Miracle-dz/UniFAR-FTUs huggingface dataset:
A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

Supplemental Digital Content is available in the text. Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte. Visual Overview: An online visual overview is available for this article.
Capillary blood tests may overestimate ketosis: Triangulation between three different measures of beta-hydroxybutyrate.

Background: The ketone body beta-hydroxybutyrate (BHB)-assessed by a point-of-care meter in venous whole blood (BHBv)-was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study, for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Method: Ketosis in the range 0-1.5 mmol/L was induced in fifteen healthy volunteers by intake of medium-chain fatty acids after a 12-hour fast. BHBv was assessed at twelve timepoints during 4 hours. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp and TK. Results: TK correlated with BHBp (Pearson's r=0.99), BHBv (r=0.91) and BHBc (r=0.91), all p< 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv-measured with the same device-was in the range 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary vs. venous blood. Conclusions: We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cut-offs, e.g. in the management of ketoacidosis, and in the evaluation and comparison of dietary interventions.
The SAUR41 subfamily of cell expansion-promoting genes modulates abscisic acid sensitivity and root touch response: a possible connection to ion homeostasis regulation

ABSTRACT Most primary auxin response genes are classified into three families, namely AUX/IAAs, GH3s, and SAURs. As a rapidly developing field of plant biology, recent studies have begun to address the function and mechanism of plant SAURs. We found that, in Arabidopsis, the SAUR41 subfamily genes were ABA-inducible, and overexpression of SAUR41 induced the biosynthesis of ABA. The saur41/40/71/72 quadruple mutants and the SAUR41 overexpression lines had an altered expression of ABA and calcium homeostasis/signaling genes, but not the AUX/IAAs and GH3s. Here, we reported that the quadruple mutants showed an increased sensitivity to ABA treatment, in terms of cotyledon greening/expansion rate, while for the overexpression lines, this was decreased. With respect to the root touch response, the overexpression of SAUR41 led to an extensive root looping phenotype, while the quadruple mutations of saur41s led to a relaxed root looping. As reported, the ion content (Na+, K+ and Fe2+), apoplast acidification ability, and salt tolerance were also abnormal in the quadruple mutants and/or the SAUR41 overexpression lines. Our work supports an emerging concept that ABA and calcium are integrated together to modulate ion homeostasis. In addition, our work demonstrates that SAUR41s might be new components for the regulation of ion homeostasis by ABA and calcium.
In Response to Gürdoğan and Akkuş

We would like to thank the authors for their interest in our paper (1) and their valuable comments. In the authors’ letter to the editor, they mentioned potential concerns regarding the diagnosis of Fabry disease in female patients. The main aim of our study (1) was to screen adult patients with hypertrophic cardiomyopathy without left ventricular outflow tract. In the diagnosis of Fabry disease, plasma α-galactosidase A activity and plasma and urine glycosphingolipid measurements as well as molecular genetic analyses of the GLA gene are used (2). Fabry disease is an X-linked disorder. According to the Lyon hypothesis, in case of X chromosome inactivation, females can be affected as much as males (3). Plasma α-galactosidase A activity can be determined close to normal values in heterozygous individuals. A definitive diagnosis should be made by molecular genetic analysis in female patients. Only measuring plasma α-galactosidase A activity in female patients may lead to a missed diagnosis. Therefore, as stated in our study, GLA gene sequence analyses were performed in all patients. Cardiac symptoms and signs may be delayed in female patients with Fabry disease compared with that in male patients. In a study by Linhart et al., pacemaker implantation, myocardial infarction, left ventricular hypertrophy, and conduction defects were observed 8 to 10 years later in female patients diagnosed with Fabry disease (4). According to the Fabry Outcome Survey study data, the mean time between symptom onset and diagnosis was 13.7 and 16.3 years for males and females, respectively (5). left ventricular hypertrophy, considered a high-risk factor for Fabry disease, was observed in 46% males and 28% females in Fabry Outcome Survey. The age at onset of left ventricular hypertrophy in males and females was 38.0 and 55.4 years, respectively (5). According to the Fabry Outcome Survey database, female patients are usually (often severely) affected. Female patients with chronic kidney disease, left ventricular hypertrophy, and/or stroke, all considered high-risk factors for Fabry disease, should be diagnosed using molecular genetic analyses. However, screening for Fabry disease in our country remains suboptimal. In the future, a countrywide approach to identify Fabry disease among high-risk patients seems warranted.
Groin pain caused by iliopsoas synovial cyst treated with endoscopic approach. A case report

The diagnosis of iliopsoas synovial cyst is a rare finding. The normal approach to treat this condition has been conservative therapies or open surgery, with its associated complications and morbidity. The arthroscopic – endoscopic surgery is less invasive and with an increase in complications and days of hospitalization. We report the case of a 70-year old woman with clinical and imaging signs of a fluid-filled cyst near iliopsoas distal tendon. After fluid aspiration, the patient reported symptom-free interval of several weeks, but then groin pain and swelling feeling return, increased with hip movements. The cyst was removed through arthroscopy approach and the iliopsoas tendon was released. The removal of iliopsoas synovial cyst is necessary to avoid complications such as pain and functional limits. Arthroscopy has the advantage of less soft-tissue damage and quicker recovery. The treatment of associated tendon pathology can be done. Hip arthroscopy can be a safe and effective technique for the removal of iliopsoas synovial cyst. (www.actabiomedica.it)
Paternal Y chromosomal genotyping reveals multiple large-scale admixtures in the formation of Lolo-Burmese–speaking populations in southwest China

Abstract Background: Bai and Yi people are two Tibeto-Burman speaking ethnic groups in Yunnan, southwest China. The genetic structure and history of these two groups are largely unknown due to a lack of available genetic data. Aim: To investigate the paternal genetic structure and population relationship of the Yi and Bai people. Subjects and methods: We collected samples from 278 Bai individuals and 283 Yi individuals from Yunnan and subsequently genotyped 43 phylogenetically relevant Y-SNPs in those samples. We estimated haplogroup frequencies and merged our data with a reference database including 46 representative worldwide populations to infer genetic relationships. Results: Y chromosomal haplogroup O-M175 is the dominant lineage in both Bai and Yi people. The Bai and Yi show a close genetic relationship with other Tibeto-Burman–speaking populations with high frequencies of haplogroup O2a2b1a1-Page23, which is also confirmed by PCA. The frequencies of the Tai-Kadai specific lineage O1a-M119, the southern China widespread lineage O1b-P31 and the eastern China enriched lineage O2a1b-002611, are also relatively high in our studied populations. Conclusions: The paternal Y chromosomal affinity of the Bai and Yi with Tibeto-Burman groups is consistent with the language classification. During the formation of the Bai and Yi populations, there were multiple large-scale admixtures, including the expansion of Neolithic farming populations from northern China, the assimilation of Tai-Kadai–speaking populations in southwest China, the demographic expansion driven by Neolithic agricultural revolution from southern China, and the admixture with populations of military immigration from northern and eastern China.
Pelvic ring fractures: what about timing?

Background and aim: Pelvic ring fractures represent a challenge for orthopaedic surgeon. Their management depends on patient’s condition, pattern of fracture and associated injuries. Optimal timing for synthesis is not yet clear. The aim of this study was to define if surgical timing influenced clinic and radiographic outcomes following open reduction and internal fixation for Tile B and C fractures. Materials and methods: 38 patients were included. Patients underwent a clinical examination with the Majeed Score, Iowa Pelvic Score and Orlando Pelvic Score. The radiographic assessment was performed according to Matta Pelvic Score. A statistical analysis of the data compared patients who were operated within 3 weeks (group 1) and those operated later (group 2). Results: Both clinical and radiological outcomes were influenced by timing of surgery. Conclusion: Pelvic ring fractures interest many polytrauma patients and, therefore, their surgical orthopedic approach is frequently delayed as consequence of the severity of the associated clinical conditions. An early surgery of pelvic rong fractures allows a better quality of reduction and osteosynthesis. (www.actabiomedica.it)
Apoptosis in the Cochlear Nucleus and Inferior Colliculus Upon Repeated Noise Exposure

The time course of apoptosis and the corresponding neuronal loss was previously shown in central auditory pathway of mice after a single noise exposure. However, repeated acoustic exposure is a major risk factor for noise-induced hearing loss. The present study investigated apoptosis by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay after a second noise trauma in the ventral and dorsal cochlear nucleus and central nucleus of the inferior colliculus. Mice [Naval Medical Research Institute (NMRI) strain] were noise exposed [115 dB sound pressure level, 5–20 kHz, 3 h) at day 0. A double group received the identical noise exposure a second time at day 7 post-exposure and apoptosis was either analyzed immediately (7-day group-double) or 1 week later (14-day group-double). Corresponding single exposure groups were chosen as controls. No differences in TUNEL were seen between 7-day or 14-day single and double-trauma groups. Interestingly, independent of the second noise exposure, apoptosis increased significantly in the 14-day groups compared to the 7-day groups in all investigated areas. It seems that the first noise trauma has a long-lasting effect on apoptotic mechanisms in the central auditory pathway that were not largely influenced by a second trauma. Homeostatic mechanisms induced by the first trauma might protect the central auditory pathway from further damage during a specific time slot. These results might help to understand the underlying mechanisms of different psychoacoustic phenomena in noise-induced hearing loss.
Single and combined effects of cisplatin and doxorubicin on the human and mouse ovary in vitro

Chemotherapy drugs are administered to patients using combination regimens, and as such the possibility of multiplicative effects between drugs need to be investigated. This study examines the individual and combined effects of the chemotherapy drugs cisplatin and doxorubicin on the human ovary. Although cisplatin and doxorubicin are known to affect female fertility, there is limited information about their direct effects on the human ovary, and none examining the possibility of combined, multiplicative effects of co-exposure to these drugs. Here, human ovarian biopsies were obtained from 14 women at the time of caesarean section, with 38 mouse ovaries also obtained from neonatal C57Bl/6J mice. Tissue was cultured for 6 days prior to analyses, with chemotherapy drugs added to culture medium on the second day of culture only. Treatment groups of a single (5 μg/mL human; 0.5 μg/mL mouse) or double (10 μg/mL human; 1.0 μg/mL mouse) dose of cisplatin, a single (1 μg/mL human; 0.05 μg/mL mouse) or double (2 μg/mL human; 0.1 μg/mL mouse) dose of doxorubicin or a combination of a single dose of both drugs together were compared to controls without drug exposure. Exposure to cisplatin or doxorubicin significantly decreased follicle health in human and mouse, supporting the suitability of the mouse as a model for the human ovary. There was also a significant reduction of mouse follicle number. Human ovarian stromal tissue exhibited increased apoptosis and decreased cell proliferation. Crucially, there was no evidence indicating the occurrence of multiplicative effects between cisplatin and doxorubicin.
Using deep learning for a diffusion-based segmentation of the dentate nucleus and its benefits over atlas-based methods

Abstract. The dentate nucleus (DN) is a gray matter structure deep in the cerebellum involved in motor coordination, sensory input integration, executive planning, language, and visuospatial function. The DN is an emerging biomarker of disease, informing studies that advance pathophysiologic understanding of neurodegenerative and related disorders. The main challenge in defining the DN radiologically is that, like many deep gray matter structures, it has poor contrast in T1-weighted magnetic resonance (MR) images and therefore requires specialized MR acquisitions for visualization. Manual tracing of the DN across multiple acquisitions is resource-intensive and does not scale well to large datasets. We describe a technique that automatically segments the DN using deep learning (DL) on common imaging sequences, such as T1-weighted, T2-weighted, and diffusion MR imaging. We trained a DL algorithm that can automatically delineate the DN and provide an estimate of its volume. The automatic segmentation achieved higher agreement to the manual labels compared to template registration, which is the current common practice in DN segmentation or multiatlas segmentation of manual labels. Across all sequences, the FA maps achieved the highest mean Dice similarity coefficient (DSC) of 0.83 compared to T1 imaging (DSC = 0.76), T2 imaging (DSC = 0.79), or a multisequence approach (DSC = 0.80). A single atlas registration approach using the spatially unbiased atlas template of the cerebellum and brainstem template achieved a DSC of 0.23, and multi-atlas segmentation achieved a DSC of 0.33. Overall, we propose a method of delineating the DN on clinical imaging that can reproduce manual labels with higher accuracy than current atlas-based tools.
Macrocyclic Metal Complexes Bearing Rigid Polyaromatic Ligands: Synthesis and Catalytic Activity.

We synthesised palladium and platinum complexes possessing cyclic and acyclic pincer-type polyaromatic ligands and investigated their structural effect on the catalysis. The pincer-type bis(6-arylpyridin-2-yl)benzene skeleton was constructed via Kröhnke pyridine synthesis under transition metal-free conditions at gram-scale quantity. Ligand structure significantly influenced catalytic activity toward the platinum-catalysed hydrosilylation of diphenyl acetylenes, despite the ligand-independence of these complexes' conformations and electronic properties.
Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes

Significance Sex differences are naturally occurring disease modifiers that, if understood, could lead to novel targets for drug development. Autoimmune diseases are more prevalent in women than in men, and sex differences in immune responses have been shown in humans and mice. Here, we discover a global parent-of-origin difference in DNA methylation on the X chromosome that affects gene expression in activated CD4+ T lymphocytes. The paternal X has more methylation than the maternal X, with higher expression of X genes in XY cells since they only express from the maternal X. Thus, parent-of-origin differences in DNA methylation of X genes can play a role in sex differences in immune responses. Many autoimmune diseases are more frequent in females than in males in humans and their mouse models, and sex differences in immune responses have been shown. Despite extensive studies of sex hormones, mechanisms underlying these sex differences remain unclear. Here, we focused on sex chromosomes using the “four core genotypes” model in C57BL/6 mice and discovered that the transcriptomes of both autoantigen and anti-CD3/CD28 stimulated CD4+ T lymphocytes showed higher expression of a cluster of 5 X genes when derived from XY as compared to XX mice. We next determined if higher expression of an X gene in XY compared to XX could be due to parent-of-origin differences in DNA methylation of the X chromosome. We found a global increase in DNA methylation on the X chromosome of paternal as compared to maternal origin. Since DNA methylation usually suppresses gene expression, this result was consistent with higher expression of X genes in XY cells because XY cells always express from the maternal X chromosome. In addition, gene expression analysis of F1 hybrid mice from CAST × FVB reciprocal crosses showed preferential gene expression from the maternal X compared to paternal X chromosome, revealing that these parent-of-origin effects are not strain-specific. SJL mice also showed a parent-of-origin effect on DNA methylation and X gene expression; however, which X genes were affected differed from those in C57BL/6. Together, this demonstrates how parent-of-origin differences in DNA methylation of the X chromosome can lead to sex differences in gene expression during immune responses.
ACL reconstruction using a bone patellar tendon bone (BPTB) allograft or a hamstring tendon autograft (GST): a single-center comparative study

Background and aim of the work: There is still debate on which graft is better indicated for anterior cruciate ligament (ACL) surgical reconstruction. The objective of this study was to evaluate the medium-term clinical outcomes of ACL reconstruction comparing patients managed with bone patellar tendon bone allograft (BPTB) versus patients treated with hamstring autograft (GST). Methods: Patients enrolled during the period 2013-2016 underwent a personal interview with the use of specific evaluation questionnaires (Tegner e Lyshom, Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee), a clinical evaluation with the use of objective functional tests (Lachman test, pivot-shift) and a physical examination of the knee. Results: In this study 43 patients were enrolled: 21 patients were treated by autograft and 22 patients by allograft. Patients who received allograft ACL reconstruction returned to normal sport activity earlier than patients operated on using autograft (11.7±10.3 vs 17.9±14.6 weeks, p<0.05). Data obtained with subjective tests, clinical and physical examination were positive overall, with no differences observed between the two groups. Finally, 15 allograft patients and 12 autograft patients accepted to perform the proprioceptive tests: no difference was found between the two groups. Conclusions: At follow-up evaluation after ACL reconstruction, both BPTB allograft and GST autograft patient groups showed similar results at subjective, objective clinical evaluation and proprioceptive properties of the limb. In particular, the use of allogenic BPTB allowed the patients to return earlier to normal activities of daily-living and sport activity. (www.actabiomedica.it)