BACKGROUND: The hypothalamus (HT) plays a crucial role in regulating eating behaviors. Disruptions in its function have been linked to the development of weight-related disorders. Nevertheless, its characterization remains a challenge. OBJECTIVES: We assessed the structural alterations of individual HT nuclei related to eating behaviors in patients with weight-related disorders, and their association with body mass index (BMI) and severity of eating disorders. METHODS: Forty-four young females with normal weight (HC, n = 21), restrictive anorexia nervosa (AN, n = 13), and living with obesity (OB, n = 10) were explored in vivo using 7-T high-resolution (0.6 mm isotropic voxel) T1 quantitative magnetic resonance imaging (MRI). Volumes and quantitative T1 values of individual HT nuclei were compared after whole-brain normalization using nonparametric tests (corrected for multiple comparisons for groups and regions). We investigated the parameters associated with BMI and eating disorders, such as MRI parameters of HT nuclei, ghrelin and leptin levels, depression, and anxiety using multivariate nonlinear partial least square (NIPALS). RESULTS: Both AN and OB showed higher volumes of HT relative to HC (Zscores: 0.78 ± 1.06; 1.43 ± 1.51). AN showed significantly higher volumes and T1 values of the right paraventricular nucleus (PaVN) (volume Zscore: 1.82 ± 1.45; T1 Zscore: 3.76 ± 4.67), and higher T1 values of the left PaVN (Zscore: 2.25 ± 2.37) and right periventricular nuclei (Zscore: 3.73 ± 4.81). NIPALS models showed that lower BMI in AN was associated with structural alterations of the bilateral PaVN, right anterior commissure, and left fornix (FX). Higher BMI in OB was associated with structural alterations within the right PaVN, bilateral FX, left posterior hypothalamic nucleus, right lateral HT, and right anterior hypothalamic area. Finally, the severity of eating disorders was associated with larger structural alterations within the bilateral PaVN, bilateral arcuate hypothalamic nuclei, right bed nucleus of stria terminalis, left medial preoptic nucleus, and right tubero-mammillary hypothalamic nucleus. CONCLUSIONS: Weight-related disorders are associated with significant micro and macrostructural alterations in HT nuclei involved in eating behaviors.

• MeSH
• Adult MeSH
• Hypothalamus * diagnostic imaging   pathology   MeSH
• Body Mass Index MeSH
• Leptin blood   MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Anorexia Nervosa * diagnostic imaging   pathology   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Obesity * diagnostic imaging   pathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Quantitative genomic mapping of DNA damage may provide insights into the underlying mechanisms of damage and repair. Sequencing based approaches are bound to the limitations of PCR amplification bias and read length which hamper both the accurate quantitation of damage events and the ability to map them to structurally complex genomic regions. Optical Genome mapping in arrays of parallel nanochannels allows physical extension and genetic profiling of millions of long genomic DNA fragments, and has matured to clinical utility for characterization of complex structural aberrations in cancer genomes. Here we present a new mapping modality, Repair-Assisted Damage Detection - Optical Genome Mapping (RADD-OGM), a method for single-molecule level mapping of DNA damage on a genome-wide scale. Leveraging ultra-long reads to assemble the complex structure of a sarcoma cell-line genome, we mapped the genomic distribution of oxidative DNA damage, identifying regions more susceptible to DNA oxidation. We also investigated DNA repair by allowing cells to repair chemically induced DNA damage, pinpointing locations of concentrated repair activity, and highlighting variations in repair efficiency. Our results showcase the potential of the method for toxicogenomic studies, mapping the effect of DNA damaging agents such as drugs and radiation, as well as following specific DNA repair pathways by selective induction of DNA damage. The facile integration with optical genome mapping enables performing such analyses even in highly rearranged genomes such as those common in many cancers, a challenging task for sequencing-based approaches.

• MeSH
• Bromates toxicity   MeSH
• Humans MeSH
• Chromosome Mapping * instrumentation   methods   MeSH
• Microfluidic Analytical Techniques * instrumentation   methods   MeSH
• Cell Line, Tumor MeSH
• Nanotechnology * instrumentation   methods   MeSH
• DNA Repair genetics   MeSH
• Oxidative Stress drug effects   genetics   MeSH
• DNA Damage * genetics   MeSH
• Gene Expression Regulation MeSH
• Gene Expression Profiling MeSH
• Toxicogenetics * instrumentation   methods   MeSH
• DNA Copy Number Variations MeSH
• Single Molecule Imaging * instrumentation   methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

MRE11 nuclease is a central player in signaling and processing DNA damage, and in resolving stalled replication forks. Here, we describe the identification and characterization of new MRE11 inhibitors MU147 and MU1409. Both compounds inhibit MRE11 nuclease more specifically and effectively than the relatively weak state-of-the-art inhibitor mirin. They also abrogate double-strand break repair mechanisms that rely on MRE11 nuclease activity, without impairing ATM activation. Inhibition of MRE11 also impairs nascent strand degradation of stalled replication forks and selectively affects BRCA2-deficient cells. Herein, we illustrate that our newly discovered compounds MU147 and MU1409 can be used as chemical probes to further explore the biological role of MRE11 and support the potential clinical relevance of pharmacological inhibition of this nuclease.

• MeSH
• MRE11 Homologue Protein * metabolism   antagonists & inhibitors   MeSH
• Enzyme Inhibitors * pharmacology   chemistry   chemical synthesis   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Drug Discovery MeSH
• DNA Repair drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.

• MeSH
• Atrophy pathology   MeSH
• White Matter * diagnostic imaging   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Brain pathology   MeSH
• Retrospective Studies MeSH
• Tay-Sachs Disease * pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Biotransformation of steroids by fungi has been raised as a successful, eco-friendly, and cost-effective biotechnological alternative for chemical derivatization. Endophytic fungi live inside vegetal tissues without causing damage to the host plant, making available unique enzymes that carry out uncommon reactions. Moreover, using nanofibrous membranes as support for immobilizing fungal cells is a powerful strategy to improve their performance by enabling the combined action of adsorption and transformation processes, along with increasing the stability of the fungal cell. In the present study, we report the use of polyacrylonitrile nanofibrous membrane (PAN NFM) produced by electrospinning as supporting material for immobilizing the endophytic fungus Penicillium citrinum H7 aiming the biotransformation of progesterone. The PAN@H7 NFM displayed a high progesterone transformation efficiency (above 90%). The investigation of the biotransformation pathway of progesterone allowed the putative structural characterization of its main fungal metabolite by GC-MS analysis. The oxidative potential of P. citrinum H7 was selective for the C-17 position of the steroidal nucleus.

• MeSH
• Biotransformation MeSH
• Nanofibers * chemistry   MeSH
• Progesterone MeSH
• Publication type
• Journal Article MeSH

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

• MeSH
• Executive Function * physiology   MeSH
• Frontotemporal Dementia * pathology   diagnostic imaging   physiopathology   psychology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging * MeSH
• Brain diagnostic imaging   pathology   MeSH
• Neuropsychological Tests * MeSH
• Cross-Sectional Studies MeSH
• Aged MeSH
• Social Cognition MeSH
• Theory of Mind * physiology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The purpose of the present study was to purify and characterize the catechol 1,2-dioxygenase (EC 1.13.11.1; catechol-oxygen 1,2-oxidoreductase; C12O) enzyme from the local isolate of Pseudomonas putida. This enzyme catalyzes the initial reaction in the ortho-pathway for phenol degradation in various gram-negative bacteria, including the genus of Pseudomonas. Pseudomonads are commonly used in the biodegradation of xenobiotics due to their versatility in degrading a wide range of chemical compounds. Eighty-nine soil samples were taken from the contaminated soil of the Midland Refineries Company (MRC) of Al-Daura refinery area at Baghdad from April to August 2021. The samples were grown in a mineral salt medium containing 250 mg per L of phenol to test their ability to biodegrade phenol. The pH was adjusted to 8.0 at 30 °C using a shaking incubator for 24-48 h. A number of 62 (69.6%) isolates of the total number were able to degrade phenol efficiently. The findings of the VITEK system and the housekeeping gene 16S rDNA confirmed that out of the positive isolates for phenol degradation, 36 from 62 (58.06%) were identified as Pseudomonas spp. isolates. Those isolates were distributed as P. aeruginosa 30 (83.3%) and P. putida 6 (16.6%). The enzyme production capabilities of the isolates were evaluated, and the highest activity was 2.39 U per mg for the isolate No. 15 which it was identified as P. putida. The previous isolate was selected for enzyme production, purification, and characterization. The enzyme was purified using ion exchange and gel filtration chromatography, with a combined yield of 36.12% and purification fold of 15.42 folds. Using a gel filtration column, the enzyme's molar mass was calculated to be 69 kDa after purification. The purified enzyme was stable at 35 °C and a pH of 6.0.

• MeSH
• Bacterial Proteins metabolism   genetics   chemistry   isolation & purification   MeSH
• Biodegradation, Environmental * MeSH
• Phenol * metabolism   MeSH
• Phylogeny MeSH
• Catechol 1,2-Dioxygenase * metabolism   genetics   MeSH
• Hydrogen-Ion Concentration MeSH
• Pseudomonas putida * enzymology   genetics   metabolism   MeSH
• Soil Microbiology * MeSH
• RNA, Ribosomal, 16S genetics   MeSH
• Temperature MeSH
• Publication type
• Journal Article MeSH

Přehledový článek se věnuje především možnostem a limitacím moderních zobrazovacích metod v předoperační diferenciální diagnostice mezenchymových nádorů dělohy. Při plánování vhodného chirurgického výkonu se řídíme nejen klinickými symptomy, věkem a reprodukčními plány, ale i zobrazovacími metodami, zejména ultrazvukovým vyšetřením a magnetickou rezonancí (MR). U těchto dvou zobrazení lze na základě recentních studií definovat znaky, které svědčí pro přítomnost malignity. V případě ultrazvukového vyšetření se jedná o obraz objemného, většinou solitárního nádoru nehomogenní struktury s cystami nepravidelného tvaru, s porušeným zevním pouzdrem, absencí kalcifikací a akustických stínů a střední nebo vysokou vaskularizací intraparenchymatózně. Maligním znakem je rovněž rychlý růst nádoru v průběhu sledování, zvláště peri- a postmenopauzálně. Při zobrazení MR mají děložní sarkomy nepravidelné ohraničení, jsou patrné hyperintenzní oblasti na T1 i T2 vážených sekvencích a centrální nekrotická oblast bez sycení kontrastní látkou. Při difuzně váženém zobrazení (DWI/MR) je patrná výrazná restrikce, ale tento znak se může objevovat i u některých variant myomů. Při suspektních nálezech v rámci předoperačního zobrazení ultrazvukem či MR lze využít biopsii silnou jehlou či hysteroskopicky, a to zejména při plánování fertilitu zachovávajících výkonů, nebo zvažujeme-li konzervativní management u asymptomatických pacientek. Co se týče dalších zobrazovacích metod, přínos výpočetní tomografie (CT) nebo pozitronové emisní tomografie v kombinaci s CT (PET/CT) je v rámci diferenciální diagnostiky značně omezený. Obě metody slouží pouze pro stanovení rozsahu onemocnění. Význam laboratorních markerů, především laktátdehydrogenázy, v diferenciální diagnostice nebyl dosud prokázán. Závěr: Ultrazvukové vyšetření anebo magnetická rezonance mohou přispět k předoperačnímu rozlišení děložních sarkomů od mnohem častějších myomů na základě přítomnosti kombinace maligních znaků. V této skupině žen se suspektními nálezy je potřeba zvolit adekvátní typ a rozsah chirurgického výkonu, především je nutné vyvarovat se intraperitoneální morcelace, která by mohla vést k iatrogenní diseminaci a zhoršení prognózy.

The narrative review article is focused on the strengths and limitations of modern imaging methods in the preoperative differential diagnosis of uterine mesenchymal tumours. In order to tailor the surgical procedures, imaging methods, namely ultrasound and magnetic resonance imaging (MRI), should be taken into account as well as clinical symptoms, age, and fertility plans. On ultrasound scans, uterine sarcomas have the appearance of large, usually solitary tumours of non-homogenous structure with irregular cysts, ill-defined outline borders (interrupted capsule), absence of calcifications with acoustic shadowing, and moderate to rich internal vascularisation. Rapid growth between follow-ups or atypical growth in peri- or post-menopause is also a sign of malignancy. On MRI, uterine sarcomas are characterized by irregular borders, hyperintense areas on T1-weighted and T2- weighted images, and central non-enhancing necrotic areas. On diffusion-weighted imaging (DWI/MRI), sarcomas exhibit markedly restricted diffusion but there is a significant overlap with some variants of fibroids. Core-needle or hysteroscopic biopsy can be used preoperatively if suspicious features are detected on ultrasound or MRI scans, particularly before myomectomy if fertility preservation is required or when conservative management is considered in asymptomatic women. Other imaging methods, such as positron emission tomography fused with CT (PET-CT) or computed tomography (CT) have limited role to distinguish uterine sarcomas from myomas and are suitable only for staging purposes. The importance of tumour markers including lactate dehydrogenase in preoperative work-up have not been verified yet. Conclusion: Uterine sarcomas can be distinguished from much more common myomas based on a combination of malignant features on ultrasound or MR imaging. In these suspicious cases the type and extent of surgery should be adjusted, avoiding intraperitoneal morcellation, which could lead to iatrogenic tumour spread and worsening of the patient’s prognosis.

• MeSH
• Biomarkers MeSH
• Biopsy methods   MeSH
• Diagnosis, Differential MeSH
• Leiomyoma surgery   diagnosis   MeSH
• Humans MeSH
• Magnetic Resonance Imaging methods   MeSH
• Uterine Neoplasms * surgery   diagnostic imaging   diagnosis   MeSH
• Surgical Clearance MeSH
• Sarcoma surgery   diagnosis   MeSH
• Ultrasonography methods   MeSH
• Check Tag
• Humans MeSH
• Female MeSH

Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.

• MeSH
• Activin Receptors, Type I antagonists & inhibitors   metabolism   MeSH
• Activin Receptors, Type II * metabolism   antagonists & inhibitors   MeSH
• Protein Kinase Inhibitors pharmacology   chemistry   MeSH
• Bone Morphogenetic Proteins metabolism   MeSH
• Humans MeSH
• Molecular Probes chemistry   MeSH
• Mice MeSH
• Drug Discovery MeSH
• Pyrazoles chemistry   pharmacology   chemical synthesis   MeSH
• Signal Transduction drug effects   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Isoforms of microtubule-associated protein 2 (MAP2) differ from their homolog Tau in the sequence and interactions of the N-terminal region. Binding of the N-terminal region of MAP2c (N-MAP2c) to the dimerization/docking domains of the regulatory subunit RIIα of cAMP-dependent protein kinase (RIIDD2) and to the Src-homology domain 2 (SH2) of growth factor receptor-bound protein 2 (Grb2) have been described long time ago. However, the structural features of the complexes remained unknown due to the disordered nature of MAP2. Here, we provide structural description of the complexes. We have solved solution structure of N-MAP2c in complex with RIIDD2, confirming formation of an amphiphilic α-helix of MAP2c upon binding, defining orientation of the α-helix in the complex and showing that its binding register differs from previous predictions. Using chemical shift mapping, we characterized the binding interface of SH2-Grb2 and rat MAP2c phosphorylated by the tyrosine kinase Fyn in their complex and proposed a model explaining differences between SH2-Grb2 complexes with rat MAP2c and phosphopeptides with a Grb2-specific sequence. The results provide the structural basis of a potential role of MAP2 in regulating cAMP-dependent phosphorylation cascade via interactions with RIIDD2 and Ras signaling pathway via interactions with SH2-Grb2.

• MeSH
• GRB2 Adaptor Protein * metabolism   chemistry   MeSH
• Humans MeSH
• Protein Domains MeSH
• Microtubule-Associated Proteins * metabolism   chemistry   genetics   MeSH
• Proto-Oncogene Proteins c-fyn metabolism   chemistry   genetics   MeSH
• Signal Transduction MeSH
• src Homology Domains MeSH
• Protein Binding * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH