Non-veridicality in Habitual Context

This paper presents a semantic-pragmatic analysis of the habitual aspect as a licensing context for Negative Polarity Items (NPIs). Further, we analyse why complex predicates (V1 + V2) in the habitual aspect form a better licensing context for NPIs than simple predicates. Habitual aspect can license certain NPIs in languages, in spite of being a non-Downward Entailing environment. Giannakidou (2002) argued that Veridicality, instead of Downward-Entailment (DE), should be the primary condition to characterize licensing contexts for NPIs. This paper attempts to further Giannakidou's (2002, 2011)  argument by proposing a Stalnakerian approach (Stalnaker, 1978) to define habitual aspect as an Iterative Pluractional and prove how it is non-veridical. Further we explore how the semantic compositionality of complex predicates makes the habitual context a better licensor for NPIs

An investigation into the mechanism of toxicity of zinc oxide nanoparticles.

The wide scale use of ZnO nanoparticles (NPs) in the world consumer market has resulted in likelihood of exposure to human beings. The present study was aimed to assess the in vitro and in vivo interactions of ZnO NPs in the mammalian system and to elucidate the possible mechanism of their toxicity. Our in vitro results using human epidermal cells (A431), primary human epidermal keratinocytes and human liver cells (HepG2) demonstrated that cells exposed to ZnO NPs exhibit a decrease in cell viability which was independent of NP dissolution. ZnO NPs also induced oxidative DNA damage as evidenced by an increase in the Fpg sensitive sites. The reactive oxygen species triggered a decrease in mitochondrial membrane potential and an increase in the ratio of Bax/Bcl2 leading to apoptosis through the intrinsic pathway. In addition, ZnO NPs induced phosphorylation of JNK, P38 and P53ser15. The results from our in vivo studies using a mouse model showed that ZnO NPs induce lipid peroxidation, oxidative DNA damage and apoptosis in liver which further confirmed our in vitro findings. The data from the present study provide valuable insights into the cellular interactions of ZnO NPs and the underlying molecular mechanism of their toxicity. The results also stress the need for a comprehensive environmental health and safety assessment of engineered nanomaterials to ensure safer nanotechnology based products

Cortical venous thrombosis in high altitude; result of an observational study

Background: High altitude, an extremely rare cause of cortical venous thrombosis (CVT) has no literature review available signifying the relation between two as per date. The aim of this study is to establish the relation of exposure to high altitude and occurrence of CVT in properly acclimatised healthy individuals exposed to high altitude having no pre-existing morbidities.Methods: An observational type of prospective study was conducted at a tertiary care centre in North India. Patients who were sent back from a high-altitude area with CNS symptoms (headache to coma) were included in the study. Magnetic resonance imaging (MRI) and magnetic resonance venography (MRV), blood investigations including complete blood count and D-dimer were done as routine examinations in all these patients. MRI and MRV findings were recorded and analyzed for features of CVT.Results: Twenty-eight patients with an average age of 31.5 years (23-51 years) were included in the study. All patients had CNS symptoms; with headache being the common symptom. In the patients of CVT, there were MRI features of parenchymal infarct in 7 (25%), hemorrhagic infarct in 11 (41.6%), subarachnoid hemorrhage in 7 (25%) and mass effect in 3 (8.4%) patients. MRV revealed involvement of multiple sinus involvement more common than single sinus involvement, of which most commonly involved sinuses were Superior sagittal sinus and transverse sinuses. D-Dimer levels were significantly raised in 23 (83%) patients.Conclusions: High altitude though a rare cause, can be the single most important contributory factor in the development of CVT in healthy acclimatised individuals with no predisposing factors. The physicians dealing with such patients at high altitude should be well aware of the scenario as early diagnosis via imaging and prompt management can drastically reduce mortality in this potentially lethal but treatable conditions

Fracture neck of femur treated with hemiarthroplasty and cannulated cancellous screw fixation: a comparative study

Background: Intracapsular fracture neck of femur has always presented great challenges to every Orthopaedic surgeons and it is remain a mystery whether to fix or to replace the fracture in the elderly. The aim of the study was to analyze the functional outcome of two widely used and accepted modalities of treatment in the age group 57-75 years, in Garden’s type I and II fractures, namely (a) cannulated cancellous screw fixation(internal fixation) and (b) modular bipolar prosthetic replacement of the femoral head (hemiarthroplasty).Methods: The total 110 patients were including in the study from age groups 57-75 (mean age 66). The Garden classification of fracture neck of femur was used to evaluate the displacement of femoral neck fractures. Only grade 1 and 2 was included in the study. 55 patients were included in each group A and B. Osteosynthesis (fracture fixation) was carried out by closed reduction and insertion of cannulated cancellous screw and in other group hemiarthroplasty was done.Results: In group A 55 patient with fracture neck of femur was treated by osteosynthesis i.e. fixation using 02 or 03 cannulated cancellous screw and in group B, 55 patients with fracture neck of femur was treated by modular bipolar replacement hemiarthroplasty. In Group A out of 55, 41 patients union was achieved between 08 to 14 months (mean 11.5 month), 09 patients developed non-union even after 16 months and 05 patients develop collapse of head with AVN with shortening at end of 02 year, however in Group B out of 55 patients 51 patients started walking after 2nd postoperative days, 02 patients developed infection, and 02 patients developed posterior dislocation.Conclusions: The fracture fixation may be tempting for fracture neck femur in age group 57-75 especially of Garden Type I but internal fixation put risk of non-union and AVN and second surgery may be required after few months or years  if patients survive. Based on results in our study we therefore can conclude that in Garden Type I and II femur neck fractures in the patients between 57-75 years of age, hemiarthroplasty is the better modality of treatment

Rehabilitation Exercise Repetition Segmentation and Counting using Skeletal Body Joints

Physical exercise is an essential component of rehabilitation programs that improve quality of life and reduce mortality and re-hospitalization rates. In AI-driven virtual rehabilitation programs, patients complete their exercises independently at home, while AI algorithms analyze the exercise data to provide feedback to patients and report their progress to clinicians. To analyze exercise data, the first step is to segment it into consecutive repetitions. There has been a significant amount of research performed on segmenting and counting the repetitive activities of healthy individuals using raw video data, which raises concerns regarding privacy and is computationally intensive. Previous research on patients' rehabilitation exercise segmentation relied on data collected by multiple wearable sensors, which are difficult to use at home by rehabilitation patients. Compared to healthy individuals, segmenting and counting exercise repetitions in patients is more challenging because of the irregular repetition duration and the variation between repetitions. This paper presents a novel approach for segmenting and counting the repetitions of rehabilitation exercises performed by patients, based on their skeletal body joints. Skeletal body joints can be acquired through depth cameras or computer vision techniques applied to RGB videos of patients. Various sequential neural networks are designed to analyze the sequences of skeletal body joints and perform repetition segmentation and counting. Extensive experiments on three publicly available rehabilitation exercise datasets, KIMORE, UI-PRMD, and IntelliRehabDS, demonstrate the superiority of the proposed method compared to previous methods. The proposed method enables accurate exercise analysis while preserving privacy, facilitating the effective delivery of virtual rehabilitation programs.Comment: 8 pages, 1 figure, 2 table

Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations

DNA damage and mutations induced by oxidative stress are associated with various different human pathologies including cancer. The facts that most human tumors are characterized by large genome rearrangements and glutathione depletion in mice results in deletions in DNA suggest that reactive oxygen species (ROS) may cause gene and chromosome mutations through DNA double strand breaks (DSBs). However, the generation of DSBs at low levels of ROS is still controversial. In the present study, we show that H2O2 at biologically-relevant levels causes a marked increase in oxidative clustered DNA lesions (OCDLs) with a significant elevation of replication-independent DSBs. Although it is frequently reported that OCDLs are fingerprint of high-energy IR, our results indicate for the first time that H2O2, even at low levels, can also cause OCDLs leading to DSBs specifically in G1 cells. Furthermore, a reverse genetic approach revealed a significant contribution of the non-homologous end joining (NHEJ) pathway in H2O2-induced DNA repair & mutagenesis. This genomic instability induced by low levels of ROS may be involved in spontaneous mutagenesis and the etiology of a wide variety of human diseases like chronic inflammation-related disorders, carcinogenesis, neuro-degeneration and aging

Molecular Dosimetry of Endogenous and Exogenous O 6 -Methyl-dG and N7-Methyl-G Adducts Following Low Dose [ D 3 ]-Methylnitrosourea Exposures in Cultured Human Cells

For DNA-reactive chemicals, a low dose linear assessment of cancer risk is the science policy default. In the present study, we quantitated the endogenous and exogenous N7-methyl-G and O6-methyl-dG adducts in human lymphoblastoid cells exposed to low dose [D3]-methylnitrosourea. Endogenous amounts of both adducts remained nearly constant, while the exogenous adducts showed linear dose-responses. The data show that O6-methyl-dG adducts ≥1.8/108 dG correlated with published studies that demonstrated significant increases of mutations under these conditions. The combined results do not support linear extrapolations to zero when data are available for science-based regulations

<html>Poor recognition of O6-isopropyl dG by MGMT triggers double strand break-mediated cell death and micronucleus induction in <i>FANC</i>-deficient cells</html>

Isopropyl methanesulfonate (IPMS) is the most potent genotoxic compound among methanesulfonic acid esters. The genotoxic potential of alkyl sulfonate esters is believed to be due to their alkylating ability of the O6 position of guanine. Understanding the primary repair pathway activated in response to IPMS-induced DNA damage is important to profile the genotoxic potential of IPMS. In the present study, both chicken DT40 and human TK6 cell-based DNA damage response (DDR) assays revealed that dysfunction of the FANC pathway resulted in higher sensitivity to IPMS compared to EMS or MMS. O6-alkyl dG is primarily repaired by methyl guanine methyltransferase (MGMT), while isopropyl dG is less likely to be a substrate for MGMT. Comparison of the cytotoxic potential of IPMS and its isomer n-propyl methanesulfonate (nPMS) revealed that the isopropyl moiety avoids recognition by MGMT and leads to higher cytotoxicity. Next, the micronucleus (MN) assay showed that FANC deficiency increases the sensitivity of DT40 cells to MN induction by IPMS. Pretreatment with O6-benzyl guanine (OBG), an inhibitor of MGMT, increased the MN frequency in DT40 cells treated with nPMS, but not IPMS. Lastly, IPMS induced more double strand breaks in FANC-deficient cells compared to wild-type cells in a time-dependent manner. All together, these results suggest that IPMS-derived O6-isopropyl dG escapes recognition by MGMT, and the unrepaired DNA damage leads to double strand breaks, resulting in MN induction. FANC, therefore, plays a pivotal role in preventing MN induction and cell death caused by IPMS

The endogenous exposome

The concept of the Exposome, is a compilation of diseases and one’s lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the Endogenous Exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions