Progress of auxetic and semi-auxetic materials

Auxetic materials with negative Poisson\u27s ratios, display the unique behavior owing to their micro-structure or geometrical build. Auxetic materials resist deformities when subjected to uniaxial, biaxial, and shearing stresses. Cellular based materials are known for their excellent impact and shock energy absorption. When foams are incorporated with auxetic geometry, their impact energy absorption increases. Combination of auxetic materials with conventional materials yield semi-auxetic materials. Ideally, layered structures where facing materials are metallic sheets sandwiching polymeric foam cores are popular. The auxetic materials can be combined with conventional materials to obtain P-N-P and N-P-N semi-auxetic sandwiched structures with diverse potential in several applications like automotive, aerospace, sports equipment, and protective armors

Bulk Viscosity of Magnetized Neutron Star Matter

We study the effect of magnetic field on the bulk viscosity of nuclear matter in neutron stars. We employ the framework of relativistic mean field theory to observe the dense nuclear matter in neutron stars. The effects are first studied for the case when the magnetic field does not exceed the critical value to confine the electrons to the lowest Landau levels. We then consider the case of intense magnetic field to evaluate viscosity for the URCA processes and show that the inequality $p_{F}(e)+p_{F}(p)\geq p_{F}(n)$ is no longer required to be satisfied for the URCA processes to proceed.Comment: Latex 2e file with four postscripts figure

Utility of Pentraxin-3 as a biomarker for diagnosis of acute appendicitis : a systematic review and meta-analysis

Purpose To systematically summarize all relevant data and to define the current evidence on the utility of Pentraxin-3 (PTX3) as a biomarker for acute appendicitis (AA) in children. Methods This review was conducted in accordance with the PRISMA guidelines. PubMed, Embase, Scopus, and Web of Science databases were systematically searched for studies comparing the levels of PTX3 in patients with AA vs healthy controls or non-specific abdominal pain (NSAP). Mean differences were calculated for all outcomes and the inverse variance method was used for weighted mean difference. The methodological quality of the included studies was assessed using the Downs and Black scale. Results Five comparative studies were included. Significantly elevated levels of PTX3 in cases with AA vs healthy controls (WMD: 9.56, 95% CI 7.24-11.88, p < 0.00001), and patients with AA vs NSAP (WMD: 8.05, 95% CI 6.81-9.29, p < 0.00001) were demonstrated. Similarly, in separate meta-analyses, the levels of PTX3 were significantly elevated in children with AA vs healthy controls (WMD: 11.18, 95% CI 10.03-12.34, p < 0.00001), and children with AA vs NSAP (WMD: 8.35, 95% CI 6.88-9.82, p < 0.00001). Conclusions PTX3-levels are elevated in AA, but differentiation between perforated and non-perforated appendicitis demands other methods.Peer reviewe

Role and regulation of coordinately expressed de novo purine biosynthetic enzymes PPAT and PAICS in lung cancer.

Cancer cells exhibit altered metabolism including aerobic glycolysis that channels several glycolytic intermediates into de novo purine biosynthetic pathway. We discovered increased expression of phosphoribosyl amidotransferase (PPAT) and phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) enzymes of de novo purine biosynthetic pathway in lung adenocarcinomas. Transcript analyses from next-generation RNA sequencing and gene expression profiling studies suggested that PPAT and PAICS can serve as prognostic biomarkers for aggressive lung adenocarcinoma. Immunohistochemical analysis of PAICS performed on tissue microarrays showed increased expression with disease progression and was significantly associated with poor prognosis. Through gene knockdown and over-expression studies we demonstrate that altering PPAT and PAICS expression modulates pyruvate kinase activity, cell proliferation and invasion. Furthermore we identified genomic amplification and aneuploidy of the divergently transcribed PPAT-PAICS genomic region in a subset of lung cancers. We also present evidence for regulation of both PPAT and PAICS and pyruvate kinase activity by L-glutamine, a co-substrate for PPAT. A glutamine antagonist, 6-Diazo-5-oxo-L-norleucine (DON) blocked glutamine mediated induction of PPAT and PAICS as well as reduced pyruvate kinase activity. In summary, this study reveals the regulatory mechanisms by which purine biosynthetic pathway enzymes PPAT and PAICS, and pyruvate kinase activity is increased and exposes an existing metabolic vulnerability in lung cancer cells that can be explored for pharmacological intervention

Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines

Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets

Učinak dodatka kondenziranih tanina putem obroka od mješavine lišća Ficus infectoria i Psidium guajava na antioksidacijski status eritrocita, imunosni odgovor i želučano-crijevne obliće u janjadi (Ovis aries)

This experimental study was carried out to assess the effect of condensed tannins (CT) through a leaf meal mixture of Ficus infectoria and Psidium guajava, on erythrocytic antioxidant status, immune response and gastrointestinal nematodes in lambs. Twenty-four non-descript lambs were randomly divided into four groups, consisting of six lambs in each, in a completely randomized block design, and randomly allocated to 4 dietary treatments: CT-0, CT-1, CT-1.5 and CT-2 containing 0, 1, 1.5 and 2.0 percent CT, respectively. The erythrocytic antioxidant status was monitored in all lambs at 0, 45, 90, 135, 180 days of feeding, however, humoral and cell mediated immune responses were determined at the end of the feeding trial. Hemoglobin was found to be highest (P<0.05) in CT-1.5 followed by CT-1, CT-2 and CT-0, respectively. CT supplementation significantly (P<0.05) improved the antioxidant status, as indicated by increased levels of glutathione peroxidase, catalase, reduced glutathione, glutathione-S-transferase, superoxide dismutase, total thiol and protein bound thiol group and decreased lipid peroxidase in the lambs. Supplementation of CT significantly (P<0.05) improved the cell mediated immune response in lambs. The fecal egg counts (FEC) in lambs were significantly (P<0.01) higher in the control group (CT-0), followed by CT-1, CT-1.5 and CT-2. The pooled fecal cultures of the lambs revealed that the majority of the infective larvae were from Haemonchus contortus. The FEC in the control was significantly higher (P<0.05) throughout the study period compared to the CT-1.5 and CT-2 groups. It may be concluded that dietary supplementation of CT (1-2%) through LMM improved the erythrocytic antioxidant status and immune response, and reduced FEC in lambs.Istraživanje je provedeno u svrhu procjene učinka kondenziranih tanina (KT), dodanih putem obroka od mješavine lišća Ficus infectoria i Psidium guajava, na antioksidacijski status eritrocita, imunosni odgovor i želučano-crijevne obliće u janjadi. Dvadeset i četiri janjeta slučajnim su odabirom bila razvrstana u četiri skupine po šest janjadi u svakoj skupini. Randomiziranim kompletnim blok-dizajnom i nasumičnim pridjeljivanjem formirane su četiri skupine s različitim udjelom KT u obroku: skupina KT-0 (0% KT), skupina KT-1 (1%), skupina KT-1,5 (1,5%) i skupina KT-2 (2%). Kod sve janjadi praćen je antioksidacijski status eritrocita 0., 45., 90., 135. i 180. dan hranidbe, a na kraju istraživanja određen je humoralni i stanični imunosni odgovor. Najviša razina (P<0,05) haemoglobina utvrđena je u skupini KT-1,5 nakon koje su slijedile skupine KT-1, KT-2 i KT-0. Dodani je KT signifikantno (P<0,05) poboljšao antioksidacijski status janjadi što su pokazale povišene razine glutation-peroksidaze, katalaze, zatim redukcija razine glutationa, glutation-S-transferaze, superoksid-dismutaze, ukupnog tiola i protein vezane tiol skupine kao i sniženje razine lipidne peroksidaze. Dodavanje KT signifikantno je (P<0,05) poboljšalo stanični imunosni odgovor janjadi. Broj jaja u fecesu bio je signifikantno (P<0,01) viši u kontrolnoj skupini (KT-0) janjadi nakon koje su slijedile skupine KT-1, KT-1,5 i KT-2. Skupne kulture iz fecesa janjadi pokazale su da većina invazivnih larvi pripada vrsti Haemonchus contortus. Broj jaja u fecesu kontrolne skupine janjadi bio je tijekom cijeloga istraživanog razdoblja signifikantno povišen (P<0,05) u odnosu na skupine KT-1,5 i KT-2. Može se zaključiti da je dodavanjem mješavine lišća s 1 – 2% KT u obroku kod janjadi poboljšan antioksidacijski status eritrocita i imunosni odgovor te smanjen broj prazitskih jajašaca u fecesu

Utility of Pentraxin-3 as a biomarker for diagnosis of acute appendicitis: a systematic review and meta-analysis

Purpose: To systematically summarize all relevant data and to define the current evidence on the utility of Pentraxin-3 (PTX3) as a biomarker for acute appendicitis (AA) in children. Methods: This review was conducted in accordance with the PRISMA guidelines. PubMed, Embase, Scopus, and Web of Science databases were systematically searched for studies comparing the levels of PTX3 in patients with AA vs healthy controls or non-specific abdominal pain (NSAP). Mean differences were calculated for all outcomes and the inverse variance method was used for weighted mean difference. The methodological quality of the included studies was assessed using the Downs and Black scale. Results: Five comparative studies were included. Significantly elevated levels of PTX3 in cases with AA vs healthy controls (WMD: 9.56, 95% CI 7.24-11.88, p Conclusions: PTX3-levels are elevated in AA, but differentiation between perforated and non-perforated appendicitis demands other methods.</p

Pathomechanisms of ALS8: altered autophagy and defective RNA binding protein (RBP) homeostasis due to the VAPB P56S mutation.

Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy

Lipopolysaccharide triggers exacerbated microglial activation, excessive cytokine release and behavioural disturbances in mice with truncated Fused-in-Sarcoma Protein (FUS)

CNS inflammation, including microglial activation, in response to peripheral infections are known to contribute to the pathology of both familial and sporadic neurodegenerative disease. The relationship between Fused-in-Sarcoma Protein (FUS)-mediated disease in the transgenic FUS[1–359] animals and the systemic inflammatory response have not been explored. Here, we investigated microglial activation, inflammatory gene expression and the behavioural responses to lipopolysaccharide-induced (LPS; 0.1 mg/kg) systemic inflammation in the FUS[1–359] transgenic mice. The pathology of these mice recapitulates the key features of mutant FUS-associated familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here, pre-symptomatic 8-week-old mutant or wild type controls were challenged with LPS or with saline and sucrose intake, novel cage exploration, marble burying and swimming behaviours were analyzed. The level of pro-inflammatory gene expression was also determined, and microglial activation was evaluated. In chronic experiments, to discover whether the LPS challenge would affect the onset of ALS-like paralysis, animals were evaluated for clinical signs from 5 to 7 weeks post-injection. Compared to controls, acutely challenged FUS[1–359]-tg mice exhibited decreased sucrose intake and increased floating behaviours. The FUS[1–359]-tg mice exhibited an increase in immunoreactivity for Iba1-positive cells in the prefrontal cortex and ventral horn of the spinal cord, which was accompanied by increased expression of interleukin-1β, tumour necrosis factor, cyclooxygenase-(COX)-1 and COX-2. However, the single LPS challenge did not alter the time to development of paralysis in the FUS[1–359]-tg mice. Thus, while the acute inflammatory response was enhanced in the FUS mutant animals, it did not have a lasting impact on disease progression

PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD.

ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in C9ORF72-ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in disease onset and progression. We provide evidence for the early onset of ER stress-mediated adaptive response in C9ORF72 patient-derived motoneurons (MNs), reflected by the elevated increase in GRP75 expression. These transiently increased GRP75 levels enhance ER-mitochondrial association, boosting mitochondrial function and sustaining cellular bioenergetics during the initial stage of disease, thereby counteracting early mitochondrial deficits. In C9orf72 rodent neurons, an abrupt reduction in GRP75 expression coincided with the onset of UPR, mitochondrial dysfunction and the emergence of PolyGA aggregates, which co-localize with GRP75. Similarly, the overexpression of PolyGA in WT cortical neurons or C9ORF72 patient-derived MNs led to the sequestration of GRP75 within PolyGA inclusions, resulting in mitochondrial calcium (Ca2+) uptake impairments. Corroborating these findings, we found that PolyGA aggregate-bearing human post-mortem C9ORF72 hippocampal dentate gyrus neurons not only display reduced expression of GRP75 but also exhibit GRP75 sequestration within inclusions. Sustaining high GRP75 expression in spinal C9orf72 rodent MNs specifically prevented ER stress, normalized mitochondrial function, abrogated PolyGA accumulation in spinal MNs, and ameliorated ALS-associated behavioral phenotype. Taken together, our results are in line with the notion that neurons in C9ORF72-ALS/FTD are particularly susceptible to ER-mitochondrial dysfunction and that GRP75 serves as a critical endogenous neuroprotective factor. This neuroprotective pathway, is eventually targeted by PolyGA, leading to GRP75 sequestration, and its subsequent loss of function at the MAM, compromising mitochondrial function and promoting disease onset