hnRNPM protects against the dsRNA-mediated interferon response by repressing LINE-associated cryptic splicing.

RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.

Loss of polarity regulators initiates gasdermin-E-mediated pyroptosis in syncytiotrophoblasts.

The syncytiotrophoblast is a human epithelial cell that is bathed in maternal blood on the maternal-facing surface of the human placenta. It therefore acts as a barrier and exchange interface between the mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblasts display a loss of microvilli, which is a marker of aberrant apical-basal polarization, but little data exist about the regulation of syncytiotrophoblast polarity. Atypical PKC isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin-E-dependent pyroptosis, a form of programmed necrosis. We also establish that TNF-α induces an isoform-specific decrease in aPKC expression and gasdermin-E-dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of the syncytiotrophoblast function and a pathogenically relevant pro-inflammatory cytokine leads to the induction of programmed necrosis at the maternal-fetal interface. Hence, our results have important implications for the pathobiology of placental disorders like preeclampsia.

Cell polarity signaling in the regulation of syncytiotrophoblast homeostasis and inflammatory response.

Maintenance of cell polarity and the structure of the apical surface of epithelial cells is a tightly regulated process necessary for tissue homeostasis. The syncytiotrophoblast of the human placenta is an entirely unique epithelial layer. It is a single giant multinucleate syncytial layer that comprises the maternal-facing surface of the human placenta. Like other epithelia, the syncytiotrophoblast is highly polarized with the apical surface dominated by microvillar membrane protrusions. Syncytiotrophoblast dysfunction is a key feature of pregnancy complications like preeclampsia. Preeclampsia is commonly associated with a heightened maternal immune response and pro-inflammatory environment. Importantly, reports have observed disruption of syncytiotrophoblast apical microvilli in placentas from preeclamptic pregnancies, indicating a loss of apical polarity, but little is known about how the syncytiotrophoblast regulates polarity. Here, we review the evolutionarily conserved mechanisms that regulate apical-basal polarization in epithelial cells, and the emerging evidence that PAR polarity complex components are critical regulators of syncytiotrophoblast homeostasis and apical membrane structure. Pro-inflammatory cytokines have been shown to disrupt the expression of polarity regulating proteins. We also discuss initial data showing that syncytiotrophoblast apical polarity can be disrupted by the addition of the pro-inflammatory cytokine tumor necrosis factor-α, revealing that physiologically relevant signals can modulate syncytiotrophoblast polarization. Since disrupted polarity is a feature of preeclampsia, further elucidation of the syncytiotrophoblast-specific polarity signaling network and testing whether the disruption of polarity-factor signaling networks may contribute to the development of preeclampsia is warranted.

Human placenta and trophoblasts simultaneously express three isoforms of atypical protein kinase-c.

Atypical protein kinase-c (aPKC) isoforms are important regulators of polarity and stem cell differentiation. There are three isoforms of aPKC: aPKC-ι, aPKC-ζ, and PKM-ζ. Recently, aPKC-ι was shown to regulate human trophoblast stem cell (TSC) differentiation. Compensation by remaining isoforms when a single aPKC isoform is lost can occur, but the expression pattern of aPKC-ζ in placenta is unknown. Here we show that aPKC-ι, aPKC-ζ and a new isoform, aPKC-ζ III, are expressed in trophoblasts. Therefore, studies examining the role of aPKC isoforms that control for potential compensation between aPKC isoforms are necessary to understand aPKC-mediated regulation of TSC differentiation.

Cucurbituril-Functionalized Nanocomposite as a Promising Industrial Adsorbent for Rapid Cationic Dye Removal.

A supramolecular cucurbit[6]uril (CB[6])-enriched magnetic montmorillonite (CBCM) nanocomposite was prepared and characterized. CB[6] played a prominent role as a capping agent, helping in better distribution of the nanoparticles, and as a binder between nanoparticles. Montmorillonite provided structural stability and fortified ultrafast adsorption toward dyes. Its application in the removal of cationic dyes from wastewater was systematically assessed. Process parameters such as pH, initial dye concentration, dosage, temperature, and time were optimized. Kinetics and isotherms of the process were described using pseudo-second-order kinetics and the Langmuir isotherm, respectively. CBCM exhibited rapid dye removal capacity in short reaction times with q max of 199.20, 78.31, and 55.62 mg g-1 and K2 of 0.0281, 0.0.0823, and 0.0953 L mg-1 min-1 for crystal violet, methylene blue, and rhodamine B, respectively. Benefiting from the synergetic effects of montmorillonite surface hydrophobicity, abundant carbonyl groups of CB[6], and magnetic properties of copper ferrite, CBCM demonstrated outstanding dye removal capacity, negligible leaching at saturation, and high tolerance toward harsh conditions. This intrinsic nature is expedient in prolonged industrial operations. To demonstrate industrial viability, syringe filtration and continuous flow fixed-bed column operations were validated. The CBCM fixed-bed column demonstrated stable dye removal efficiency with 10-100 mg mL-1 dye at 10-50 mL min-1 flow rates. Utilizing the magnetic and catalytic activities of the copper ferrite nanoparticles, CBCM was recycled using a magnet, regenerated, and reused for several cycles. CB[6] remarkably improved the performance of the nanocomposite and made it suitable for different effluent treatment techniques. This may pave a sustainable way toward the efficient onsite treatment of effluent at the industrial scale.

Effect of Implant Angulation and Depth on the Accuracy of Casts Using the Open Tray Splinted Impression Technique.

The purpose of this study was to evaluate the accuracy of open tray dental implant impressions when the implants are placed with varying implant angulations and depths. Four partially edentulous models were fabricated using photopolymer resin, each having different angulation and depth of the implant analogs. A total of 40 open tray elastomeric impressions were made, which were poured in type IV die stone (n = 10). These casts were evaluated and compared for accurate reproduction of the spatial orientation of the implant analogs in the models using digitization in 3 dimensions. The results were analyzed using the independent T test. Statistically significant differences were observed when the casts were compared with their respective master models. These casts had the implant replicas placed deeper within the replicated soft tissue. Making accurate impressions in partially edentulous situations with dental implants placed with varying depth and angulation is critical and clinically demanding. There is a need for future in vivo research to identify methods and materials, exploring digital impression techniques as well, in order to make precise impressions.

A PEX5 missense allele preferentially disrupts PTS1 cargo import into Arabidopsis peroxisomes.

The sorting of eukaryotic proteins to various organellar destinations requires receptors that recognize cargo protein targeting signals and facilitate transport into the organelle. One such receptor is the peroxin PEX5, which recruits cytosolic cargo carrying a peroxisome-targeting signal (PTS) type 1 (PTS1) for delivery into the peroxisomal lumen (matrix). In plants and mammals, PEX5 is also indirectly required for peroxisomal import of proteins carrying a PTS2 signal because PEX5 binds the PTS2 receptor, bringing the associated PTS2 cargo to the peroxisome along with PTS1 cargo. Despite PEX5 being the PTS1 cargo receptor, previously identified Arabidopsis pex5 mutants display either impairment of both PTS1 and PTS2 import or defects only in PTS2 import. Here we report the first Arabidopsis pex5 mutant with an exclusive PTS1 import defect. In addition to markedly diminished GFP-PTS1 import and decreased pex5-2 protein accumulation, this pex5-2 mutant shows typical peroxisome-related defects, including inefficient ß-oxidation and reduced growth. Growth at reduced or elevated temperatures ameliorated or exacerbated pex5-2 peroxisome-related defects, respectively, without markedly changing pex5-2 protein levels. In contrast to the diminished PTS1 import, PTS2 processing was only slightly impaired and PTS2-GFP import appeared normal in pex5-2. This finding suggests that even minor peroxisomal localization of the PTS1 protein DEG15, the PTS2-processing protease, is sufficient to maintain robust PTS2 processing.

Chloride anion transporters inhibit growth of methicillin-resistant Staphylococcus aureus (MRSA) in vitro.

A series of aminopyrrolic receptors were tested as anion transporters using POPC liposome model membranes. Many were found to be effective Cl(-) transporters and to inhibit clinical strains of Staphylococcus aureus growth in vitro. The best transporters proved effective against the methicillin-resistant Staphylococcus aureus (MRSA) strains, Mu50 and HP1173. Tris-thiourea tren-based chloride transporters were also shown to inhibit the growth of S. aureus in vitro.

Study of clinical and radiological profile and outcome in patients of intracranial hemorrhage.

BACKGROUND: Incidence of intracerebral hemorrhage (ICH) is twice as high as in Western countries. Prognostic factors for predicting function outcome and mortality play a major role in determining the treatment outcome. METHODS: A prospective study of male and female patients ≥12 years with primary nontraumatic intracranial hemorrhage were included. Hemorrhage caused by trauma, anticoagulant or thrombolytic drugs, brain tumor, saccular arterial aneurysm or vascular malformation were excluded. Functional outcome of patients was determined by modified Rankin's scale. Glasgow Coma Scale (GCS) score and ICH score were calculated for each patient. RESULTS: Hypertension was present in 45 out of 49 patients (92%) with ICH of basal ganglia. Hypertension was significantly associated with worst clinical outcome. Mortality was high if the patient was comatose/stuporous compared to drowsy state (P < 0.0001). Mortality was found to be high when the size exceeded 30 cm3. High ICH score, low GCS score at the time of admission, presence of intraventricular hemorrhage, and midline shift were significantly associated with poor clinical outcome. CONCLUSIONS: Intracranial hemorrhage can be deleterious if present with low GCS score, high ICH score, intraventricular extension, and midline shift.

Draft Genome Sequences of Four Genetically Distinct Human Isolates of Streptococcus dysgalactiae subsp. equisimilis.

ß-Hemolytic group C and group G streptococci (GCS-GGS; Streptococcus dysgalactiae subsp. equisimilis) emerged as human pathogens in the late 1970s. We report here the draft genome sequences of four genetically distinct human strains of GCS-GGS isolated between the 1960s and 1980s. Comparative analysis of these genomes may provide a deeper understanding of GCS-GGS genome and virulence evolution.