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Abstract Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3′−5′ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

Electroencephalography (EEG) is a non-intrusive and powerful tool for understanding the complex nature of the brain. Epileptic seizures, a neurological disorder, are characterized by excessively synchronized neuronal activity within the brain. This abnormal synchronization disrupts the normal functioning of neural networks, leading to seizures. This work proposes to use the Gaussian-based Stockwell Transform (GST) to segment EEG signals into various frequency bands such as delta, theta, alpha, beta, and gamma band for analysis. The feature extraction process on these sub-band signals generates a feature set, encompassing the fluctuation index, relative amplitude, holoentropy, logarithmic band power, and the newly introduced Hermite polynomial-based delta amplitude modulation spectrogram. To differentiate between epileptic and non-epileptic events in EEG signals, the previous features have been applied to the Random Forest Classifier (RFC) algorithm. The effectiveness of our proposed method is validated using a benchmark EEG dataset, with GST and RFC demonstrating accurate results in distinguishing seizure activity. Experimental results show an optimal classification accuracy of 96.4 %, a sensitivity of 97 %, and a specificity of 96.4 %.

This study investigates the feasibility of using grape biodiesel from the wine industry as a sustainable and cost-effective alternative to traditional fuels. The research focuses on optimizing key parameters like blend ratio, injection timing, injection pressure, engine load, and exhaust gas recirculation in a Common Rail Direct Injection engine to achieve low emissions without compromising performance. Due to grape biodiesel's higher viscosity, different energy content, and varying ignition delays compared to diesel, precise adjustments are essential for complete combustion and reduced emissions. This study uses response surface methodology and a Central Composite Design matrix to find the best values for a number of parameters in modern CRDI engines that use advanced electronic control units. Through fifty input combinations, the study aims to minimize specific fuel consumption, hydrocarbons, nitrogen oxides, and carbon monoxide while maximising brake thermal efficiency, brake mean effective pressure, and mechanical efficiency. The optimal configuration includes a fuel injection timing of 6° bTDC, an engine load of 82 %, 6.7 % EGR, 1000 bar injection pressure, and a 33 % grape biodiesel blend. These optimum input conditions yielded outputs of 3.55 bar BMEP, 31.85 % BTE, 64 % mechanical efficiency, 0.278 kg/kWh SFC, 0.127 % CO, 357 ppm NOx, and 8 ppm of HC. These adjustments ensure low emissions and efficient engine operation, highlighting grape biodiesel's potential as a viable alternative fuel.

Abstract Background Congenital dyserythropoietic anemias (CDAs) are a very rare and heterogeneous group of disorders characterized by ineffective erythropoiesis. CDA II is caused by mutations in the SEC23B gene. The most common mutation reported in India is c.1385 A > G, p.Y462C. There is no simple and cost-effective confirmatory diagnostic test available for CDA, and therefore, many patients remain undiagnosed. High-resolution melting curve (HRM) analysis is a polymerase chain reaction (PCR) based technique applied to identify genetic differences and scan nucleic acid sequences. HRM can be used to rapidly screen the common mutation causing CDA II in the Indian population. Thus, we studied the use of High-Resolution Melting Curve Analysis to detect common mutation causing CDA II in the Indian population. Method 11 patients having SEC23B (Y462C) mutation causing CDA II are considered for this study. HRM was used to check the presence of Y462C mutation. To verify the accuracy of the HRM analysis, we compared HRM results with the results of Sanger sequencing. This helped us to confirm the diagnosis. Results We have described the clinical, hematological, and genetic data of eleven patients suffering from CDAII. According to HRM and Sanger sequencing, a homozygous SEC23B (Y462C) mutation was present in all patients, whereas a heterozygous Y462C mutation was present in their parents. Conclusion Our data showed that High-Resolution Melting (HRM) analysis could be used to rapidly screen common SEC23B mutation that causes CDA II in the Indian population.

Summary: Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFBhi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

Summary: CD137 is a costimulatory receptor expressed on natural killer cells, T cells, and subsets of dendritic cells. An agonistic monoclonal antibody (mAb) against CD137 has been used to reduce tumor burden or reverse autoimmunity in animal models and clinical trials. Here, we show that mice treated with an agonistic anti-CD137 mAb have reduced numbers of germinal center (GC) B cells and follicular dendritic cells (FDCs) in lymphoid tissues, which impair antibody responses to multiple T-cell-dependent antigens, including infectious virus, viral proteins, and conjugated haptens. These effects are not due to enhanced apoptosis or impaired proliferation of B cells but instead correlate with changes in lymphoid follicle structure and GC B cell dispersal and are mediated by CD137 signaling in CD4+ and CD8+ T cells. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may impair long-term antibody and B cell memory responses.

Summary: STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer’s patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.

Beneficiation of coal fines with high ash content was attempted in an operating coal preparation plant by retrofitting a 0.5 m diameter pilot plant scale flotation column in the circuit. The collector and frother dosage were optimized as 0.680 kg/t and 0.058 kg/t respectively. At these reagent conditions the operating parameters of pilot scale flotation column were also optimized. The maximum yield of the froth obtained was 67.5% at the targeted ash level of 14% from a feed of 25% ash content. This was obtained at the operating parameters of 0.85 cm/s superficial air flow velocity, 0.57 cm/s superficial feed slurry velocity and 600 mm froth height. The performance of flotation column was found to be marginally better than that of the conventional flotation cells in the washery. Also, advantages such as low operational, maintenance and energy costs and operational flexibility in the case of flotation column could lead to financial accruals over a long run.

A low grade graphite run-of-mine (r.o.m) ore from eastern India was studied for its amenability to beneficiation by flotation technique. The petrography studies indicate that the ore primarily consists of quartz and graphite with minor quantity of mica. It analyzed 89.89% ash and 8.59% fixed carbon. The ore was crushed in stages followed by primary coarse wet grinding to 212 μm (d80). Rougher flotation was carried out in Denver flotation cell to eliminate gangue as much as possible in the form of primary tailings with minimal loss of carbon. Diesel & pine oil were used as collector and frother respectively. Regrinding of rougher concentrate to150 μm (d80) was resorted to further liberate the graphite values and was followed by multi-stage cleaning. This two-stage grinding approach involving a primary coarse grinding and regrinding of rougher float followed by its multi-stage cleaning was found to yield required grade of concentrate for applications such as refractories, batteries and high temperature lubricants. This approach is supposed to retain the flake size of coarse, free and liberated graphite, if available, during primary coarse grinding and rougher flotation stage with minimal grinding energy costs as against the usual practice of single stage grinding in the case of many ores. A final concentrate of 8.97% weight recovery with 5.80% ash and 92.13% fixed carbon could be achieved.

Severe cardiovascular responses in the form of tachycardia and hypertension following nasal speculum insertion occur during sublabial rhinoseptal trans-sphenoid approach for resection of small pituitary tumours. We compare the effects of preoperative administration of clonidine (α-2 agonist) and atenolol (α-blocker) over haemodynamic response, caused by speculum insertion during trans-sphenoid pituitary resection. We enrolled 66 patients in age range 18-65 years, of ASA I-II, and of either sex undergoing elective sublabial rhinoseptal trans-sphenoidal hypophysectomy. Group I (control) received placebo, group II (clonidine) received tablet clonidine 5 μg/kg, and group III (atenolol) received tablet atenolol 0.5 mg/kg. The heart rate increased on speculum insertion and 5 and 10 minutes following speculum insertion as compared to the pre-speculum values in the control group, while no change in the heart rate was observed in other groups (P

Thelaziasis is an Arthropod-born disease of the eye and adnexa caused by Thelazia callipaeda, a nematode parasite transmitted by drosophilid flies to carnivores and humans. Because of its distribution mainly confined to South Asian countries and Russia, it is commonly known as Oriental Eye worm. It is often under-reported and not been given its due clinical importance. We report first case of human Thelaziasis from Hassan District, Karnataka. Five creamy-white, translucent worms were removed from the conjunctival sac of a 74-year-old male patient. Based on morphological characters, the worms were identified as nematodes belonging to the genus Thelazia and speciation was confirmed by CDC, Atlanta as callipaeda. Rarity of the disease and its ability to cause both extra and intraocular manifestations leading to ocular morbidity is the reason for presenting this case. From the available data, this is the first case report from Karnataka, India.

The link between serum cholesterol levels and the incidence of stroke still remain to be established. There are conflicting reports from a series of observational cohort studies. However, clinical trials with HMG CoA reductase inhibitors (also called statins) have shown that cholesterol lowering therapy used in the primary and secondary prevention of myocardial infarction significantly reduced cardiovascular events including strokes. Meta analysis of trials with statins have shown a relative risk reduction in stroke of 12 to 48% in patients with coronary heart disease after MI. It has been postulated that the clinical action of statins is the result of pleiotropic / antiatherogenic effects rather than simply a reduction in cholesterol. The putative beneficial effect of statins in stroke involve blocking of macrophage and platelet activation, improvement of endothelial cell vasomotor function, enhancement of endothelial fibrinolytic function, immunosuppressive and anti-inflammatory action, inhibition of smooth muscle cell proliferation and particularly enhancement of endothelial nitric oxide synthase (eNOS).

Some headaches are relatively uncommon. They may be either primary of secondary and their recognition is dependent on the characterization of symptoms as well as identification of certain specific situations in which they need to be considered in the differential diagnosis. Primary headache syndromes like the paroxysmal hemicranias, SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing), cough headaches and hypnic headaches are uncommonly encountered in routine clinical practice. They have subtle unique features and specific therapies which differentiate them from the commoner primary headaches. Among the secondary causes, headaches may be an uncommon presenting feature of known clinical disorders, lack of awareness of which may result in significant morbidity. These disorders which may present with headache as the main symptom will be the focus of discussion in this review.

Idiopathic CD4 T-lymphocytopenia (ICL) is a syndrome characterized by depletion of CD4 T-cells without evidence of human immunodeficiency virus (HIV) infection. There are a few reported cases of ICL associated with different diseases and clinical conditions, most commonly the opportunistic infections like Tuberculosis, fungal and parasitic diseases which are also seen in HIV-positive patients. We report a case without risk factors or laboratory evidence of HIV infection who presented with refractory cryptococcal meningitis and was found to have ICL.

Abstract Background Epidemiology of acute stroke in developing countries differs from that in the developed world, for example, the age at stroke, risk factors, subtypes of stroke and prognosis. Hypertension remains a dominant risk factor and prognostic indicator in patients with stroke in all communities. The risk of stroke is directly related to elevations of blood pressure. A number of clinical studies have shown that the control of hypertension leads to a reduction in the incidence of stroke in a community. However there is still considerable controversy surrounds the changes in blood pressure in various subtypes of strokes and problem of management of elevated BP after stroke. We studied the circadian rhythm of blood pressure in patients following acute stroke. Methods To study the circadian rhythm of blood pressure, fifty consecutive patients with an acute stroke who were admitted to medical emergency within 120 hours of onset were included in the study. After a detailed history and clinical examination, a continuous blood pressure monitor (Spacelab 90207) was attached on the side ipsilateral to intracranial lesion (unaffected arm). The blood pressure was recorded for 24 hours at 15 minutes interval during daytime (6.00 am–6.00 pm) and 20 minutes interval overnight (6 pm to 6 am). Results Risk factors for stroke in 50 patients included hypertension in 31(62%), diabetes mellitus in 4 (8%), smoking in 13 (26%) and previous history of transient ischemic attack in 7 (14%) patients. Mean systolic pressure and diastolic pressure at admission were higher in patients with hemorrhagic stroke -29 patients (177 ± 24 mmHg and 105 ± 19 mmHg respectively) compared to patients with ischemic strokes-21 patients (150 ± 36 mm Hg and 89 ± 18 mm Hg respectively, p value Conclusions Therefore, we showed a pathologically reduced or abolished circadian BP variation after stroke. Absence of normal dipping results in a higher 24 hour blood pressure load and may have more target organ damage than those with normal diurnal variation of blood pressure.

Purpose: A dual‐source CT system can be operated in a high‐pitch helical mode to provide a temporal resolution of 66 ms, which reduces motion artifacts in CT pulmonary angiography (CTPA). It can also be operated in a multi‐energy (ME) mode to provide iodine maps, beneficial in the evaluation of pulmonary embolism (PE). No energy‐integrating detector (EID) CT can perform simultaneous ME and high‐pitch acquisition. This phantom study aimed to evaluate the ability of a photon‐counting‐detector (PCD) CT to perform simultaneous high‐pitch and ME imaging for CTPA. Methods: A motion phantom was used to mimic the respiratory motion. Two tubes filled with iodine with intravascular thrombus mimicked by injecting glue within the tubes were placed along with 5, 10, and 15 mg/mL iodine samples, on a motion phantom at 20 and 30 revolutions per minute. Separate high‐pitch and ME EID‐CT scans and a single high‐pitch ME PCD scan were acquired and virtual monoenergetic images and iodine maps reconstructed. Percent thrombus occlusion was measured and compared between static and moving images. Results: When there was motion, EID‐CT ME suffered from significant motion artifacts. The measured iodine concentrations with PCD‐CT in high‐pitch ME were more stable when there was a motion, with a lower standard deviation than EID‐CT in ME mode. The estimated percent thrombus occlusion dropped significantly with applied motion on EID‐CT, while PCD‐CT high‐pitch ME mode showed good agreement between measurements on static or moving images. Conclusion: PCD‐CT with combined ME and high‐pitch mode facilitates simultaneous accurate iodine quantification and assessment of intravascular occlusion. [ABSTRACT FROM AUTHOR]