Pathological Relevance of Post-translationally Modified Alpha-Synuclein (pSer87, pSer129, nTyr39) in Idiopathic Parkinson’s Disease and Multiple System Atrophy

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson's disease and Multiple System Atrophy.

Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson′s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α-synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Tax Expenditures in Local Taxes - an Effective Instrument of Local Tax Policy? The Example of Poland

This study examines the size and diversity of tax expenditures (TEs) by gminas (municipalities) in Poland between 2007 and 2019. Consequences of gminas' taxing power and the reduction of revenues resulting from statutory tax preferences were taken into account. To analyze the data, we used: scatter graphs (showing the relationship between two selected variables) and plot graphs (showing the course of the values of the studied variables over time, to show the dynamics of the phenomena). The scatter graphs showed, sometimes strong, linear correlative relationships. No clear curvilinear relationships were found, therefore we applied Pearson correlation. Gminas used TEs to a small but also highly variable extent. The factors determining their use involved: the type and potential of the gmina; the type of local tax. The research hypothesis was partially positively verified. The increase in the incremental % of TEs' share in tax revenue has a positive impact on the incremental trend of revenue growth in the following year. The use of TEs in real estate and vehicle taxes may have strengthened the revenue potential of some gminas in the consecutive years.

MORG1—A Negative Modulator of Renal Lipid Metabolism in Murine Diabetes

Renal fatty acid (FA) metabolism is severely altered in type 1 and 2 diabetes mellitus (T1DM and T2DM). Increasing evidence suggests that altered lipid metabolism is linked to tubulointerstitial fibrosis (TIF). Our previous work has demonstrated that mice with reduced MORG1 expression, a scaffold protein in HIF and ERK signaling, are protected against TIF in the db/db mouse model. Renal TGF-ß1 expression and EMT-like changes were reduced in mice with single-allele deficiency of MORG1. Given the well-known role of HIF and ERK signaling in metabolic regulation, here we examined whether protection was also associated with a restoration of lipid metabolism. Despite similar features of TIF in T1DM and T2DM, diabetes-associated changes in renal lipid metabolism differ between both diseases. We found that de novo synthesis of FA/cholesterol and β-oxidation were more strongly disrupted in T1DM, whereas pathological fat uptake into tubular cells mediates lipotoxicity in T2DM. Thus, diminished MORG1 expression exerts renoprotection in the diabetic nephropathy by modulating important factors of TIF and lipid dysregulation to a variable extent in T1DM and T2DM. Prospectively, targeting MORG1 appears to be a promising strategy to reduce lipid metabolic alterations in diabetic nephropathy.

Differences in Cell-Intrinsic Inflammatory Programs of Yolk Sac and Bone Marrow Macrophages

Background: Tissue-resident macrophages have mixed developmental origins. They derive in variable extent from yolk sac (YS) hematopoiesis during embryonic development. Bone marrow (BM) hematopoietic progenitors give rise to tissue macrophages in postnatal life, and their contribution increases upon organ injury. Since the phenotype and functions of macrophages are modulated by the tissue of residence, the impact of their origin and developmental paths has remained incompletely understood. Methods: In order to decipher cell-intrinsic macrophage programs, we immortalized hematopoietic progenitors from YS and BM using conditional HoxB8, and carried out an in-depth functional and molecular analysis of differentiated macrophages. Results: While YS and BM macrophages demonstrate close similarities in terms of cellular growth, differentiation, cell death susceptibility and phagocytic properties, they display differences in cell metabolism, expression of inflammatory markers and inflammasome activation. Reduced abundance of PYCARD (ASC) and CASPASE-1 proteins in YS macrophages abrogated interleukin-1β production in response to canonical and non-canonical inflammasome activation. Conclusions: Macrophage ontogeny is associated with distinct cellular programs and immune response. Our findings contribute to the understanding of the regulation and programming of macrophage functions.

A unified model for the biogenesis of mitochondrial outer membrane multi-span proteins

The mitochondrial outer membrane (MOM) harbors proteins that traverse the membrane via several helical segments, so-called multi-span proteins. Two contradicting mechanisms were suggested to describe their integration into the MOM. The first proposes that the mitochondrial import (MIM) complex facilitates this process and functions as an insertase, whereas the second suggests that such proteins can integrate into the lipid phase without the assistance of import factors in a process that is enhanced by phosphatidic acid. To resolve this discrepancy and obtain new insights on the biogenesis of these proteins, we addressed this issue using yeast mitochondria and the multi-span protein Om14. Testing different truncation variants, we show that only the full-length protein contains all the required information that assure targeting specificity. Employing a specific insertion assay and several single and double deletion strains, we show that neither the import receptor Tom70 nor any other protein with a cytosolically exposed domain have a crucial contribution to the biogenesis process. We further demonstrate that Mim1 and Porin are required for optimal membrane integration of Om14 but none of them is absolutely required. Unfolding of the newly synthesized protein, its optimal hydrophobicity, as well as higher fluidity of the membrane dramatically enhanced the import capacity of Om14. Collectively, our findings suggest that MOM multi-span proteins can follow different biogenesis pathways in which proteinaceous elements and membrane behavior contribute to a variable extent to the combined efficiency.

Animals for Tools: The Origin and Development of Bone Technologies in China

The origin and development of bone technologies in China are reviewed in the light of recent discoveries and compared to trends emerging from the European and African archaeological records. Three categories of osseous tools are targeted: 1) unmodified bone fragments bearing traces of use in technological activities; 2) bone fragments modified to a variable extent with techniques generally used in stone technologies; 3) osseous fragments entirely shaped with techniques fit for the manufacture of formal bone tools. Early evidence of bone technologies in China are sporadically found in contexts dated between 1.8 and 1.0 Ma. By the late MIS6–early MIS5, bone tools are well-integrated in the technological systems of Pleistocene populations and the rules guiding their use appear increasingly standardized. In addition, the first evidence for the use of osseous material in symbolic activities emerges in the archaeological record during this period. Finally, between 40 and 35 ka, new manufacturing techniques and products are introduced in Late Palaeolithic technological systems. It is first apparent in the manufacture of personal ornaments, and followed by the production and diversification of formal bone tools. By that time, population dynamics seem to become materialized in these items of material culture. Despite regional specificities, the cultural trajectories identified for the evolution of bone technologies in China seem entirely comparable to those observed in other regions of the world.

Antrochaonal Polyp in a 4 Years Old Child

Antrochoanal polyp (ACP) is a benign, solitary polypoidal lesion arises from the maxillary antral mucosa that traverses through the ostium to the choana extending in a variable extent to the naso/oropharynx. It is usually unilateral and appears mainly in adults and rarely in children. It should be on differential diagnosis of any patients with nasal obstruction and chronic nasal discharge. Nasal endoscopy, computed tomography (CT), cone beam computed tomography (CBCT) and magnetic resonance imaging (MRI) are the main diagnostic techniques. Complete endoscopic surgical removal from the antral portionis recommended to prevent recurrence. Here a 4-year-old child of antrochoanal polyp that underwent functional endoscopic sinus surgery (FESS) with complete clearance from the maxillary antrum is presented. Bangladesh J Otorhinolaryngol 2021; 27(2): 188-193

A rare case of Diastematomyelia with syrinx and tethered cord in a newborn

Diastematomyelia or Split cord syndrome is a rare form of spinal dysraphism characterized by longitudinal splitting of spinal cord, conus medullaris or filum terminale to a variable extent. Presence of SCM is suggested by certain superficial markers like skin pigmentation, hemangioma, lipoma, dermal sinus and hypertrichosis. Meningocele or myelomenigocele may also be present. Affected children usually present with progressive sensorimotor symptoms and bowel and bladder dysfunction. Development of sensorimotor symptoms and progressive loss of function emphasis the need for antenatal diagnosis of the spinal deformities which paves way for early intervention and management thus minimizing the morbidity.

Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

Inhibitors of WEE1 and ATR kinases are considered promising for cancer treatment, either as monotherapy or in combination with chemo- or radiotherapy. Here, we addressed whether simultaneous inhibition of WEE1 and ATR might be advantageous. Effects of the WEE1 inhibitor MK1775 and ATR inhibitor VE822 were investigated in U2OS osteosarcoma cells and in four lung cancer cell lines, H460, A549, H1975, and SW900, with different sensitivities to the WEE1 inhibitor. Despite the differences in cytotoxic effects, the WEE1 inhibitor reduced the inhibitory phosphorylation of CDK, leading to increased CDK activity accompanied by ATR activation in all cell lines. However, combining ATR inhibition with WEE1 inhibition could not fully compensate for cell resistance to the WEE1 inhibitor and reduced cell viability to a variable extent. The decreased cell viability upon the combined treatment correlated with a synergistic induction of DNA damage in S-phase in U2OS cells but not in the lung cancer cells. Moreover, less synergy was found between ATR and WEE1 inhibitors upon co-treatment with radiation, suggesting that single inhibitors may be preferable together with radiotherapy. Altogether, our results support that combining WEE1 and ATR inhibitors may be beneficial for cancer treatment in some cases, but also highlight that the effects vary between cancer cell lines.