bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of DPP-4 Inhibitors on Interleukin Levels in Type 2 Diabetes Mellitus
Authors: Feng Yiduo , Shang Beibei , Yang Yu , Zhang Donglei , Liu Changbin , Qin Zheng , Zhou Yilun , Meng Jie , Liu Xin 
Published: November 2024

Abstract

Background and Objective
Accumulating evidence had implicated pathological involvement of interleukins (ILs) in progression and complications in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP-4i) produced favorable effects on glucose homeostasis in T2DM. This study aimed to evaluate the impact of DPP-4i on IL concentrations in T2DM.

Data Sources
PubMed, Embase, and the Cochrane library were systematically searched for relevant articles from inception to May 31, 2024. The search included DPP-4i, T2DM, and randomized controlled trials (RCTs) and related terms.

Study Selection and Data Extraction
Placebo- or active agents-controlled human studies were screened. All the RCTs were identified if they provided detailed information on changes of ILs during DPP-4i treatment.

Data Synthesis
A total of 14 RCTs involving 850 participants were identified. Pooled estimates revealed that DPP-4i significantly lowered IL-6 concentrations (−0.54 pg/mL; 95% CI, −0.82 to −0.25; I2 = 10%, P = .0003) compared to placebo. Similar effects were demonstrated for IL-1β (−16.33 pg/mL; 95% CI, −19.56 to −13.11; I2 = 0%, P &lt; .00001), whereas the effect on IL-18 was not statistically significant (−13.55 pg/mL; 95% CI, −76.95 to 49.85; I2 = 0%, P = .68). Subgroup analysis on IL-6 demonstrated that marked effects were found in groups of basal IL-6 concentrations (&lt; 5 pg/mL), body mass index (≥ 28 kg/m2) and type of DPP-4i (linagliptin).

Conclusion
DPP-4i favorably decreased IL-6 levels in patients with T2DM. The impact of DPP-4i on IL-1β and IL-18 needed to be explored with more studies. Further trials should be performed to elucidate this anti-inflammatory effect of DPP-4i during treatment of T2DM.
Homozygous Familial Hypercholesterolemia in Spain: Data From Registry of the Spanish Atherosclerosis Society
Authors: Sánchez-Hernández Rosa M , Ibarretxe Daiana , Fuentes Jiménez Francisco , Martínez-Hervás Sergio , Blanco-Echevarría Agustín , Cortés Rodríguez Begoña , Rodríguez-Carnero Gemma , Martín Ordiales María Mercedes , Pérez Antonio , González-Bustos Pablo , Argüeso Armesto Rosa , Sánchez-Sobrino Paula , Masana Luis , Civeira Fernando 
Published: November 2024

Abstract

Context
Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by the presence of 2 pathogenic variants in the LDLR, APOB, PCSK9, or LDLRAP1 genes, which cause very high levels of LDL-cholesterol and premature atherosclerotic cardiovascular disease (ASCVD).

Objective
To analyze the current situation regarding diagnosis, cardiovascular disease, lipid-lowering treatment, and degree of control of lipids in patients with HoFH in the National Dyslipidemia Registry of the Spanish Atherosclerosis Society.

Methods
Subjects with HoFH, confirmed by the presence of 2 pathogenic variants in the genes mentioned above, included in the registry from 2013 to June 2023 with an updated review were analyzed.

Results
Of 71 included subjects with HoFH, 40.8% were women, aged 52 [24-62] years, 57 adults and 13 children. The median follow-up was 7 [4-13] years. Age of diagnosis was 14 [2-26] years, with 10% of ASCVD at diagnosis and 27% of current ASCVD at 40.6 (13.4) years of age; 38% were on PCSK9 inhibitors, 9 patients on lomitapide, 9 on LDL apheresis, and 1 patient on evinacumab. Subjects with more than 4 therapies achieved &gt;80% reduction in LDLc. In the last visit, the median LDLc was 139.3 [89.4-204.2] mg/dL. ASCVD was strongly associated with male sex and family history of ASCVD, relative risk 5.26 (1.53-18.10) and 2.53 (1.03-6.26), P &lt; .05, respectively. Only 18% and 10% meet the recommended LDLc goal in primary and secondary prevention respectively.

Conclusion
The current situation of HoFH in Spain is better than expected, with marked reductions in LDLc levels with new treatments. In this population, recommended LDLc goals are difficult to achieve despite maximum lipid-lowering therapy. ASCVD has been reduced and delayed by 2 decades.
RNA-first Approach Identifies Deep Intronic PHEX Variants in X-linked Hypophosphatemic Rickets
Authors: Ludwig Karissa , Wu Zenghui , Bardai Ghalib , Miranda Valancy , Alos Nathalie , Ward Leanne M , Rauch Frank 
Published: November 2024

Abstract

Context
Up to 20% of patients with X-linked hypophosphatemic rickets (XLH) have no causative variant identified on routine molecular diagnostic testing.

Objective
To identify intronic variants causing PHEX mis-splicing in patients with XLH.

Setting
The metabolic bone clinic of a pediatric orthopedic hospital.

Participants
Four patients (age 6 to 12 years; 3 girls) with clinically diagnosed XLH and no PHEX variant on routine testing.

Main Outcome Measures
RNA and DNA sequence analysis of PHEX.

Methods
Urine-derived cells were cultured, and mRNA was extracted and transcribed to cDNA. PHEX cDNA was amplified by PCR, followed by sequencing of PCR products. Sequencing of PHEX intronic DNA regions was performed to identify variants causing mis-splicing observed on RNA analysis.

Results
PHEX mis-splicing was identified in 3 of the 4 participants, and an intronic variant was identified in all 3 cases. In a 12-year-old boy, transcript analysis showed skipping of PHEX exon 13, while sequencing of PHEX intronic regions revealed a de novo 18 bp deletion in intron 13. In a 7-year-old girl, a pseudoexon in PHEX intron 17 was found, associated with a de novo deep intronic variant (c.1768 + 173A &gt; G) that activated a cryptic splice donor site. Finally, an 84 bp pseudoexon in PHEX intron 21 caused by a recurrent de novo deep intronic variant (c.2147 + 1197A &gt; G) was identified in an 11-year-old girl.

Conclusion
Analysis of RNA from urine-derived cells combined with sequencing of PHEX introns can identify deep intronic variants in individuals with XLH without a detectable PHEX variant in routine exon-centric molecular diagnosis.
F2-Isoprostanes Are Associated With Increased Fracture Risk in Type 2 Diabetes
Authors: Wang Bowen , Dhaliwal Ruban , Ewing Susan K , Schwartz Ann V , Vashishth Deepak 
Published: November 2024

Abstract

Context
Fracture risk is higher in type 2 diabetes (T2D) for a given bone mineral density (BMD) level. Increased oxidative stress in T2D induces diabetic complications and may affect T2D bone fragility.

Objective
To investigate whether the levels of plasma F2-isoprostanes, a reliable oxidative stress marker, are associated with incident clinical fracture risk in older adults with diabetes.

Methods
An observational cohort study was conducted in a well-characterized cohort from Health, Aging, and Body Composition study.

Participants
Older Black and White ambulatory adults with baseline plasma F2-isoprostanes measurements (baseline age 70-79 years, T2D: N = 132; nondiabetes: N = 571) were selected from the study cohort of 3075 individuals. Risk of incident clinical fractures was assessed.

Results
In the Cox proportional hazard model with multivariate adjustments (including BMD, medications, and other risk factors), a 93% increase in incident clinical fracture risk was significantly associated with each SD increase in log plasma F2-isoprostanes in the T2D group (hazard ratio [HR] = 1.93 [95% CI, 1.26-2.9] P = .002), but there was no evidence of an association in the nondiabetes group (HR = 0.98 [95% CI 0.81-1.18] P = .79, P for interaction &lt;.001). Log plasma F2-isoprostanes were moderately correlated with a decline in baseline total hip BMD (r = −0.25, P = .003), and with a 4-year decrease in total hip BMD (r = −0.28, P = .008) in T2D. There was no evidence of correlation between log plasma F2-isoprostanes and circulating glycoxidation markers or bone turnover markers in either group.

Conclusion
Plasma F2-isoprostanes levels in individuals with diabetes are associated with increased incident clinical fracture risk independently of baseline BMD.
Genetics and Bone Mineral Density Predict the Fractures in Adults With Osteogenesis Imperfecta: A Prospective Study
Authors: Blandin Camille , Collet Corinne , Ostertag Agnes , Funck-Brentano Thomas , Cohen-Solal Martine 
Published: November 2024

Abstract

Context
Osteogenesis imperfecta (OI) is a rare genetic bone disorder characterized by recurrent fractures. In adults, the value of bone mineral density (BMD) in fracture risk is unknown.

Objective
We prospectively investigated changes in BMD over time and analyzed the determinants of fracture in OI.

Methods
Among 106 individuals with grade 1 and 4 OI in the Reference Centre of Rare Bone Diseases in Paris, we included those with BMD measurements at 1 or more skeletal sites (hip, lumbar spine, radius) from 2000 to 2022.

Results
For 71 individuals with reliable measurements (44 women, 8 postmenopausal; mean age 41.4 ± 13.7 years), baseline BMD was low at the lumbar spine only (mean Z-score −2.3 ± 1.5), affecting mainly men (mean Z-score −3 ± 1.6). Longitudinal changes were assessed for a median follow-up of 5.1 years (interquartile range 3.2-8.8). On adjustment for age, sex, and body mass index, BMD did not significantly change at any site. Logistic regression analysis revealed a high probability of fracture with baseline BMD Z-score &lt;−2 SD vs ≥−2 SD [odds ratio 4.38, 95% confidence interval (CI) 1.10-21.75, P = .048] and harboring splicing, stop codon, and frameshift variants of COL1 gene (odds ratio 29.8, 95% CI 2.56-1503, P = .024).

Conclusion
Our OI cohort showed low BMD at the lumbar spine but no significant change at any site after a median of 5.0 years of follow-up. The probability of fracture was associated with baseline BMD Z-score &lt;−2 SD vs ≥−2 SD and harboring COL1 splicing, stop codon, and frameshift variants.
Establishment of CRISPR/Cas9-based knock-in in a hemimetabolous insect: targeted gene tagging in the cricket Gryllus bimaculatus
Authors: Matsuoka Yuji , Nakamura Taro , Watanabe Takahito , Barnett Austen A. , Tomonari Sayuri , Ylla Guillem , Whittle Carrie A. , Noji Sumihare , Mito Taro , Extavour Cassandra G. 
Published: November 2024

ABSTRACT
Studies of traditional model organisms such as the fruit fly Drosophila melanogaster have contributed immensely to our understanding of the genetic basis of developmental processes. However, the generalizability of these findings cannot be confirmed without functional genetic analyses in additional organisms. Direct genome editing using targeted nucleases has the potential to transform hitherto poorly understood organisms into viable laboratory organisms for functional genetic study. To this end, we present a method to induce targeted genome knockout and knock-in of desired sequences in an insect that serves as an informative contrast to Drosophila, the cricket Gryllus bimaculatus. The efficiency of germline transmission of induced mutations is comparable with that reported for other well-studied laboratory organisms, and knock-ins targeting introns yield viable, fertile animals in which knock-in events are directly detectable by visualization of a fluorescent marker in the expression pattern of the targeted gene. Combined with the recently assembled and annotated genome of this cricket, this knock-in/knockout method increases the viability of G. bimaculatus as a tractable system for functional genetics in a basally branching insect.
Differential vegfc expression dictates lymphatic response during zebrafish heart development and regeneration
Authors: Duca Sierra , Xia Yu , Abd Elmagid Laila , Bakis Isaac , Qiu Miaoyan , Cao Yingxi , Guo Ylan , Eichenbaum James V. , McCain Megan L. , Kang Junsu , Harrison Michael R. M. , Cao Jingli 
Published: November 2024

ABSTRACT
Vascular endothelial growth factor C (Vegfc) is crucial for lymphatic and blood vessel development, yet its cellular sources and specific functions in heart development remain unclear. To address this, we created a vegfc reporter and an inducible overexpression line in zebrafish. We found vegfc expression in large coronary arteries, circulating thrombocytes, cardiac adipocytes, and outflow tract smooth muscle cells. Notably, although coronary lymphangiogenesis aligns with Vegfc-expressing arteries in juveniles, it occurs only after coronary artery formation. Vegfc overexpression induced ectopic lymphatics on the ventricular surface prior to arterial formation, indicating that Vegfc abundance, rather than arterial presence, drives lymphatic development. However, this overexpression did not affect coronary artery coverage, suggesting a specific role for Vegfc in lymphatic, rather than arterial, development. Thrombocytes emerged as the initial Vegfc source during inflammation following heart injuries, transitioning to endocardial and myocardial expression during regeneration. Lower Vegfc levels in an amputation model corresponded with a lack of lymphatic expansion. Importantly, Vegfc overexpression enhanced lymphatic expansion and promoted scar resolution without affecting cardiomyocyte proliferation, highlighting its role in regulating lymphangiogenesis and promoting heart regeneration.
Shear stress-stimulated AMPK couples endothelial cell mechanics, metabolism and vasodilation
Authors: Cronin Nicholas M. , Dawson Logan W. , DeMali Kris A. 
Published: November 2024

ABSTRACT
Endothelial cells respond to mechanical force by stimulating cellular signaling, but how these pathways are linked to elevations in cell metabolism and whether metabolism supports the mechanical response remains poorly understood. Here, we show that the application of force to endothelial cells stimulates VE-cadherin to activate liver kinase B1 (LKB1; also known as STK11) and AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. VE-cadherin-stimulated AMPK increases eNOS (also known as NOS3) activity and localization to the plasma membrane, reinforcement of the actin cytoskeleton and cadherin adhesion complex, and glucose uptake. We present evidence for the increase in metabolism being necessary to fortify the adhesion complex, actin cytoskeleton and cellular alignment. Together, these data extend the paradigm for how mechanotransduction and metabolism are linked to include a connection to vasodilation, thereby providing new insight into how diseases involving contractile, metabolic and vasodilatory disturbances arise.
Topology surveillance of the lanosterol demethylase CYP51A1 by signal peptide peptidase
Authors: Sergejevs Nikita , Avci Dönem , van de Weijer Michael L. , Corey Robin A. , Lemberg Marius K. , Carvalho Pedro 
Published: November 2024

ABSTRACT
Cleavage of transmembrane segments on target proteins by the aspartyl intramembrane protease signal peptide peptidase (SPP, encoded by HM13) has been linked to immunity, viral infection and protein quality control. How SPP recognizes its various substrates and specifies their fate remains elusive. Here, we identify the lanosterol demethylase CYP51A1 as an SPP substrate and show that SPP-catalysed cleavage triggers CYP51A1 clearance by endoplasmic reticulum-associated degradation (ERAD). We observe that SPP targets only a fraction of CYP51A1 molecules, and we identify an amphipathic helix in the CYP51A1 N terminus as a key determinant for SPP recognition. SPP recognition is remarkably specific to CYP51A1 molecules with the amphipathic helix aberrantly inserted in the membrane with a type II orientation. Thus, our data are consistent with a role for SPP in topology surveillance, triggering the clearance of certain potentially non-functional conformers.
Balanced crystalloids for fluid resuscitation in diabetic ketoacidosis in place of saline
Authors: Jones Adam F , Jadzinski Patryk , Brickell Tracey L 
Published: November 2024

Background: Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes. With rising mortality from the condition and associated healthcare costs, prompt prehospital recognition and optimum management are necessary to improve patient outcomes. Upon recognition of DKA, it is recommended that fluid resuscitation be started immediately with sodium chloride 0.9%. Aim: To examine the literature investigating the effectiveness of balanced crystalloids and saline in the management of DKA and the potential implications of this for practice. Methodology: A literature review was undertaken using five databases and the evidence was critically appraised. Themes were developed to explore the results. Results: The three included studies indicated that balanced crystalloids may lead to faster DKA resolution than saline. Better electrolyte outcomes were also noted in the balanced crystalloid group, with no increased adverse effects observed. Conclusion: The adoption of balanced crystalloids in the prehospital setting has the potential to improve patient outcomes. Further research and clinical trials are required to validate these findings and inform guideline revisions.
Nonlinearity mitigation in bandwidth limited blue LED-based OFDM-UOWC systems using differential pre-emphasis
Authors: Krishna Gopal , Mathew Jimson , Gupta Sumanta 
Published: November 2024

Direct current biased optical orthogonal frequency division multiplexing (DCO-OFDM) is widely used in blue light-emitting diode (LED)–based underwater optical wireless communication (UOWC), but the limited LED bandwidth leads to nonlinear distortions at higher frequencies. Using experiments, this paper proposes and validates a differential pre-emphasis (DPE) scheme for OFDM signal transmission in underwater channels to mitigate LED modulation bandwidth-induced nonlinearity, therefore improving transmission system performance. It is shown that the optimum DPE value leads to shorter rise time and fall time of the received signal and also avoids over- and under-shoots. The DPE scheme is validated through numerical simulations for QPSK, 16-QAM, and 64-QAM at symbol rates of 10 MS/s, 20 MS/s, and 25 MS/s, respectively, with an LED bandwidth of 8 MHz. The bit error rate (BER) performances are estimated at different values of the DPE factor for each modulation format and symbol rate. The simulation results indicate an optimized modulation format and symbol rate-dependent DPE factor for achieving minimum BER values. We further validate the DPE scheme on QPSK, 16-QAM, and 64-QAM-based OFDM transmissions in a 2.5 m tap water UOWC experimental setup. Results confirm that the optimized DPE factor depends on the modulation format and symbol rate for achieving the best BER performance. Experimental results show that the DPE scheme improves BER performance significantly, providing over 4 orders of BER improvement for all modulation formats at their respective maximum symbol rates. Successful transmissions of the OFDM signal at data rates of 24.09 Mb/s for QPSK, 48.19 Mb/s for 16-QAM, and 72.28 Mb/s for 64-QAM using an 8 MHz blue-LED-based transmitter in the presence and absence of air-bubble-induced turbulence in the water channel are experimentally demonstrated in this paper.
Association of METS-IR index with Type 2 Diabetes: A cross-sectional analysis of national health and nutrition examination survey data from 2009 to 2018
Authors: Hou Yisen , Li Rui , Xu Zhen , Chen Wenhao , Li Zhiwen , Jiang Weirong , Meng Yong , Han Jianli 
Published: November 2024

Background
With rising global diabetes prevalence, precise early identification and management of diabetes risk are critical research areas. The metabolic score for insulin resistance (METS-IR), a novel non-insulin-based tool, is gaining attention for quantifying insulin resistance using multiple metabolic parameters. Despite its potential in predicting diabetes and its precursors, evidence on its specific relationship with diabetes is limited, especially in large-scale population validation and mechanistic exploration.

Objective
This study aims to analyze the association between METS-IR and type 2 diabetes (T2DM) in American adults.

Methods
We conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) data from 2009 to 2018. Participants aged 20 years and above were included, excluding individuals with missing data on BMI, fasting blood glucose, high-density lipoprotein cholesterol glycated hemoglobin and diabetes status. Logistic regression analysis, subgroup analysis, and restricted cubic spline analysis were used to assess the association between METS-IR and T2DM, controlling for potential confounding factors.

Results
After adjusting for age, gender, race, education level, smoking status, drinking habits, depression, physical activity, hypertension, and hyperlipidemia, we found a positive association between METS-IR and the risk of T2DM. Specifically, each unit increase in METS-IR was associated with a 7% increase in the risk of T2DM (OR = 1.07, 95% CI: 1.06, 1.08). Subgroup analysis showed that the association between METS-IR and T2DM incidence was significantly positive in the highest quartile group, particularly among Mexican Americans over 40 years old and those diagnosed with depression, hypertension, or hyperlipidemia.

Conclusion
Our study revealed a significant positive association between METS-IR and the prevalence of T2DM, indicating that this relationship persists even after controlling for various confounding factors. Therefore, monitoring METS-IR may provide a valuable tool for the early identification of individuals at risk of glucose metabolism disorders. Further research should focus on the applicability of METS-IR in different populations and its potential impact on clinical practice.