bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using metabolic abnormalities of carriers in the neonatal period to evaluate the pathogenicity of variants of uncertain significance in methylmalonic acidemia
Authors: Xiao Dongfan , Shi Congcong , Zhang Yinchun , Li Sitao , Ye Yuhao , Yuan Guilong , Miu Taohan , Ma Haiyan , Diao Shiguang , Su Chaoyun , Li Zhitao , Li Haiyan , Zhuang Guiying , Wang Yuanli , Lu Feiyan , Gu Xia , Zhou Wei , Xiao Xin , Huang Weiben , Wei Tao , Hao Hu 
Published: July 2024

ObjectiveTo accurately verify the pathogenicity of variants of uncertain significance (VUS) in MUT and MMACHC genes through mass spectrometry and silico analysis.MethodsThis multicenter retrospective study included 35 participating units (ClinicalTrials.gov ID: NCT06183138). A total of 3,071 newborns (within 7 days of birth) were sorted into carrying pathogenic/likely pathogenic (P/LP) variants and carrying VUS, non-variant groups. Differences in metabolites among the groups were calculated using statistical analyses. Changes in conservatism, free energy, and interaction force of MMUT and MMACHC variants were analyzed using silico analysis.ResultsThe percentage of those carrying VUS cases was 68.15% (659/967). In the MMUT gene variant, we found that C3, C3/C2, and C3/C0 levels in those carrying the P/LP variant group were higher than those in the non-variant group (p &lt; 0.000). The conservative scores of those carrying the P/LP variant group were &gt;7. C3, C3/C0, and C3/C2 values of newborns carrying VUS (c.1159A&gt;C and c.1286A&gt;G) were significantly higher than those of the non-variant group and the remaining VUS newborns (p &lt; 0.005). The conservative scores of c.1159A&gt;C and c.1286A&gt;G calculated by ConSurf analysis were 9 and 7, respectively. Unfortunately, three MMA patients with c.1159A&gt;C died during the neonatal period; their C3, C3/C0, C3/C2, and MMA levels were significantly higher than those of the controls.ConclusionCommon variants of methylmalonic acidemia in the study population were categorized as VUS. In the neonatal period, the metabolic biomarkers of those carrying the P/LP variant group of the MUT gene were significantly higher than those in the non-variant group. If the metabolic biomarkers of those carrying VUS are also significantly increased, combined with silico analysis the VUS may be elevated to a likely pathogenic variant. The results also suggest that mass spectrometry and silico analysis may be feasible screening methods for verifying the pathogenicity of VUS in other inherited metabolic diseases.
Gut microbiota linked to hydrocephalus through inflammatory factors: a Mendelian randomization study
Authors: Shen Yingjie , Li Changyu , Zhang Xi , Wang Yaolou , Zhang Haopeng , Yu Zhao , Gui Binbin , Hu Renjie , Li Qi , Gao Aili , Liang Hongsheng 
Published: July 2024

BackgroundThe gut microbiota (GM) has been implicated in neurological disorders, but the relationship with hydrocephalus, especially the underlying mechanistic pathways, is unclear. Using Mendelian randomization (MR), we aim to discover the mediating role of inflammatory factors in the relationship between GM and hydrocephalus.MethodsAfter removing confounders, univariable and multivariable MR analyses were performed using summary statistics to assess the causal relationships between GM, inflammatory factors (IL-17A and IL-27), and types of hydrocephalus. Meta-analyses were used to reconcile the differences in MR results between different hydrocephalus sources. Finally, mediator MR analyses were applied to determine the mediating effect of inflammatory factors. Various sensitivity analysis methods were employed to ensure the reliability and stability of the results.ResultsAfter correction for P-values, Firmicutes (phylum) (OR, 0.34; 95%CI, 0.17–0.69; P = 2.71E-03, PFDR = 2.44E-02) significantly reduced the risk of obstructive hydrocephalus. The remaining 18 different taxa of GM had potential causal relationships for different types of hydrocephalus. In addition, Firmicutes (phylum) decreased the risk of obstructive hydrocephalus by increasing levels of IL-17A (mediating effect = 21.01%), while Eubacterium ruminantium group (genus) increased the risk of normal-pressure hydrocephalus by decreasing levels of IL-27 (mediating effect = 7.48%).ConclusionWe reveal the connection between GM, inflammatory factors (IL-17A and IL-27), and hydrocephalus, which lays the foundation for unraveling the mechanism between GM and hydrocephalus.
Lipopolysaccharide-responsive beige-like anchor is involved in regulating NF-κB activation in B cells
Authors: Pérez-Pérez Daniela , Fuentes-Pananá Ezequiel M. , Flores-Hermenegildo José Mizael , Romero-Ramirez Hector , Santos-Argumedo Leopoldo , Kilimann Manfred W. , Rodríguez-Alba Juan Carlos , Lopez-Herrera Gabriela 
Published: July 2024

IntroductionLipopolysaccharide-responsive and beige-like anchor (LRBA) is a scaffolding protein that interacts with proteins such as CTLA-4 and PKA, the importance of which has been determined in various cell types, including T regulatory cells, B cells, and renal cells. LRBA deficiency is associated with an inborn error in immunity characterized by immunodeficiency and autoimmunity. In addition to defects in T regulatory cells, patients with LRBA deficiency also exhibit B cell defects, such as reduced cell number, low memory B cells, hypogammaglobulinemia, impaired B cell proliferation, and increased autophagy. Although Lrba-/- mice do not exhibit the immunodeficiency observed in humans, responses to B cell receptors (BCR) in B cells have not been explored. Therefore, a murine model is for elucidating the mechanism of Lrba mechanism in B cells.AimTo compare and evaluate spleen-derived B cell responses to BCR crosslinking in C57BL6 Lrba-/- and Lrba+/+ mice.Materials and methodsSpleen-derived B cells were obtained from 8 to 12-week-old mice. Subpopulations were determined by immunostaining and flow cytometry. BCR crosslinking was assessed by the F(ab’)2 anti-μ chain. Activation, proliferation and viability assays were performed using flow cytometry and protein phosphorylation was evaluated by immunoblotting. The nuclear localization of p65 was determined using confocal microscopy. Nur77 expression was evaluated by Western blot.ResultsLrba-/- B cells showed an activated phenotype and a decreased proportion of transitional 1 B cells, and both proliferation and survival were affected after BCR crosslinking in the Lrba-/- mice. The NF-κB pathway exhibited a basal activation status of several components, resulting in increased activation of p50, p65, and IκBα, basal p50 activation was reduced by the Plcγ2 inhibitor U73122. BCR crosslinking in Lrba-/- B cells resulted in poor p50 phosphorylation and p65 nuclear localization. Increased levels of Nur77 were detected.DiscussionThese results indicate the importance of Lrba in controlling NF-κB activation driven by BCR. Basal activation of NF-κB could impact cellular processes, such as, activation, differentiation, proliferation, and maintenance of B cells after antigen encounter.
A rare presentation of acute-onset chronic inflammatory demyelinating polyneuropathy with the detection of anti-GM3 and anti-sulfatides antibodies: a case report
Authors: Sun Ruohan , Meng Yao , Li Lingyu , Chen Wei-hong , Xu Jing , Lv Peiyuan , Dong Yanhong 
Published: July 2024

ObjectivesChronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated neuropathy defined by clinical progression for more than 2 months. 16-20% of CIDP patients may present with rapidly progressive weakness that resembles GBS, known as acute-onset CIDP (A-CIDP). However, it is challenging to distinguish from GBS-TRF because of their similar clinical symptom and features. In this case review, we report a patient with A-CIDP with the detection of anti-GM3 and anti-sulfatides antibodies, which rarely have been in A-CIDP and may account for her progressive and recurrent symptoms.MethodsWe analyzed existing medical literature and described a clinical case of A-CIDP with antibodies positive.ResultsWe reported a 56-year-old female presented with bilateral lower extremity weakness and distal numbness. She experienced similar symptoms four times and responded well to the IVIg therapy. Lumbar puncture demonstrated albumin-cytologic dissociation and EDX examination revealed multiple peripheral nerve damage. After ruling out other demyelination diseases, a diagnosis of A-CIDP was made.DiscussionThe antiganglioside and anti-sulfatide antibodies are involved in CIDP pathogenesis and can help to distinguish A-CIDP and other variants. To prevent secondary damage, it is important to monitor relapse and remission symptoms along the treatment line. A rare case of A-CIDP is discussed concerning the detection of anti-GM3 and anti-sulfatides antibodies, thus making a retrospective comparison of antibodies in some literature to understand A-CIDP better.
A combined radio-immunotherapy regimen eradicates late-stage tumors in mice
Authors: Rakhmilevich Alexander L. , Tsarovsky Noah W. , Felder Mildred , Zaborek Jen , Moram Sritha , Erbe Amy K. , Pieper Alexander A. , Spiegelman Dan V. , Cheng Emily M. , Witt Cole M. , Overwijk Willem W. , Morris Zachary S. , Sondel Paul M. 
Published: July 2024

BackgroundThe majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen.MethodsCRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects.ResultsTumors with volumes of 2,000 mm3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory.ConclusionsThese findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors.
Hyper-reflective foci changes in RRMS under natalizumab therapy
Authors: Puthenparampil Marco , Basili Elisa , Ponzano Marta , Mauceri Valentina Annamaria , Miscioscia Alessandro , Pilotto Elisabetta , Perini Paola , Rinaldi Francesca , Bovis Francesca , Gallo Paolo 
Published: July 2024

IntroductionMicroglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug’s mechanism of intrathecal action.ObjectiveTo analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS.Materials and methodsThe effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months.ResultsHRF count significantly increased under NTZ therapy (p&lt;0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12.ConclusionIn RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology.
Bibliometric analysis of neuroinflammation and Alzheimer’s disease
Authors: Sun Wenxian , Gong Jin , Li Shaoqi , Wang Pin , Han Xiaodong , Xu Chang , Luan Heya , Li Ruina , Wen Boye , Wei Cuibai 
Published: July 2024

BackgroundAlzheimer’s disease (AD) is the predominant cause of dementia on a global scale, significantly impacting the health of the elderly population. The pathogenesis of AD is closely linked to neuroinflammation. The present study employs a bibliometric analysis to examine research pertaining to neuroinflammation and AD within the last decade, with the objective of providing a comprehensive overview of the current research profile, hotspots and trends.MethodsThis research conducted a comprehensive review of publications within the Science Citation Index Expanded of the Web of Science Core Collection Database spanning the years 2014 to 2024. Bibliometric analyses were performed using VOSviewer (version 1.6.19) and CiteSpace (version 6.3.R1) software to visualize data on countries, institutions, authors, journals, keywords, and references.ResultsA total of 3,833 publications on neuroinflammation and AD were included from January 2014 to January 2024. Publications were mainly from the United States and China. Zetterberg, Henrik emerged as the author with the highest publication output, while Edison, Paul was identified as the most cited author. The most productive journal was Journal of Alzheimers Disease, and the most co-cited was Journal of Neuroinflammation. Research hotspot focused on microglia, mouse models, oxidative stress, and amyloid-beta through keyword analysis. Additionally, keywords such as blood–brain barrier and tau protein exhibited prolonged citation bursts from 2022 to 2024.ConclusionThis study provides a comprehensive review of the last 10 years of research on neuroinflammation and AD, including the number and impact of research findings, research hotspots, and future trends. The quantity of publications in this field is increasing, mainly in the United States and China, and there is a need to further strengthen close cooperation with different countries and institutions worldwide. Presently, research hotspots are primarily concentrated on microglia, with a focus on inhibiting their pro-inflammatory responses and promoting their anti-inflammatory functions as a potential direction for future investigations.
Intra-articular sprouting of nociceptors accompanies progressive osteoarthritis: comparative evidence in four murine models
Authors: Obeidat Alia M. , Ishihara Shingo , Li Jun , Adamczyk Natalie S. , Lammlin Lindsey , Junginger Lucas , Maerz Tristan , Miller Richard J. , Miller Rachel E. , Malfait Anne-Marie 
Published: July 2024

ObjectiveKnee joints are densely innervated by nociceptors. In human knees and rodent models, sprouting of nociceptors has been reported in late-stage osteoarthritis (OA). Here, we sought to describe progressive nociceptor remodeling in early and late-stage OA, using four distinct experimental mouse models.MethodsSham surgery, destabilization of the medial meniscus (DMM), partial meniscectomy (PMX), or non-invasive anterior cruciate ligament rupture (ACLR) was performed in the right knee of 10-12-week old male C57BL/6 NaV1.8-tdTomato mice. Mice were euthanized (1) 4, 8 or 16 weeks after DMM or sham surgery; (2) 4 or 12 weeks after PMX or sham; (3) 1 or 4 weeks after ACLR injury or sham. Additionally, a cohort of naïve male wildtype mice was evaluated at age 6 and 24 months. Mid-joint cryosections were assessed qualitatively and quantitatively for NaV1.8+ or PGP9.5+ innervation. Cartilage damage, synovitis, and osteophytes were assessed.ResultsProgressive OA developed in the medial compartment after DMM, PMX, and ACLR. Synovitis and associated neo-innervation of the synovium by nociceptors peaked in early-stage OA. In the subchondral bone, channels containing sprouting nociceptors appeared early, and progressed with worsening joint damage. Two-year old mice developed primary OA in the medial and the lateral compartment, accompanied by nociceptor sprouting in the synovium and the subchondral bone. All four models showed increased nerve signal in osteophytes.ConclusionThese findings suggest that anatomical neuroplasticity of nociceptors is intrinsic to OA pathology. The detailed description of innervation of the OA joint and its relationship to joint damage might help in understanding OA pain.
Postural instability and lower extremity dysfunction in upper motor neuron-dominant amyotrophic lateral sclerosis
Authors: Liu Xiangyi , Chen Lu , Ye Shan , Liu Xiaoxuan , Zhang Yingshuang , Fan Dongsheng 
Published: July 2024

BackgroundUpper motor neuron-dominant ALS (UMND ALS) is recognized to have early onset and good prognosis, but may have a rapid decline in motor function due to gait instability in the early stage. We investigated changes in lower extremity function in UMND ALS, particularly UMND ALS patients accompanied with postural instability or repeated falls (UMND ALS plus).ResultsAmong the 2,353 ALS patients reviewed, 211 (9.0%) had UMND ALS. UMND ALS had a longer diagnosis delay and restricted symptoms. Although UMND ALS patients had better lower extremity function and strength than matched classic ALS patients on first evaluation, there was no difference in the time of needing assistance or not being able to walk after disease onset. In contrast, UMND ALS plus has severe UMN symptoms and a more rapid decline in motor function. The lower extremity function was no better than that in the matched classic ALS. The prognosis of UMND ALS and UMND ALS plus were significantly better than those of overall ALS.ConclusionUMND ALS has restricted symptoms but has a rapid decline in lower extremity function in the early stage of the disease. The motor function decline of UMND ALS plus is as fast as classic ALS. Whether these patients represent a distinct subgroup of ALS deserves further investigation.
Blocking Aδ- and C-fiber neural transmission by sub-kilohertz peripheral nerve stimulation
Authors: Zhang Shaopeng , Chen Longtu , Ladez Sajjad Rigi , Seferge Ahmet , Liu Jia , Feng Bin 
Published: July 2024

IntroductionWe recently showed that sub-kilohertz electrical stimulation of the afferent somata in the dorsal root ganglia (DRG) reversibly blocks afferent transmission. Here, we further investigated whether similar conduction block can be achieved by stimulating the nerve trunk with electrical peripheral nerve stimulation (ePNS).MethodsWe explored the mechanisms and parameters of conduction block by ePNS via ex vivo single-fiber recordings from two somatic (sciatic and saphenous) and one autonomic (vagal) nerves harvested from mice. Action potentials were evoked on one end of the nerve and recorded on the other end from teased nerve filaments, i.e., single-fiber recordings. ePNS was delivered in the middle of the nerve trunk using a glass suction electrode at frequencies of 5, 10, 50, 100, 500, and 1000 Hz.ResultsSuprathreshold ePNS reversibly blocks axonal neural transmission of both thinly myelinated Aδ-fiber axons and unmyelinated C-fiber axons. ePNS leads to a progressive decrease in conduction velocity (CV) until transmission blockage, suggesting activity-dependent conduction slowing. The blocking efficiency is dependent on the axonal conduction velocity, with Aδ-fibers efficiently blocked by 50–1000 Hz stimulation and C-fibers blocked by 10–50 Hz. The corresponding NEURON simulation of action potential transmission indicates that the disrupted transmembrane sodium and potassium concentration gradients underly the transmission block by the ePNS.DiscussionThe current study provides direct evidence of reversible Aδ- and C-fiber transmission blockage by low-frequency (&lt;100 Hz) electrical stimulation of the nerve trunk, a previously overlooked mechanism that can be harnessed to enhance the therapeutic effect of ePNS in treating neurological disorders.
Zebrafish myo7aa affects congenital hearing by regulating Rho-GTPase signaling
Authors: Xie Binling , Liang Jiaxin , Jiang Jifan , Zeng Ting , Liu Ling , Xie Dinghua , Zhu Ganghua , Xiong Lei , Zhang Kanjia , Liu Dong , Gong Jie , Chen Xiangding , Lai Ruosha , Xie Huaping 
Published: July 2024

Introductionmyo7aa, the homolog of the human Usher 1B syndrome pathogenic gene, myo7A, plays an important role in stereociliary development and maintenance, therefore, is critical for hearing and balance. However, the molecular mechanisms that myo7aa regulate hearing and balance still need to be studied.MethodsIn this study, we generated two independent zebrafish myo7aa knockout lines using CRISPR/Cas9 technology. To investigate the effects of myo7aa on hearing, YO-PRO-1 staining and startle response assay were used. To gain insight into the specific molecular mechanisms by which myo7aa affects hearing, transcriptome sequencing and bioinformatics analysis were employed.ResultsOur study showed that hair cells of myo7aa-/- zebrafish can not take up YO-PRO-1 fluorescent dye and are insensitive to acoustic stimulation in myo7aa-/- zebrafish compared to wild type. Genes related to the Rho GTPase signaling pathway, such as arhgap33, dab2ip, and arghef40, are significantly down-regulated in myo7aa-/- zebrafish embryos at 3 dpf. GTP and ATP compensation can partially rescue the hair cell defects in myo7aa knockout zebrafish.DiscussionOur findings suggest that zebrafish myo7aa affects congenital hearing by regulating Rho GTPase signaling, and loss of myo7aa leads to abnormal Rho GTPase signaling and impairs hair cell function. myo7aa, myo7A, arhgap33, dab2ip, arghef40 and myo7aa-/- fonts in the abstract are italicized. -/- is a superscript format.
Diabetes-specific formula with standard of care improves glycemic control, body composition, and cardiometabolic risk factors in overweight and obese adults with type 2 diabetes: results from a randomized controlled trial
Authors: Tey Siew Ling , Chee Winnie S.S. , Deerochanawong Chaicharn , Berde Yatin , Lim Lee-Ling , Boonyavarakul Apussanee , Wakefield Brittany , Baggs Geraldine , Huynh Dieu Thi Thu 
Published: July 2024

Background and aimsMedical nutrition therapy is important for diabetes management. This randomized controlled trial investigated the effects of a diabetes-specific formula (DSF) on glycemic control and cardiometabolic risk factors in adults with type 2 diabetes (T2D).MethodsParticipants (n = 235) were randomized to either DSF with standard of care (SOC) (DSF group; n = 117) or SOC only (control group; n = 118). The DSF group consumed one or two DSF servings daily as meal replacement or partial meal replacement. The assessments were done at baseline, on day 45, and on day 90.ResultsThere were significant reductions in glycated hemoglobin (−0.44% vs. –0.26%, p = 0.015, at day 45; −0.50% vs. −0.21%, p = 0.002, at day 90) and fasting blood glucose (−0.14 mmol/L vs. +0.32 mmol/L, p = 0.036, at day 90), as well as twofold greater weight loss (−1.30 kg vs. –0.61 kg, p  &lt; 0.001, at day 45; −1.74 kg vs. –0.76 kg, p &lt; 0.001, at day 90) in the DSF group compared with the control group. The decrease in percent body fat and increase in percent fat-free mass at day 90 in the DSF group were almost twice that of the control group (1.44% vs. 0.79%, p = 0.047). In addition, the percent change in visceral adipose tissue at day 90 in the DSF group was several-fold lower than in the control group (−6.52% vs. –0.95%, p &lt; 0.001). The DSF group also showed smaller waist and hip circumferences, and lower diastolic blood pressure than the control group (all overall p ≤ 0.045).ConclusionDSF with SOC yielded significantly greater improvements than only SOC in glycemic control, body composition, and cardiometabolic risk factors in adults with T2D.