bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of a novel frameshift variant and a known deleterious variant in MMR genes with Lynch syndrome in Chinese families
Authors: Li Juyi , Ni Haichun , Wang Xiufang , Cheng Wenzhuo , Li Li , Cheng Yong , Liu Chao , Li Yuanyuan , Deng Aiping 
Published: January 2024

Abstract
Background
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This condition is characterized by germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. In this study, we analyzed the molecular defects and clinical manifestations of two families affected with CRC and proposed appropriate individual preventive strategies for all carriers of the variant.

Methods
We recruited two families diagnosed with CRC and combined their family history and immunohistochemical results to analyze the variants of probands and those of other family members by using whole exome sequencing. Subsequently, gene variants in each family were screened by comparing them with the variants available in the public database. Sanger sequencing was performed to verify the variant sites. An online platform (https://www.uniprot.org) was used to analyze the functional domains of mutant proteins.

Results
A novel frameshift variant (NM_001281492, c.1129_1130del, p.R377fs) in MSH6 and a known deleterious variant (NM_000249.4:c.1731G > A, p.S577S) in MLH1 were identified in the two families with CRC. Using bioinformatics tools, we noted that the frameshift variant reduced the number of amino acids in the MSH6 protein from 1230 to 383, thereby leading to no MSH6 protein expression. The silent variant caused splicing defects and was strongly associated with LS. 5-Fluorouracil-based adjuvant chemotherapy is not recommended for patients with LS.

Conclusions
The novel frameshift variant (MSH6, c.1129_1130del, p.R377fs) is likely pathogenic to LS, and the variant (MLH1, c.1731G > A, p.S577S) has been further confirmed to be pathogenic to LS. Our findings underscore the significance of genetic testing for LS and recommend that genetic consultation and regular follow-ups be conducted to guide individualized treatment for cancer-afflicted families, especially those with a deficiency in MMR expression.
Single-nucleus transcriptomic analysis reveals the relationship between gene expression in oligodendrocyte lineage and major depressive disorder
Authors: Xie Yinping , Chen Lijuan , Wang Leimin , Liu Tongou , Zheng Yage , Si Lujia , Ge Hailong , Xu Hong , Xiao Ling , Wang Gaohua 
Published: January 2024

Abstract
Background
Major depressive disorder (MDD) is a common mental illness that affects millions of people worldwide and imposes a heavy burden on individuals, families and society. Previous studies on MDD predominantly focused on neurons and employed bulk homogenates of brain tissues. This paper aims to decipher the relationship between oligodendrocyte lineage (OL) development and MDD at the single-cell resolution level.

Methods
Here, we present the use of a guided regularized random forest (GRRF) algorithm to explore single-nucleus RNA sequencing profiles (GSE144136) of the OL at four developmental stages, which contains dorsolateral prefrontal cortex of 17 healthy controls (HC) and 17 MDD cases, generated by Nagy C et al. We prioritized and ordered differentially expressed genes (DEGs) based on Nagy et al., which could predominantly discriminate cells in the four developmental stages and two adjacent developmental stages of the OL. We further screened top-ranked genes that distinguished between HC and MDD in four developmental stages. Moreover, we estimated the performance of the GRRF model via the area under the curve value. Additionally, we validated the pivotal candidate gene Malat1 in animal models.

Results
We found that, among the four developmental stages, the onset development of OL (OPC2) possesses the best predictive power for distinguishing HC and MDD, and long noncoding RNA MALAT1 has top-ranked importance value in candidate genes of four developmental stages. In addition, results of fluorescence in situ hybridization assay showed that Malat1 plays a critical role in the occurrence of depression.

Conclusions
Our work elucidates the mechanism of MDD from the perspective of OL development at the single-cell resolution level and provides novel insight into the occurrence of depression.
Combination of mutations in genes controlling DNA repair and high mutational load plays a prognostic role in pancreatic ductal adenocarcinoma (PDAC): a retrospective real-life study in Sardinian population
Authors: Sini Maria Cristina , Doro Maria Grazia , Frogheri Laura , Zinellu Angelo , Paliogiannis Panagiotis , Porcu Alberto , Scognamillo Fabrizio , Delogu Daniele , Santeufemia Davide Adriano , Persico Ivana , Palomba Grazia , Maestrale Giovanni Battista , Cossu Antonio , Palmieri Giuseppe 
Published: January 2024

Abstract
Background
Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia.

Methods
A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms.

Results
Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival.

Conclusions
The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.
Evaluation of three-dimensional reconstructed palatal morphology in skeletal class III subjects with different vertical patterns using cone beam computed tomography
Authors: Huang Xiaoyi , Huang Wenbin , Pei Tao , Zhao Yijiao , Wang Yong , Gu Yan , Bai Xueqin 
Published: January 2024

Abstract
Background
This study aims to evaluate the difference of three-dimensional (3D) reconstructed palatal morphology between subjects with skeletal Class III and skeletal Class I in different vertical patterns using cone beam computed tomography (CBCT).

Methods
In this study, 89 subjects with skeletal Class III (49 females, 40 males; 25.45 ± 3.81 years) and 85 subjects with skeletal Class I (45 females, 40 males; 23.95 ± 4.45 years) were collected retrospectively and divided into hyperdivergent, normodivergent and hypodivergent groups. Dolphin software was used to reorient the CBCT images of these subjects. After segmenting 3D object of maxilla from the 3D skull by ProPlan software, Geomagic Studio was used to reconstruct 3D palatal morphology and establish an average 3D palatal morphology for each group. The differences of 3D palatal morphology between different groups were compared by deviation patterns on 3D colored map analysis.

Results
3D colored map analysis showed the posterior part of male’s palate was higher and wider than that of female’s palate in skeletal Class III subjects. In skeletal Class III subjects, males with hyperdivergent pattern had a higher and narrower palate compared with hypodivergent subjects, while females with hyperdivergent had a higher but not obviously narrower palate compared with hypodivergent subjects. In the similar vertical patterns, skeletal Class III subjects had a flatter but not narrower palate compared with skeletal Class I subjects, along with a smaller palate volume.

Conclusions
This method allows more intuitive between-group comparisons of the differences of 3D palatal morphology. In skeletal Class III subjects, as the vertical dimension increased, the palate tends to be higher and narrower. Therefore, the influence of vertical patterns on the palatal morphology should be fully considered in the orthodontic and orthognathic treatment of skeletal Class III subjects.
Co-linear chaining on pangenome graphs
Authors: Rajput Jyotshna , Chandra Ghanshyam , Jain Chirag 
Published: January 2024

AbstractPangenome reference graphs are useful in genomics because they compactly represent the genetic diversity within a species, a capability that linear references lack. However, efficiently aligning sequences to these graphs with complex topology and cycles can be challenging. The seed-chain-extend based alignment algorithms use co-linear chaining as a standard technique to identify a good cluster of exact seed matches that can be combined to form an alignment. Recent works show how the co-linear chaining problem can be efficiently solved for acyclic pangenome graphs by exploiting their small width and how incorporating gap cost in the scoring function improves alignment accuracy. However, it remains open on how to effectively generalize these techniques for general pangenome graphs which contain cycles. Here we present the first practical formulation and an exact algorithm for co-linear chaining on cyclic pangenome graphs. We rigorously prove the correctness and computational complexity of the proposed algorithm. We evaluate the empirical performance of our algorithm by aligning simulated long reads from the human genome to a cyclic pangenome graph constructed from 95 publicly available haplotype-resolved human genome assemblies. While the existing heuristic-based algorithms are faster, the proposed algorithm provides a significant advantage in terms of accuracy. Implementation (https://github.com/at-cg/PanAligner).
Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy
Authors: Alcalá Sonia , Villarino Lara , Ruiz-Cañas Laura , Couceiro José R. , Martínez-Calvo Miguel , Palencia-Campos Adrián , Navarro Diego , Cabezas-Sainz Pablo , Rodriguez-Arabaolaza Iker , Cordero-Barreal Alfonso , Trilla-Fuertes Lucia , Rubiolo Juan A. , Batres-Ramos Sandra , Vallespinos Mireia , González-Páramos Cristina , Rodríguez Jéssica , Gámez-Pozo Angelo , Vara Juan Ángel Fresno , Fernández Sara Fra , Berlinches Amparo Benito , Moreno-Mata Nicolás , Redondo Ana María Torres , Carrato Alfredo , Hermann Patrick C. , Sánchez Laura , Torrente Susana , Fernández-Moreno Miguel Ángel , Mascareñas José L. , Sainz Bruno 
Published: January 2024

Abstract
Background
Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.

Methods
The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action.

Results
We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration.

Conclusions
Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.
Effect of remimazolam vs propofol in high-risk patients undergoing upper gastrointestinal endoscopy: a non-inferiority randomized controlled trial
Authors: Li Zhi , Yuan Daming , Yu Yu , Xu Jie , Yang Weili , Chen Li , Luo Nanbo 
Published: January 2024

Abstract
Background
Procedural sedation is essential for optimizing upper gastrointestinal endoscopy, particularly in high-risk patients with multiple underlying diseases. Respiratory and circulatory complications present significant challenges for procedural sedation in this population. This non-inferiority randomized controlled trial aims to investigate the safety and comfort of remimazolam compared to propofol for procedural sedation during upper gastrointestinal endoscopy in high-risk patients.

Methods
A total of 576 high-risk patients scheduled to undergo upper gastrointestinal endoscopy are planned to be enrolled in this study and randomly allocated to either the remimazolam or propofol group. The primary outcome measure is a composite endpoint, which includes (1) achieving a Modified Observer’s Alertness/Sedation scale (MOAA/S) score ≤ 3 before endoscope insertion, (2) successful completion of the endoscopic procedure, (3) the absence of significant respiratory instability during the endoscopy and treatment, and (4) the absence of significant circulatory instability during the examination. The noninferiority margin was 10%. Any adverse events (AEs) that occur will be reported.

Discussion
This trial aims to determine whether remimazolam is non-inferior to propofol for procedural sedation during upper gastrointestinal endoscopy in high-risk patients, regarding success rate, complication incidence, patient comfort, and satisfaction.

Trial registration {2a and 2b}
Chinese Clinical Trial Registry ClinicalTrials.gov ChiCTR2200066527. Registered on 7 December 2022.
Changes in saliva protein profile throughout Rhipicephalus microplus blood feeding
Authors: da Silva Vaz Junior Itabajara , Lu Stephen , Pinto Antônio F. M. , Diedrich Jolene K. , Yates John R. , Mulenga Albert , Termignoni Carlos , Ribeiro José Marcos , Tirloni Lucas 
Published: January 2024

Abstract
Background
When feeding on a vertebrate host, ticks secrete saliva, which is a complex mixture of proteins, lipids, and other molecules. Tick saliva assists the vector in modulating host hemostasis, immunity, and tissue repair mechanisms. While helping the vector to feed, its saliva modifies the site where pathogens are inoculated and often facilitates the infection process. The objective of this study is to uncover the variation in protein composition of Rhipicephalus microplus saliva during blood feeding.

Methods
Ticks were fed on calves, and adult females were collected, weighed, and divided in nine weight groups, representing the slow and rapid feeding phases of blood feeding. Tick saliva was collected, and mass spectrometry analyses were used to identify differentially secreted proteins. Bioinformatic tools were employed to predict the structural and functional features of the salivary proteins. Reciprocal best hit analyses were used to identify conserved families of salivary proteins secreted by other tick species.

Results
Changes in the protein secretion profiles of R. microplus adult female saliva during the blood feeding were observed, characterizing the phenomenon known as “sialome switching.” This observation validates the idea that the switch in protein expression may serve as a mechanism for evading host responses against tick feeding. Cattle tick saliva is predominantly rich in heme-binding proteins, secreted conserved proteins, lipocalins, and protease inhibitors, many of which are conserved and present in the saliva of other tick species. Additionally, another remarkable observation was the identification of host-derived proteins as a component of tick saliva.

Conclusions
Overall, this study brings new insights to understanding the dynamics of the proteomic profile of tick saliva, which is an important component of tick feeding biology. The results presented here, along with the disclosed sequences, contribute to our understanding of tick feeding biology and might aid in the identification of new targets for the development of novel anti-tick methods.

Graphical Abstract
An evaluation of the Invisalign® Aligner Technique and consideration of the force system: a systematic review
Authors: Caruso Silvia , De Felice Maria Elena , Valenti Chiara , Pagano Stefano , Caruso Sara , Gatto Roberto , Lombardo Guido 
Published: January 2024

Abstract
Objective
Since its introduction 25 years ago, the Invisalign® system has undergone multiple digital and biomechanical evolutions and its effectiveness is often compared to traditional systems without considering the many differences which characterize them. The main aim of this systematic review is to look at the literature dealing with studies on teeth movements using the Invisalign® system and the management of these movements through digital planning and artificial intelligence.

Materials and methods
The following electronic databases were searched: MEDLINE, Embase, the Cochrane Oral Health Group’s Trials Register, and CENTRAL. Unpublished studies were searched on ClinicalTrials.gov, the National Research Register, and Pro-Quest Dissertation Abstracts and Thesis database.

Results
Twenty-four studies (15 retrospective, 5 prospective, 2 pilot, and 2 case–control) were included. The results of the analysis carried out on the available literature show that the Invisalign® system is recognized to be a valid alternative to conventional orthodontic treatment in no-extraction cases. The results are influenced by the methods for assessing the effectiveness of this technique and by the comparison bias of the traditional system with the innovative digital system.

Conclusions
Since the introduction of SmartForce and SmartTrack material, the efficacy of the treatment has improved. There is still a shortage of high-quality evidence concerning the treatment modality. In order to make the treatment with the aligners more efficient, a correct management of the ClinCheck® software and a proper use of the biomechanics are necessary. The aligned force-driven system should be taken into account when developing the digital planning.
No causal association between allergic rhinitis and migraine: a Mendelian randomization study
Authors: Lv Hao , Liu Kunyu , Xie Yulie , Wang Yunfei , Chen Siyuan , Liu Peiqiang , Guan Mengting , Cong Jianchao , Xu Yu 
Published: January 2024

Abstract
Purpose
Allergic rhinitis (AR) and migraine are among the most common public health problems worldwide. Observational studies on the correlation between AR and migraine have reported inconsistent results. This study aimed to investigate the causal relationship of AR with migraine and its subtypes, including migraine with aura (MA) and migraine without aura (MO).

Methods
Bidirectional two-sample Mendelian randomization (MR) analysis was performed with publicly available summary-level statistics of large genome-wide association studies to estimate the possible causal effects. The inverse variance-weighted method was selected for primary analysis and was supplemented with the weighted median, weighted mode, and MR-Egger methods. The causal analysis using summary effect estimates (CAUSE) were further performed to verify the causality. Several sensitivity tests, including the leave-one-out, Cochran’s Q, MR-Egger intercept, and MR-PRESSO tests, were performed to assess the robustness of the results.

Results
AR did not exhibit a significant causal correlation with the elevated risk of any migraine (odd ratio (OR), 0.816; 95% confidence interval (CI), 0.511–1.302; P = 0.394), MA (OR, 0.690; 95% CI 0.298–1.593; P = 0.384), or MO (OR, 1.022; 95% CI 0.490–2.131; P = 0.954). Consistently, reverse MR analysis did not reveal causal effects of any migraine or its subtypes on AR. Almost all sensitivity analyses supported the robustness of the results.

Conclusions
This MR study did not reveal a clear causal association between AR and migraine risk. More research is warranted to reveal the complex association between AR and migraine.
MDM4 was associated with poor prognosis and tumor-immune infiltration of cancers
Authors: Liu Jie , Yang Jie , Pan Qilong , Wang Xiangyu , Wang Xinyin , Chen Han , Zheng Xiaoling , Huang Qingling 
Published: January 2024

AbstractMDM4 is one of the MDM protein family and is generally recognized as the key negative regulator of p53. As a cancer-promoting factor, it plays a non-negligible role in tumorigenesis and development. In this article, we analyzed the expression levels of MDM4 in pan-cancer through multiple databases. We also investigated the correlations between MDM4 expression and prognostic value, immune features, genetic mutation, and tumor-related pathways. We found that MDM4 overexpression is often accompanied by adverse clinical features, poor prognosis, oncogenic mutations, tumor-immune infiltration and aberrant activation of oncogenic signaling pathways. We also conducted transcriptomic sequencing to investigate the effect of MDM4 on transcript levels in colon cancer and performed qPCR to verify this. Finally, we carried out some in vitro experiments including colony formation assay, chemoresistance and senescence-associated β-galactosidase activity assay to study the anti-tumor treatment effect of small molecule MDM4 inhibitor, NSC146109. Our research confirmed that MDM4 is a prognostic biomarker and potential therapeutic target for a variety of malignancies.