes: median [interquartile range] 10.5 [8.6, 12.9] % vs. 15.2 [12.4, 19.0] %). In this study, the optimal puncture time point of PO-FMD in the LR group was 26 s, and in the HR group was 46 s. It would be helpful to guide the time point in radial artery catheterization after PO-FMD.

Chinese Clinical Trial Registry identifier: ChiCTR2200066214.
Exploring the role of cyclodextrins as a cholesterol scavenger: a molecular dynamics investigation of conformational changes and thermodynamics
Authors: Ganjali Koli Mokhtar , Fogolari Federico
Published: December 2023

This study presents a comprehensive analysis of the cholesterol binding mechanism and conformational changes in cyclodextrin (CD) carriers, namely βCD, 2HPβCD, and MβCD. The results revealed that the binding of cholesterol to CDs was spontaneous and thermodynamically favorable, with van der Waals interactions playing a dominant role, while Coulombic interactions have a negligible contribution. The solubility of cholesterol/βCD and cholesterol/MβCD complexes was lower compared to cholesterol/2HPβCD complex due to stronger vdW and Coulombic repulsion between water and CDs. Hydrogen bonding was found to have a minor role in the binding process. The investigation of mechanisms and kinetics of binding demonstrated that cholesterol permeates into the CD cavities completely. Replicas consideration indicated that while the binding to 2HPβCD occurred perpendicularly and solely through positioning cholesterol's oxygen toward the primary hydroxyl rim (PHR), the mechanism of cholesterol binding to βCD and MβCD could take place with the orientation of oxygen towards both rims. Functionalization resulted in decreased cavity polarity, increased constriction tendency, and altered solubility and configuration of the carrier. Upon cholesterol binding, the CDs expanded, increasing the cavity volume in cholesterol-containing systems. The effects of cholesterol on the relative shape anisotropy (κ2) and asphericity parameter (b) in cyclodextrins were investigated. βCD exhibited a spherical structure regardless of cholesterol presence, while 2HPβCD and MβCD displayed more pronounced non-sphericity in the absence of cholesterol. Loading cholesterol transformed 2HPβCD and MβCD into more spherical shapes, with increased probabilities of higher κ2. MβCD showed a higher maximum peak of κ2 compared to 2HPβCD after cholesterol loading, while 2HPβCD maintained a significant maximum peak at 0.2 for b.
Rotavirus genotype diversity in Tanzania during Rotavirus vaccine implementation between 2013 and 2018
Authors: Michael Fausta , Mirambo Mariam M. , Lyimo Dafrossa , Salehe Abdul , Kyesi Furaha , Msanga Delfina R. , Mahamba Dina , Nyawale Helmut , Kwiyolecha Elizabeth , Okamo Bernard , Mwanyika Paul J. , Maghina Victoria , Bendera Elice , Salehe Mohammed , Hokororo Adolfine , Mwipopo Ernestina , Khamis Asha C. , Nyaki Honest , Magodi Richard , Mujuni Delphius , Konje Eveline T. , Katembo Betina , Wilillo Ritha , Mshana Stephen E.
Published: December 2023

The study aims to determine Rotavirus genotypes between 2013 and 2018 during implementation of ROTARIX vaccine in Tanzania. The analysis of surveillance data obtained between 2013 and 2018 was done to determine circulating genotypes after introduction of Rotarix vaccine. From 2013 to 2018, a total of 10,557 samples were collected and screened for Rotavirus using an enzyme immunoassay. A significant decrease in Rotavirus positivity (29.3% to 17.8%) from 2013 to 2018 (OR 0.830, 95% CI 0.803–0.857, P < 0.001) was observed. A total of 766 randomly selected Rotavirus positive samples were genotyped. Between 2013 and 2018, a total of 18 Rotavirus genotypes were detected with G1P [8] being the most prevalent. The G1P [8] strain was found to decrease from 72.3% in 2015 to 13.5% in 2018 while the G9P [4] strain increased from 1 to 67.7% in the same years. G2P [4] was found to decrease from 59.7% in 2013 to 6.8% in 2018 while G3P [6] decreased from 11.2% in 2014 to 4.1% in 2018. The data has clearly demonstrated that ROTARIX vaccine has provided protection to varieties of the wild-type Rotavirus strains. Continuous surveillance is needed to monitor the circulation of Rotavirus strains during this era of vaccine implementation.
Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition
Authors: Sengal Asmerom T. , Bonazzi Vanessa , Smith Deborah , Moiola Cristian P. , Lourie Rohan , Rogers Rebecca , Colas Eva , Gil-Moreno Antonio , Frentzas Sophia , Chetty Naven , Perrin Lewis , Pollock Pamela M.
Published: December 2023

Endometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. Here we report the establishment of 16 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. In vitro treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial.
Transcranial photobiomodulation improves insulin therapy in diabetic microglial reactivity and the brain drainage system
Authors: Liu Shaojun , Li Dongyu , Yu Tingting , Zhu Jingtan , Semyachkina-Glushkovskaya Oxana , Zhu Dan
Published: December 2023

The dysfunction of microglia in the development of diabetes is associated with various diabetic complications, while traditional insulin therapy is insufficient to rapidly restore the function of microglia. Therefore, the search for new alternative methods of treating diabetes-related dysfunction of microglia is urgently needed. Here, we evaluate the effects of transcranial photobiomodulation (tPBM) on microglial function in diabetic mice and investigate its mechanism. We find tPBM treatment effectively improves insulin therapy on microglial morphology and reactivity. We also show that tPBM stimulates brain drainage system through activation of meningeal lymphatics, which contributes to the removal of inflammatory factor, and increase of microglial purinergic receptor P2RY12. Besides, the energy expenditure and locomotor activity of diabetic mice are also improved by tPBM. Our results demonstrate that tPBM can be an efficient, non-invasive method for the treatment of microglial dysfunction caused by diabetes, and also has the potential to prevent diabetic physiological disorders.
Phenotypic profiling of solute carriers characterizes serine transport in cancer
Authors: Papalazarou Vasileios , Newman Alice C. , Huerta-Uribe Alejandro , Legrave Nathalie M. , Falcone Mattia , Zhang Tong , McGarry Lynn , Athineos Dimitris , Shanks Emma , Blyth Karen , Vousden Karen H. , Maddocks Oliver D. K.
Published: December 2023

Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes
Authors: Parker Victoria E. R. , Robertson Darren , Erazo-Tapia Edmundo , Havekes Bas , Phielix Esther , de Ligt Marlies , Roumans Kay H. M. , Mevenkamp Julian , Sjoberg Folke , Schrauwen-Hinderling Vera B. , Johansson Edvin , Chang Yi-Ting , Esterline Russell , Smith Kenneth , Wilkinson Daniel J. , Hansen Lars , Johansson Lars , Ambery Philip , Jermutus Lutz , Schrauwen Patrick
Published: December 2023

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994.
A mechanistic marker-based screening tool to predict clinical immunogenicity of biologics
Authors: Jarvi Nicole L. , Balu-Iyer Sathy V.
Published: December 2023

Background

The efficacy and safety of therapeutic proteins are undermined by immunogenicity driven by anti-drug antibodies. Immunogenicity risk assessment is critically necessary during drug development, but current methods lack predictive power and mechanistic insight into antigen uptake and processing leading to immune response. A key mechanistic step in T-cell-dependent immune responses is the migration of mature dendritic cells to T-cell areas of lymphoid compartments, and this phenomenon is most pronounced in the immune response toward subcutaneously delivered proteins.

Methods

The migratory potential of monocyte-derived dendritic cells is proposed to be a mechanistic marker for immunogenicity screening. Following exposure to therapeutic protein in vitro, dendritic cells are analyzed for changes in activation markers (CD40 and IL-12) in combination with levels of the chemokine receptor CXCR4 to represent migratory potential. Then a transwell assay captures the intensity of dendritic cell migration in the presence of a gradient of therapeutic protein and chemokine ligands.

Results

Here, we show that an increased ability of the therapeutic protein to induce dendritic cell migration along a gradient of chemokine CCL21 and CXCL12 predicts higher immunogenic potential. Expression of the chemokine receptor CXCR4 on human monocyte-derived dendritic cells, in combination with activation markers CD40 and IL-12, strongly correlates with clinical anti-drug antibody incidence.

Conclusions

Mechanistic understanding of processes driving immunogenicity led to the development of a predictive tool for immunogenicity risk assessment of therapeutic proteins. These predictive markers could be adapted for immunogenicity screening of other biological modalities.
Localisation, isolation and leaching of single hot particles from various environmental matrices in the vicinity of the Chernobyl nuclear power plant
Authors: Leifermann Laura , Weiss Martin , Chyzhevskyi Ihor , Dubchak Sergiy , Hanemann Paul , Raiwa Manuel , Schulz Wolfgang , Steinhauser Georg , Weissenborn Tobias , Walther Clemens
Published: December 2023

For decades now, leaching and corrosion of fuel-containing ‘hot’ particles have been a constant source of bioavailable contamination in the Chernobyl Exclusion Zone. With the decline in average size and activity of these particles due to weathering effects, their identification and separation from various environmental matrices has become increasingly difficult. In this work, we showcase and compare the applicability of different identification methods for the extraction of very small (10-200 µm in diameter) individual particles. Flotation and radiometric methods are optimized to the environmental matrix and particle type. Single particles glued to tungsten needles are immersed into liquids to correlate radionuclide leaching with particle morphology and composition.
A molecular dynamics study of helium clustering in high temperature plutonium dioxide
Authors: Murray Elanor , Zhou Ying , Slater Peter , Smith Roger , Goddard Pooja , Steele Helen
Published: December 2023

The behaviour of helium in high temperature PuO2 has been examined via molecular dynamics calculations. In an initially defect free lattice helium is mobile at temperatures above 1500 K, making inter-site hops via thermally generated oxygen vacancies. Over a 5 ns time scale, helium clustering does not occur until above 2400 K, at which temperature temporary plutonium Frenkel pairs are possible. The created Pu vacancy can be pinned by either oxygen vacancies (as a Schottky trio), or by the addition of extra He before Pu recombination occurs. This site then acts as a helium cluster seed location to which further He can be attracted. The time evolution of helium clusters was analysed and a mean He:vacancy ratio of 0.75:1 was obtained. Throughout the dynamical evolution of the cluster, a He:vacancy ratio below 1:1 was always found in contrast to previous static calculations which predicted a theoretical maximum ratio of 3.5:1.
Research reactor support for nuclear forensics studies and the development of a companion graduate course
Authors: Landsberger S. , Haas D.
Published: December 2023

The term nuclear forensics encompasses the detection and analysis of nuclear materials before they are used in a weapon, the analysis of radioactive debris following a nuclear event or the investigation of the pedigree of nuclear materials in non-proliferation. Nuclear forensics typically encompasses these three main broad areas: radiochemistry, chemical instrumentation and non-destructive techniques (typically gamma-ray spectrometry). Research reactors (10kW – 10MW) are a great resource to perform research and development in nuclear forensics as well as in the critical need of education. Research reactors' ability to produce isotopes in small or large amounts means that researchers have a unique source of material for nuclear forensics studies. A graduate course in nuclear forensics was developed as a companion to a research project with a grant through the US Department of Homeland Security. Besides the usual lectures on the basics of nuclear phenomena, a successful effort was made to include a significant amount of historical background. In addition, several guest lecturers from national laboratories and universities were added to the curriculum, resulting in a more meaningful and current course. Due to COVID-19 restrictions, all the laboratories were virtually delivered in both fully remote and hybrid modes across several semesters.