Abnormal Fibers Research Articles

Actin‐related proteomic changes in age‐related, diabetic and post‐vitrectomy cataract

Aims/Purpose: Actin has been implicated in lens opacification; however, the specific actin‐related pathways involved in cataracts remain unclear. In this study, actin‐related signaling pathways involved in the development of different types of cataract were evaluated.Methods: Two sample types were collected during routine cataract surgery; the anterior capsule (AC) and phacoemulsification cassette contents (PCC). Participants were divided into three groups. Age‐related cataract (ARC) group included 12 patients without a history of DM, and age > 75 years; Diabetic cataract (DC) group included 11 patients with diabetes mellitus (DM) and age < 65 years.; and Post‐vitrectomy cataract (PVC) group included 7 patients without a history of DM, who had vitrectomy surgery in the past 12 months. The sample preparation was based on Sp3 protocol (Single‐Pot, Solid‐Phase‐enhanced, Sample‐Preparation). Liquid chromatography online with tandem mass spectrometry was used for protein recognition and quantification. DIA‐NN software was applied for data analysis. Statistical analysis was performed on Perseus software.Results: In PCC samples, proteins with significant differential expression in ARC compared to DC and PVC were involved in pathways including actin binding, actin cytoskeleton reorganization, and small GTPase‐mediated signal transduction pathways. In AC samples, proteins with significant differential expression in ARC compared to DC and PVC were involved in actin binding and actin cytoskeleton reorganization pathways.Conclusions: Our findings suggested that actin‐binding pathway may be involved in ARC formation by causing abnormal lens fiber cell elongation and differentiation. The results of the present study revealed that small GTPase‐mediated signal transduction pathway exhibit lower expression in ARC than in the DC and PVC groups in PCC, and this may be linked to ARC formation through abnormal fiber cell organization, leading to lens opacification and cataract.

Clinical Implications Of Functional Imaging In The Assessment Of Bronchiectasis-Associated Sarcopenia

Bronchiectasis is a complex lung disease with poorly studied systemic manifestations. Patients with bronchiectasis-associated sarcopenia exhibit a specific differential profile of functional muscle phenotype (vastus lateralis, VL), which may be analyzed using imaging (ultrasound and magnetic resonance imaging, MRI). Ultrasound and MRI were used to explore functional imaging parameters in quadriceps of 20 patients with stable bronchiectasis and 10 healthy controls. In muscle specimens (open biopsy procedures), muscle phenotype (fiber morphometry and structural abnormalities, immunohistochemistry) was also evaluated. Patients and controls were clinically and functionally evaluated. In muscles of patients compared to controls, a significant decline in body composition parameters (BMI and FFMI), muscle function (upper and lower limbs), lung function, and exercise capacity was detected, ultrasonography revealed decreased muscle thickness and area, while MRI demonstrated increased fat infiltration, which positively correlated with the bronchiectasis severity scores. Structural parameters (proportions of hybrid fibers, internal nuclei, abnormal fibers, and apoptotic nuclei) were significantly greater in the VL of patients than in controls and inversely correlated with quadriceps muscle function and exercise capacity in the former. In patients with stable mild-to-moderate bronchiectasis, sarcopenia was clinically evidenced through the significant reduction in muscle mass and upper and lower limb muscle function. Non-invasive ultrasound and MRI techniques showed that features of muscle quality architecture and fat infiltration are hallmarks of bronchiectasis-associated sarcopenia. Functional radiological tools should be implemented in clinical settings to early diagnose and monitor sarcopenia in these patients.

A Systematic Review of the Association of Elastosis Perforans Serpiginosa and Congenital Disorders

Background: Elastosis perforans serpiginosa (EPS) is a skin condition marked by transepidermal elimination of abnormal elastic fibers, with a classical presentation of papules or plaques arranged in serpiginous, annular, or arcuate patterns on the neck, face, arms, or other flexural regions. A previous review of the literature reported that approximately 1/4 of EPS cases are associated with congenital disorders, including Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. To the knowledge of these authors, no review examining the association of EPS and congenital disorders has been performed since 1968. Objective: The primary objective of this paper is to perform an updated review of the literature focused on the associations between EPS and congenital disorders. Methods: We searched electronic databases (Medline, Web of Science, PubMed) for literature pertaining to EPS and Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. Results: Evidence for the association of EPS and congenital disorders is 57 cases from 48 published papers. Conclusions: Our results suggest an association between EPS and congenital disorders. However, current evidence is limited to case reports, underscoring the need for future research investigating the relationship between EPS and congenital disorders.

Fibin is a crucial mitochondrial regulatory gene in skeletal muscle development

Fin bud initiation factor homolog (Fibin) is a secreted protein that is relatively conserved among species. It is closely related to fin bud development and can regulate a variety of cellular processes. In our previous high-throughput chromosome conformation capture (Hi-C) study of pig embryonic muscle development, it was found that Fibin has high expression and activity during the development of pig primary muscle fibers. Therefore, we speculated Fibin participated in myogenesis severely. Specific deletion of Fibin in mouse skeletal muscle resulted in abnormal primary muscle fiber development during the embryonic period and a substantial decrease in skeletal muscle mass in adulthood. In vitro, knocking out Fibin in C2C12 cells promoted cell proliferation; however, after myogenic induction, cells lacking Fibin had almost no ability to differentiate into myotubes. During myogenic differentiation, loss of Fibin disrupts the normal function of mitochondria and impairs oxidative phosphorylation, resulting in decrease of NADH and FADH in the electron transport chain. Transmission electron microscopy also showed that mitochondrial morphology of Fibin-deficient C2C12 was impaired. In conclusion, our research has unveiled a novel mechanism of myogenesis regulation in mitochondrial function and potential target Fibin, and improved understanding of a broad range of mitochondrial muscle diseases.

Comprehensive analysis of Hibisci mutabilis Folium extract's mechanisms in alleviating UV-induced skin photoaging through enhanced network pharmacology and experimental validation.

Skin photoaging induced by ultraviolet A (UVA) and ultraviolet B (UVB) radiation manifests as skin roughness, desquamation, pigmentation, and wrinkle formation. Current treatments, such as sunscreen, hormones, and antioxidants, have limitations and side effects. Traditional Chinese Medicine Hibisci Mutabilis Folium (HMF), or Mu-Fu-Rong-Ye in Chinese name, refers to the dried leaves of the plant Hibiscus mutabilis L., which belongs to the Malvaceae family. It has been used traditionally to treat acute mastitis, parotitis, neurodermatitis, burns. The reported activities of HMF include anti-inflammatory and anti-oxidant effects. However, the therapeutic potential of HMF in preventing and treating UV-induced skin photoaging remains unexplored. This study aimed to investigate the protective effects of HMF extract (EHMF) against UV-induced skin photoaging and the underlying mechanisms of action, by using network pharmacology and experimental verification. Network pharmacology was employed to identify the effective chemical components of EHMF. Potential targets were identified via PPI network analysis. Representative compounds were characterized using UPLC-MS/MS. In vitro validation involved assessing HaCaT cell viability, observing live/dead cell staining through fluorescence microscopy, and measuring inflammatory factors using ELISA. For in vivo validation, a UV-induced skin photoaging mice model was treated transdermally with EHMF or Methotrexate daily for 7 days. Dermatitis severity, skin morphology, and collagen fiber pathology were evaluated. Inflammatory cytokine and protein expression in dorsal skin lesions was confirmed using Elisa Kits, Western blot and immunohistochemistry. A total of 22 active ingredients of EHMF were identified. GO enrichment and KEGG pathway analyses revealed a focus on inflammatory signaling pathways. In vitro experiments showed that EHMF significantly reduced UV-induced inflammatory factors in HaCaT cells and improved cell survival rates. In vivo, EHMF alleviated back skin lesions in UV-exposed mice, reducing epidermal and dermal thickening and pathological inflammatory cell infiltration. It also decreased abnormal MMP-9 expression and collagen fiber proliferation, along with levels of inflammatory factors like TNF-α, IL-6, IL-17, and EGFR. Western blot and immunohistochemistry results indicated that the over-activation of the AKT-STAT3 signaling pathway was inhibited. EHMF effectively reduced UV-induced skin damage, inflammation, and wrinkles, providing strong support for its clinical application as a dermatological agent.

Excessive collagen fiber deposition in idiopathic scrotal calcinosis: a case report

BackgroundIdiopathic scrotal calcinosis (ISC) is a manifestation of idiopathic calcinosis cutis, and its etiology is still unknown.Case presentationWe report a 36-year-old patient manifested multiple gradually increasing yellowish-white scrotal nodules with occasional itching and stinging in the past 6 years and was successfully cured via surgical excision. The laboratory test combined with pathological analysis confirmed the diagnosis of ISC. Like pathological calcinosis in other soft tissues, a large amount of collagen fiber deposition was observed around the calcification nodule, suggesting that abnormal collagen fiber deposition might be an important factor leading to idiopathic calcinosis in the scrotum. Moreover, koilocytes, which indicate human papillomavirus (HPV) infection, were also detected around calcified nodules, indicating the potential pathogenic role of HPV infection in ISC.ConclusionsHere, we report that ISC shows abnormal excessive deposition of collagen fibers around calcified nodules, which may be a vital factor contributing to the disease. Furthermore, combined with the literature review, a new pathogenic mechanism of ISC is proposed, and the site specificity of scrotal calcinosis is explained, providing a basis for further exploration of the pathogenic mechanism of ISC.

Objective Determination of Site-of-Lesion in Auditory Neuropathy.

Auditory neuropathy (AN), a complex hearing disorder, presents challenges in diagnosis and management due to limitations of current diagnostic assessment. This study aims to determine whether diffusion-weighted magnetic resonance imaging (MRI) can be used to identify the site and severity of lesions in individuals with AN. This case-control study included 10 individuals with AN of different etiologies, 7 individuals with neurofibromatosis type 1 (NF1), 5 individuals with cochlear hearing loss, and 37 control participants. Participants were recruited through the University of Melbourne's Neuroaudiology Clinic and the Murdoch Children's Research Institute specialist outpatient clinics. Diffusion-weighted MRI data were collected for all participants and the auditory pathways were evaluated using the fixel-based analysis metric of apparent fiber density. Data on each participant's auditory function were also collected including hearing thresholds, otoacoustic emissions, auditory evoked potentials, and speech-in-noise perceptual ability. Analysis of diffusion-weighted MRI showed abnormal white matter fiber density in distinct locations within the auditory system depending on etiology. Compared with controls, individuals with AN due to perinatal oxygen deprivation showed no white matter abnormalities ( p > 0.05), those with a neurodegenerative conditions known/predicted to cause VIII cranial nerve axonopathy showed significantly lower white matter fiber density in the vestibulocochlear nerve ( p < 0.001), while participants with NF1 showed lower white matter fiber density in the auditory brainstem tracts ( p = 0.003). In addition, auditory behavioral measures of speech perception in noise and gap detection were correlated with fiber density results of the VIII nerve. Diffusion-weighted MRI reveals different patterns of anatomical abnormality within the auditory system depending on etiology. This technique has the potential to guide management recommendations for individuals with peripheral and central auditory pathway abnormality.

Imbalanced segmentation for abnormal cotton fiber based on GAN and multiscale residual U-Net

The scale of white foreign fibers in bobbin yarn is small, resulting in multiple types of data imbalance in the dataset. These imbalances include a severe imbalance of foreign fiber pixels compared to background pixels and an imbalance in the size target scale. Consequently, conventional semantic segmentation networks struggle to segment these fibers effectively. First, in tackling the scarcity of white foreign fiber instances within bobbin yarn samples, this research utilizes original foreign fiber images to train the DCGAN and generate adequate training samples. Secondly, a multiscale residual U-Net is constructed to extract foreign fiber features from different scales. The network is encouraged to learn semantic features at each scale and each layer of the decoding stage. This overcomes the problem of scale imbalance in the foreign fiber dataset and enhances the model's capability to extract weak semantic information from small targets. Thirdly, a weighted binary cross-entropy loss function is integrated into the network's training phase to rectify the class imbalance and refine segmentation performance. This function adjusts the weighting of foreign fiber pixel data, thereby addressing the disproportionate distribution between foreign fibers and background pixels within the dataset. Finally, the proposed method is experimentally validated using a dataset of white foreign fibers. The experimental results show that the proposed method achieves better results in the critical evaluation metrics, as evidenced by the accuracy of 97.52 %, the MIoU of 95.26 %, the DICE coefficient of 81.29 %, and the F1 Score of 84.92 %. These statistics demonstrate the method's efficacy in achieving high-precision segmentation of white foreign fibers.

Role of actin-binding proteins in cataract formation.

Actin has been implicated in lens opacification; however, the specific actin-related pathways involved in cataracts remain unelucidated. In this study, actin-related proteome changes and signaling pathways involved in the development of cataracts were evaluated. The anterior capsule and phacoemulsification (phaco) cassette contents were collected during cataract surgery from 11 patients with diabetic cataract (DC), 12 patients with age-related cataract (ARC), and seven patients with post-vitrectomy cataract (PVC). Untargeted, global identification and quantification of proteins was performed through liquid chromatography-mass spectrometry with the data-independent acquisition (DIA). In phaco cassette samples, proteins with significantly lower expression in ARC than in DC and PVC were involved in various pathways, including actin binding, actin cytoskeleton reorganization, actin filament capping, cortical actin cytoskeleton organization, and small GTPase-mediated signal transduction pathways. In anterior capsules, proteins with significantly lower expression in ARC than in DC and PVC were involved in actin binding and actin cytoskeleton reorganization pathways. Actin cytoskeleton and actin-binding proteins are involved in lens fiber elongation and differentiation. Rho GTPases contribute to actin cytoskeletal reorganization, and their inactivation is linked to abnormal lens fiber migration. These findings link actin binding to lens fiber integrity, lens opacification, and cataracts.

Sustained corneal nerve loss predicts the development of diabetic neuropathy in type 2 diabetes.

This study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D). Participants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4-7 years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD, <24 fibers/mm2), corneal nerve branch density (CNBD, <21 branches/mm2), and corneal nerve fiber length (CNFL, <16 mm/mm2) persisting for ≥50% of the study duration. A total of 107 participants with a mean duration of T2D of 13.3 ± 7.3 years, aged 54.8 ± 8.5 years, underwent baseline and follow-up assessments over a median duration of 4 years, ranging from 1 to 7 years. The DPN prevalence at baseline was 18/107 (16.8%), and of the 89 participants without DPN at baseline, 13 (14.6%) developed DPN during follow-up. Approximately half of the cohort had sustained corneal nerve damage, and corneal nerve measures were significantly lower in this group than those without sustained damage (p < 0.0001). Sustained corneal nerve damage was associated with the development of DPN (p < 0.0001), a progressive loss of vibration perception (p ≤ 0.05), an increased incidence of burning pain, numbness, or a combination of both (p = 0.01-0.001), and a borderline association with progressive sudomotor dysfunction (p = 0.07). Sustained abnormal CNFL effectively distinguished between participants who developed DPN and those who did not (AUC: 76.3, 95% CI: 65.9-86.8%, p < 0.0001), while baseline and other sustained measures did not predict DPN onset. Sustained abnormal CCM is associated with more severe corneal nerve damage, DPN development, and the progression of neuropathic symptoms and deficits. Regular CCM monitoring may enable the identification of those at greater risk of developing and worsening DPN who may benefit from more aggressive risk factor reduction.

In Search of Mouse Models for Exfoliation Syndrome

Exfoliation syndrome (XFS) is a systemic connective tissue disorder with elusive pathophysiology. We hypothesize that a mouse model with elastic fiber defects caused by lack of lysyl oxidase like 1 (LOXL1 encoded by Loxl1), combined with microfibril deficiency due to Fbn1 mutation (encoding fibrillin-1, Fbn1C1041G/+) will display ocular and systemic phenotypes of XFS. Loxl1-/- was crossed with Fbn1C1041G/+ to create double mutant (dbm) mice. Intraocular pressure (IOP), visual acuity (VA), electroretinogram (ERG) and biometry were characterized in 4 genotypes (wt, Fbn1C1041G/+, Loxl1-/-, dbm) at 16 weeks old. Optic nerve area was measured by ImageJ and axon counting was achieved by AxonJ. Deep whole-body phenotyping was performed in wt and dbm mice. Two-tailed Student's t-test was used for statistical analysis. There was no difference in IOP between the 4 genotypes. VA was significantly reduced only in dbm mice. The majority of biometric parameters showed significant differences in all 3 mutant genotypes compared to wt, and dbm had exacerbated anomalies compared to single mutants. Dbm mice showed reduced retinal function and significantly enlarged ON area when compared with wt. Dbm mice exhibited severe systemic phenotypes related to abnormal elastic fibers, such as pelvic organ prolapse, cardiovascular and pulmonary abnormalities. Ocular and systemic findings in dbm mice support functional overlap between fibrillin-1 and LOXL1, two prominent components of exfoliation material. Although no elevated IOP or reduction of axon numbers was detected in dbm mice at 16-week-old, their reduced retinal function and enlarged ON area indicate early retinal ganglion cell dysfunction. Dbm mice also provide insight on the link between XFS and systemic diseases in humans.

ABI3BP promotes renal aging through Klotho-mediated ferroptosis

The aging process of the kidneys is accompanied with several structural diseases. Abnormal fiber formation disrupts the balance of kidney structure and function, causing to end-stage renal disease and subsequent renal failure. Despite this, the precise mechanism underlying renal damage in aging remains elusive. In this study, ABI3BP gene knockout mice were used to investigate the role of ABI3BP in renal aging induced by irradiation. The results revealed a significant increase in ABI3BP expression in HK2 cells and kidney tissue of aging mice, with ABI3BP gene knockout demonstrating a mitigating effect on radiation-induced cell aging. Furthermore, the study observed a marked decrease in Klotho levels and an increase in ferroptosis in renal tissue and HK2 cells following irradiation. Notably, ABI3BP gene knockout not only elevated Klotho expression but also reduced ferroptosis levels. A significant negative correlation between ABI3BP and Klotho was established. Further experiments demonstrated that Klotho knockdown alleviated the aging inhibition caused by ABI3BP downregulation. This study identifies the upregulation of ABI3BP in aged renal tubular epithelial cells, indicating a role in promoting ferroptosis and inducing renal aging by inhibiting Klotho expression.

A mandibular advancement device attenuates the abnormal morphology and function of mitochondria from the genioglossus in obstructive sleep apnea-hypopnea syndrome rabbits.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a serious and potentially life-threatening disease. Mandibular advancement device (MAD) has the characteristics of non-invasive, comfortable, portable and low-cost, making it the preferred treatment for mild-to-moderate OSAHS. Our previous studies found that abnormal contractility and fibre type distribution of the genioglossus could be caused by OSAHS. However, whether the mitochondria participate in these tissue changes is unclear. The effect of MAD treatment on the mitochondria of the genioglossus in OSAHS is also uncertain. To examine the morphology and function of mitochondria from the genioglossus in a rabbit model of obstructive sleep apnea-hypopnea syndrome (OSAHS), as well as these factors after insertion of a mandibular advancement device (MAD). Thirty male New Zealand white rabbits were randomised into three groups: control, OSAHS and MAD, with 10 rabbits in each group. Animals in Group OSAHS and Group MAD were induced to develop OSAHS by injection of gel into the submucosal muscular layer of the soft palate. The rabbits in Group MAD were fitted with a MAD. The animals in the control group were not treated. Further, polysomnography (PSG) and cone-beam computed tomography (CBCT) scan were used to measure MAD effectiveness. CBCT of the upper airway and PSG suggested that MAD was effective. Rabbits in the three groups were induced to sleep for 4-6 h per day for eight consecutive weeks. The genioglossus was harvested and detected by optical microscopy and transmission electron microscopy. The mitochondrial membrane potential was determined by laser confocal microscopy and flow cytometry. Mitochondrial complex I and IV activities were detected by mitochondrial complex assay kits. OSAHS-like symptoms were induced successfully in Group OSAHS and rescued by MAD treatment. The relative values of the mitochondrial membrane potential, mitochondrial complex I activity and complex IV activity were significantly lower in Group OSAHS than in the control group; however, there was no significant difference between Group MAD and the control group. The OSAHS-induced injury and the dysfunctional mitochondria of the genioglossus muscle were reduced by MAD treatment. Damaged mitochondrial structure and function were induced by OSAHS and could be attenuated by MAD treatment.

Desmin gene expression is not ubiquitous in all upper airway myofibers and the pattern differs between healthy and sleep apnea subjects

BackgroundDesmin is a major cytoskeletal protein considered ubiquitous in mature muscle fibers. However, we earlier reported that a subgroup of muscle fibers in the soft palate of healthy subjects and obstructive sleep apnea patients (OSA) lacked immunoexpression for desmin. This raised the question of whether these fibers also lack messenger ribonucleic acid (mRNA) for desmin and can be considered a novel fiber phenotype. Moreover, some fibers in the OSA patients had an abnormal distribution and aggregates of desmin. Thus, the aim of the study was to investigate if these desmin protein abnormalities are also reflected in the expression of desmin mRNA in an upper airway muscle of healthy subjects and OSA patients.MethodsMuscle biopsies from the musculus uvulae in the soft palate were obtained from ten healthy male subjects and six male patients with OSA. Overnight sleep apnea registrations were done for all participants. Immunohistochemistry, in-situ hybridization, and reverse transcription–quantitative polymerase chain reaction (RT–qPCR) techniques were used to evaluate the presence of desmin protein and its mRNA.ResultsOur findings demonstrated that a group of muscle fibers lacked expression for desmin mRNA and desmin protein in healthy individuals and OSA patients (12.0 ± 5.6% vs. 23.1 ± 10.8%, p = 0.03). A subpopulation of these fibers displayed a weak subsarcolemmal rim of desmin accompanied by a few scattered mRNA dots in the cytoplasm. The muscles of OSA patients also differed from healthy subjects by exhibiting muscle fibers with reorganized or accumulated aggregates of desmin protein (14.5 ± 6.5%). In these abnormal fibers, the density of mRNA was generally low or concentrated in specific regions. The overall quantification of desmin mRNA by RT–qPCR was significantly upregulated in OSA patients compared to healthy subjects (p = 0.01).ConclusionsOur study shows evidence that muscle fibers in the human soft palate lack both mRNA and protein for desmin. This indicates a novel cytoskeletal structure and challenges the ubiquity of desmin in muscle fibers. Moreover, the observation of reorganized or accumulated aggregates of desmin mRNA and desmin protein in OSA patients suggests a disturbance in the transcription and translation process in the fibers of the patients.

Imaging of the anterior cruciate ligament and anterolateral rotational instability of the knee joint

The anterior cruciate ligament (ACL) is essential for the stability of the knee joint and ACL tears are one of the most common sports injuries with ahigh incidence, especially in sports that require rotational movements and abrupt changes in direction. Injuries of the ACL are rarely isolated and are often accompanied by meniscal and other internal knee injuries, which increase the risk of osteoarthritis. The spectrum of ACL injuries includes strains, partial tears and complete tears. Magnetic resonance imaging (MRI) plays apivotal role in the diagnostics as it can accurately depict not only the ACL but also accompanying injuries. Proton density and T2-weighted sequences are particularly suitable for evaluating the ACL, which is usually well visible and assessable in all planes. In addition to depicting fiber disruption as adirect sign and central diagnostic indicator of an ACL tear, there are numerous other direct and indirect signs of an ACL injury in MRI. These include abnormal fiber orientations, signal increases and an anterior subluxation of the tibia relative to the femur. The bone marrow edema patterns often associated with ACL tears are indicative of the underlying injury mechanism. The treatment of ACL tears can be conservative or surgical depending on various factors, such as the patient's activity level and the presence of accompanying injuries. The precise and comprehensive description of ACL injuries by radiology is crucial for optimal treatment planning. Anterolateral rotational instability (ALRI) of the knee joint characterizes acondition of excessive lateral and rotational mobility of the tibia in relation to the femur in the anterolateral knee region. This instability is primarily caused by arupture of the ACL, with the anterolateral ligament (ALL) that was rediscovered about 10 years ago, also being attributed arole in stabilizing the knee. Although ALRI is primarily diagnosed through clinical examinations, MRI is indispensable for detecting injuries to the ACL, ALL, and other internal knee structures, which is essential for developing an optimal treatment strategy.

Baseline symptom-related white matter tracts predict individualized treatment response to 12-week antipsychotic monotherapies in first-episode schizophrenia

There is significant heterogeneity in individual responses to antipsychotic drugs, but there is no reliable predictor of antipsychotics response in first-episode psychosis. This study aimed to investigate whether psychotic symptom-related alterations in fractional anisotropy (FA) and mean diffusivity (MD) of white matter (WM) at the early stage of the disorder may aid in the individualized prediction of drug response. Sixty-eight first-episode patients underwent baseline structural MRI scans and were subsequently randomized to receive a single atypical antipsychotic throughout the first 12 weeks. Clinical symptoms were evaluated using the eight “core symptoms” selected from the Positive and Negative Syndrome Scale (PANSS-8). Follow-up assessments were conducted at the 4th, 8th, and 12th weeks by trained psychiatrists. LASSO regression model and cross-validation were conducted to examine the performance of baseline symptom-related alterations FA and MD of WM in the prediction of individualized treatment outcome. Fifty patients completed both clinical follow-up assessments by the 8th and 12th weeks. 30 patients were classified as responders, and 20 patients were classified as nonresponders. At baseline, the altered diffusion properties of fiber tracts in the anterior thalamic radiation, corticospinal tract, callosum forceps minor, longitudinal fasciculi (ILF), inferior frontal-occipital fasciculi (IFOF) and superior longitudinal fasciculus (SLF) were related to the severity of symptoms. These abnormal fiber tracts, especially the ILF, IFOF, and SLF, significantly predicted the response to antipsychotic treatment at the individual level (AUC = 0.828, P < 0.001). These findings demonstrate that early microstructural WM changes contribute to the pathophysiology of psychosis and may serve as meaningful individualized predictors of response to antipsychotics.

Dynamic changes in mitral valve extracellular matrix, tissue mechanics and function in a mouse model of Marfan syndrome

ObjectiveMouse models of Marfan syndrome (MFS) with Fibrillin 1 (Fbn1) variant C1041G exhibit cardiovascular abnormalities, including myxomatous valve disease (MVD) and aortic aneurism, with structural extracellular matrix (ECM) dysregulation. In this study, we examine the structure-function-mechanics relations of the mitral valve related to specific transitions in ECM composition and organization in progressive MVD in MFS mice from Postnatal day (P)7 to 1 year-of-age. Approach and resultsMechanistic links between mechanical forces and biological changes in MVD progression were examined in Fbn1C1041G/+ MFS mice. By echocardiography, mitral valve dysfunction is prevalent at 2 months with a decrease in cardiac function at 6 months, followed by a preserved cardiac function at 12 months. Mitral valve (MV) regurgitation occurs in a subset of mice at 2–6 months, while progressive dilatation of the aorta occurs from 2 to 12 months. Mitral valve tissue mechanical assessments using a uniaxial Permeabilizable Fiber System demonstrate decreased stiffness of MFS MVs at all stages. Histological and microscopic analysis of ECM content, structure, and fiber orientation demonstrate that alterations in ECM mechanics, composition, and organization precede functional abnormalities in Fbn1C1041G/+MFS MVs. At 2 months, ECM abnormalities are detected with an increase in proteoglycans and decreased stiffness of the mitral valve. By 6–12 months, collagen fiber remodeling is increased with abnormal fiber organization in MFS mitral valve leaflets. At the same time, matrifibrocyte gene expression characteristic of collagen-rich connective tissue is increased, as detected by RNA in situ hybridization and qPCR. Together, these studies demonstrate early prevalence of proteoglycans at 2 months followed by upregulation of collagen structure and organization with age in MVs of MFS mice. ConclusionsAltogether, our data indicate dynamic regulation of mitral valve structure, tissue mechanics, and function that reflect changes in ECM composition, organization, and gene expression in progressive MVD. Notably, increased collagen fiber organization and orientation, potentially dependent on increased matrifibrocyte cell activity, is apparent with altered mitral valve mechanics and function in aging MFS mice.

Serum glial cell line-derived neurotrophic factor: a potential biomarker for white matter alteration in Parkinson's disease with mild cognitive impairment.

Mild cognitive impairment (MCI) is a common non-motor manifestation of Parkinson's disease, commonly referred to as PD-MCI. However, there is a lack of comprehensive data regarding the role of glial cell line-derived neurotrophic factor (GDNF) and cerebral white matter damage in the pathogenesis of PD-MCI. The objective of this study is to investigate the association between alterations in GDNF levels and cerebral white matter damage in individuals diagnosed with PD-MCI, as well as to explore their potential involvement in cognitive progression. Neuropsychological assessments were conducted on 105 patients with Parkinson's disease and 45 healthy volunteers to examine various cognitive domains. An enzyme-linked immunosorbent assay (ELISA) was employed to measure serum levels of GDNF. Additionally, all participants underwent 3.0T magnetic resonance imaging (MRI) to acquire diffusion tensor images (DTI), and a voxel-based analysis (VBA) approach was utilized to compare the fractional anisotropy (FA) values of white matter in the brain. There was a significant correlation between the right corpus callosum, right cingulate gyrus, and the Digit Span Backward Test (DSB-T) as well as the Trail Making Test A (TMT-A), both of which assess attention and working memory functions. The left internal capsule exhibited a significant correlation with the Trail Making Test B (TMT-B) and the Clock Drawing Test (CDT), which evaluate executive function. Additionally, the right cingulate gyrus showed a significant association with scores on the Auditory Verbal Learning Test-HuaShan (AVLT-H), assessing memory function. Abnormal fiber structures that demonstrated significant correlations with serum GDNF levels included the left internal capsule, left corticospinal tract, right corpus callosum, and right cingulate gyrus. The decrease in serum GDNF levels among PD-MCI patients exhibiting impairments in attention and working memory function was significantly correlated with alterations in the corpus callosum (knee) and posterior cingulate gyrus. Furthermore, the reduction of serum GDNF levels in PD-MCI patients with impaired executive function is associated with changes in the internal capsule (forelimb) projection fibers. Additionally, the decline of serum GDNF levels in PD-MCI patients experiencing memory function impairment is related to alterations in the right cingulate gyrus.

Brain Pathways in LIS1-Associated Lissencephaly Revealed by Diffusion MRI Tractography.

Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both genetic and non-genetic factors. Despite frequent studies about the cortex, comprehensive elucidation of structural abnormalities and their effects on the white matter is limited. The main objective of this study is to analyze abnormal neuronal migration pathways and white matter fiber organization in LIS1-associated LIS using diffusion MRI (dMRI) tractography. For this purpose, slabs of brain specimens with LIS (n = 3) and age and sex-matched controls (n = 4) were scanned with 3T dMRI. Our high-resolution ex vivo dMRI successfully identified common abnormalities across the samples. The results revealed an abnormal increase in radially oriented subcortical fibers likely associated with radial migration pathways and u-fibers and a decrease in association fibers in all LIS specimens.

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions.

Progressive external ophthalmoplegia (PEO) is a common subtype of mitochondrial encephalomyopathy. The study aimed to investigate the relationship between mitochondrial DNA (mtDNA) abnormalities, muscle pathology, and clinical manifestations in Chinese patients with single large-scale mtDNA deletion presenting with PEO. This is a retrospective single-center study. Patients with PEO who had a single large deletion in mitochondrial DNA were included in this study. The associations were analyzed between mtDNA deletion patterns, myopathological changes, and clinical characteristics. In total, 155 patients with mitochondrial PEO carrying single large-scale mtDNA mutations were enrolled, including 137 chronic progressive external ophthalmoplegia (CPEO) and 18 Kearns-Sayre syndrome (KSS) patients. The onset ages were 9.61 ± 4.12 in KSS and 20.15 ± 9.06 in CPEO. The mtDNA deletions ranged from 2225 bp to 9131 bp, with m.8470_13446del being the most common. The KSS group showed longer deletions than the CPEO group (p = 0.004). Additionally, a higher number of deleted genes encoding respiratory chain complex subunits (p = 0.001) and tRNA genes (p = 0.009) were also observed in the KSS group. A weak negative correlation between the mtDNA deletion size and ages of onset (p < 0.001, r = -0.369) was observed. The proportion of ragged red fibers, ragged blue fibers, and cytochrome c negative fibers did not correlate significantly with onset ages (p > 0.05). However, a higher percentage of abnormal muscle fibers corresponds to an increased prevalence of exercise intolerance, limb muscle weakness, dysphagia, and cerebellar ataxia. We reported a large Chinese cohort consisting of mitochondrial PEO patients with single large-scale mtDNA deletions. Our results demonstrated that the length and locations of mtDNA deletions may influence onset ages and clinical phenotypes. The severity of muscle pathology could not only indicate diagnosis but also may be associated with clinical manifestations beyond the extraocular muscles.