Dermoscopy and Trichoscopy in Dermatomyositis—A Cross-Sectional Study

Background: (Video)dermoscopy is a non-invasive diagnostic technique that has a well-established role in dermatooncology. In recent years, this method has also been increasingly used in the assessment of inflammatory dermatoses. So far, little is known about the (video)dermoscopic features of dermatomyositis (DM). Methods: Consecutive patients with DM were included in the study and videodermoscopic assessments of the nailfolds, scalp, and active skin lesions were performed. Results: Fifteen patients with DM (10 women and 5 men) were included. Capillaroscopy showed elongated capillaries (90.9%), avascular areas (81.8%), disorganized vessel architecture (81.8%), tortuous capillaries (72.7%), dilated capillaries (72.7%), and hemorrhages (72.7%). The trichoscopic findings included linear branched vessels (80.0%), linear vessels (60.0%), linear curved vessels (53.3%), perifollicular pigmentation (40.0%), perifollicular erythema (33.3%), scaling (20.0%), white (20.0%) or yellow (20%) interfollicular scales, and white (20.0%) or pinkish (13.3%) structureless areas. Polymorphic vessels of an unspecific distribution and white or pink structureless areas were frequently observed under dermoscopy in cutaneous manifestations of DM, including Gottron’s papules and Gottron’s sign. Conclusions: Dermoscopy of the nailfolds (capillaroscopy), scalp (tricoscopy), and active cutaneous lesions may be of value in the preliminary diagnosis of DM.

A Role of Phosphatidylserine in the Function of Recycling Endosomes

Cells internalize proteins and lipids in the plasma membrane (PM) and solutes in the extracellular space by endocytosis. The removal of PM by endocytosis is constantly balanced by the replenishment of proteins and lipids to PM through recycling pathway. Recycling endosomes (REs) are specific subsets of endosomes. Besides the established role of REs in recycling pathway, recent studies have revealed unanticipated roles of REs in membrane traffic and cell signalling. In this review, we highlight these emerging issues, with a particular focus on phosphatidylserine (PS), a phospholipid that is highly enriched in the cytosolic leaflet of RE membranes. We also discuss the pathogenesis of Hermansky Pudlak syndrome type 2 (HPS2) that arises from mutations in the AP3B1 gene, from the point of view of dysregulated RE functions.

A peptide derived from GAPDH enhances resistance to DNA damage in budding yeast

Social behaviors do not only exist in higher organisms but are also present in microbes that interact for the common good. Here, we report that budding yeast cells interact with their neighboring cells after exposure to DNA damage. Yeast cells irradiated with DNA-damaging ultraviolet light secrete signal peptides that can increase the survival of yeast cells exposed to DNA-damaging stress. The secreted peptide is derived from glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and it induced cell death of a fraction of yeast cells in the group. The data suggest that the GAPDH-derived peptide serves in budding yeast’s social interaction in response to DNA-damaging stress. Importance Many studies have shown that microorganisms, including bacteria and yeast, display increased tolerance to stress after exposure to the same stressor. However, the mechanism remains unknown. In this manuscript, we report a striking finding that S. cerevisiae cells respond to DNA damage by secreting a peptide that facilitates resistance to DNA-damaging stress. Although it has been shown that GAPDH possesses many key functions in cells aside from its well-established role in glycolysis, this study demonstrated that GAPDH is also involved in the social behaviors response to DNA-damaging stress. The study opens the gate to an interesting research field about microbial social activity for adaptation to a harsh environment.

Reducing Addiction in Bipolar Disorder via Hacking the Dopaminergic System

The dopaminergic system plays a central and decisive role in substance use disorder (SUD), bipolar disorder (BD), and possibly in a subgroup of patients with refractory depression. Common genetic markers and underlying cellular processes, such as kindling, support the close link between these disorders, which is also expressed by the high rate of comorbidity. Although partial dopamine agonists/antagonists acting on D2 and D3 receptors have an established role in treating BD, their usefulness in SUD is less clear. However, dopamine D3 receptors were shown to play a central role in SUD and BD, making D2/D3 partial agonists/antagonists a potential target for both disorders. This narrative review examines whether these substances bear the promise of a future therapeutic approach especially in patients with comorbid BD and SUD.

Placenta Accreta Syndrome- A Calamitous Diagnosis

Increasing incidence of Placenta accrete syndrome has become a worrisome issue due to its associated life-threatening complications for both the mother and the fetus. The ideal management for PAS disorder remains the matter of debate still. The critical step in its effective management being its suspicion knowing the underlying risk factors and its diagnosis in antenatal period. Still, cesarean hysterectomy remains the gold standard procedure with many newer conservative approaches under evaluation. Our basic aim behind writing this review is to highlight the recent changes in classifying and diagnosing PAS owing to the ever-increasing incidence of this catastrophic entity. Also, it will emphasize the well-established role of radical over conservative management and also all modalities used in conservative management so far.

Deep learning-based artificial intelligence applications in prostate MRI: brief summary

Prostate cancer (PCa) is the most common cancer type in males in the Western World. MRI has an established role in diagnosis of PCa through guiding biopsies. Due to multistep complex nature of the MRI-guided PCa diagnosis pathway, diagnostic performance has a big variation. Developing artificial intelligence (AI) models using machine learning, particularly deep learning, has an expanding role in radiology. Specifically, for prostate MRI, several AI approaches have been defined in the literature for prostate segmentation, lesion detection and classification with the aim of improving diagnostic performance and interobserver agreement. In this review article, we summarize the use of radiology applications of AI in prostate MRI.

An amino residue that guides the correct photoassembly the water-oxidation complex but not required for high affinity Mn2+ binding

The assembly of the Mn4O5Ca cluster of the photosystem II (PSII) starts from the initial binding and photooxidation of the first Mn2+ at a high affinity site (HAS). Recent cryo-EM apo-PSII structures reveal an altered geometry of amino ligands in this region and suggest the involvement of D1-Glu189 ligand in the formation of the HAS. We now find that Gln and Lys substitution mutants photoactivate with reduced quantum efficiency compared to the wild-type. However, the affinity of Mn2+ at the HAS in D1-E189K was very similar to the wild-type (~2.2 μM). Thus, we conclude that D1-E189 does not form the HAS (~2.9 μM) and that the reduced quantum efficiency of photoactivation in D1-E189K cannot be ascribed to the initial photooxidation of Mn2+ at the HAS. Besides reduced quantum efficiency, the D1-E189K mutant exhibits a large fraction of centers that fail to recover activity during photoactivation starting early in the assembly phase, becoming recalcitrant to further assembly. Fluorescence relaxation kinetics indicate on the presence of an alternative route for the charge recombination in Mn-depleted samples in all studied mutants and exclude damage to the photochemical reaction center as the cause for the recalcitrant centers failing to assemble and show that dark incubation of cells reverses some of the inactivation. This reversibility would explain the ability of these mutants to accumulate a significant fraction of active PSII during extended periods of cell growth. The failed recovery in the fraction of inactive centers appears to a reversible mis-assembly involving the accumulation of photooxidized, but non-catalytic high valence Mn at the donor side of photosystem II, and that a reductive mechanism exists for restoration of assembly capacity at sites incurring mis-assembly. Given the established role of Ca2+ in preventing misassembled Mn, we conclude that D1-E189K mutant impairs the ligation of Ca2+ at its effector site in all PSII centers that consequently leads to the mis-assembly resulting in accumulation of non-catalytic Mn at the donor side of PSII. Our data indicate that D1-E189 is not functionally involved in Mn2+ oxidation\binding at the HAS but rather involved in Ca2+ ligation and steps following the initial Mn2+ photooxidation.

It’s Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals

For almost the entire period of the last two decades, translational research in the area of integrin-targeting radiopharmaceuticals was strongly focused on the subtype αvβ3, owing to its expression on endothelial cells and its well-established role as a biomarker for, and promoter of, angiogenesis. Despite a large number of translated tracers and clinical studies, a clinical value of αvβ3-integrin imaging could not be defined yet. The focus of research has, thus, been moving slowly but steadily towards other integrin subtypes which are involved in a large variety of tumorigenic pathways. Peptidic and non-peptidic radioligands for the integrins α5β1, αvβ6, αvβ8, α6β1, α6β4, α3β1, α4β1, and αMβ2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvβ6, αvβ8, and α6β1/β4, were subsequently translated into humans during the last few years. αvβ6-Integrin has arguably attracted most attention because it is expressed by some of the cancers with the worst prognosis (above all, pancreatic ductal adenocarcinoma), which substantiates a clinical need for the respective theranostic agents. The receptor furthermore represents a biomarker for malignancy and invasiveness of carcinomas, as well as for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and probably even for Sars-CoV-2 (COVID-19) related syndromes. Accordingly, the largest number of recent first-in-human applications has been reported for radiolabeled compounds targeting αvβ6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvβ3 by αvβ6 as the most popular integrin in theranostics.

Glutathione Transferases as Efficient Ketosteroid Isomerases

In addition to their well-established role in detoxication, glutathione transferases (GSTs) have other biological functions. We are focusing on the ketosteroid isomerase activity, which appears to contribute to steroid hormone biosynthesis in mammalian tissues. A highly efficient GST A3-3 is present in some, but not all, mammals. The alpha class enzyme GST A3-3 in humans and the horse shows the highest catalytic efficiency with kcat/Km values of approximately 107 M−1s−1, ranking close to the most active enzymes known. The expression of GST A3-3 in steroidogenic tissues suggests that the enzyme has evolved to support the activity of 3β-hydroxysteroid dehydrogenase, which catalyzes the formation of 5-androsten-3,17-dione and 5-pregnen-3,20-dione that are substrates for the double-bond isomerization catalyzed by GST A3-3. The dehydrogenase also catalyzes the isomerization, but its kcat of approximately 1 s−1 is 200-fold lower than the kcat values of human and equine GST A3-3. Inhibition of GST A3-3 in progesterone-producing human cells suppress the formation of the hormone. Glutathione serves as a coenzyme contributing a thiolate as a base in the isomerase mechanism, which also involves the active-site Tyr9 and Arg15. These conserved residues are necessary but not sufficient for the ketosteroid isomerase activity. A proper assortment of H-site residues is crucial to efficient catalysis by forming the cavity binding the hydrophobic substrate. It remains to elucidate why some mammals, such as rats and mice, lack GSTs with the prominent ketosteroid isomerase activity found in certain other species. Remarkably, the fruit fly Drosophila melanogaster, expresses a GSTE14 with notable steroid isomerase activity, even though Ser14 has evolved as the active-site residue corresponding to Tyr9 in the mammalian alpha class.

MAP4K3 inhibits Sirtuin-1 to repress LKB1-AMPK to promote amino acid dependent activation of mTORC1

mTORC1 is the key rheostat controlling cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here we examined the process of MAP4K3 activation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to prevent TSC1/2 complex inactivation of Rheb. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor Sirtuin-1 and phosphorylates Sirtuin-1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.