Search Results (3,403)

This study focused on the discovery of the antimicrobial peptide (AMP) derived from mangrove bacteria. The most promising isolate, NNS5-6, showed the closest taxonomic relation to Paenibacillus thiaminolyticus, with the highest similarity of 74.9%. The AMP produced by Paenibacillus thiaminolyticus NNS5-6 exhibited antibacterial activity against various Gram-negative pathogens, especially Pseudomonas aeruginosa and Klebsiella pneumoniae. The peptide sequence consisted of 13 amino acids and was elucidated as Val-Lys-Gly-Asp-Gly-Gly-Pro-Gly-Thr-Val-Tyr-Thr-Met. The AMP mainly exhibited random coil and antiparallel beta-sheet structures. The stability study indicated that this AMP was tolerant of various conditions, including proteolytic enzymes, pH (1.2–14), surfactants, and temperatures up to 40 °C for 12 h. The AMP demonstrated 4 µg/mL of MIC and 4–8 µg/mL of MBC against both pathogens. Time-kill kinetics showed that the AMP acted in a time- and concentration-dependent manner. A cell permeability assay and scanning electron microscopy revealed that the AMP exerted the mode of action by disrupting bacterial membranes. Additionally, nineteen biosynthetic gene clusters of secondary metabolites were identified in the genome. NNS5-6 was susceptible to various commonly used antibiotics supporting the primary safety requirement. The findings of this research could pave the way for new therapeutic approaches in combating antibiotic-resistant pathogens. Full article

Desulfovibrio, resident gut sulfate-reducing bacteria (SRB), are found to overgrow in diseases such as inflammatory bowel disease and Parkinson’s disease. They activate a pro-inflammatory response, suggesting that Desulfovibrio may play a causal role in inflammation. Class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway regulates key events in the inflammatory response to infection. Dysfunctional PI3K/Akt signaling is linked to numerous diseases. Bacterial-induced PI3K/Akt pathway may be activated downstream of toll-like receptor (TLR) signaling. Here, we tested the hypothesis that Desulfovibrio vulgaris (DSV) may induce tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) expression via PI3K/Akt in a TLR 2-dependent manner. RAW 264.7 macrophages were infected with DSV, and protein expression of p-Akt, p-p70S6K, p-NF-κB, p-IkB, TNF-α, and iNOS was measured. We found that DSV induced these proteins in a time-dependent manner. Heat-killed and live DSV, but not bacterial culture supernatant or a probiotic Lactobacillus plantarum, significantly caused PI3K/AKT/TNF/iNOS activation. LY294002, a PI3K/Akt signaling inhibitor, and TL2-C29, a TLR 2 antagonist, inhibited DSV-induced PI3K/AKT pathway. Thus, DSV induces pro-inflammatory TNF-α and iNOS via PI3K/Akt pathway in a TLR 2-dependent manner. Taken together, our study identifies a novel mechanism by which SRB such as Desulfovibrio may trigger inflammation in diseases associated with SRB overgrowth. Full article

Although the vast majority of CTCL subtypes are of the CD4+ T-helper cell differentiation phenotype, there is a spectrum of CD8+ variants that manifest wide-ranging clinical, histologic, and phenotypic features that inform the classification of the disease. CD8, like CD4, and cytotoxic molecules (including TIA and granzyme) are readily detectable via IHC staining of tissue and, when expressed on the phenotypically abnormal T-cell population, can help distinguish specific CTCL subtypes. Nonetheless, given that the histopathologic differential for CD8+ lymphoproliferative disorders and lymphomas may range from very indolent lymphomatoid papulosis (LyP) to aggressive entities like CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (AECTCL), CD8 and/or cytotoxic molecule expression alone is insufficient for diagnosis and is not in itself an indicator of prognosis. We present a review of CTCL subtypes that can demonstrate CD8 positivity: CD8+ mycosis fungoides (MF), LyP type D, subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma/delta T-cell lymphoma (PCGDTL), CD8+ AECTCL, and acral CD8+ T-cell lymphoproliferative disorder (acral CD8+ TCLPD). These diseases may have different clinical manifestations and distinctive treatment algorithms. Due to the rare nature of these diseases, it is imperative to integrate clinical, histologic, and immunohistochemical findings to determine an accurate diagnosis and an appropriate treatment plan. Full article

The AKT1 oncogene is related to various cancers due to its critical role in the PIC3CA/AKT1 pathway; however, most of the studies screened the hotspot mutation AKT1 (E17K) with various incidences. Low frequency or lack of AKT1 (E17K) mutation was reported in prostate cancer (PC) patients. This study aims to explore genetic alterations in the AKT1 PH domain by extending the sequencing to include AKT1 gene exons 3 and 4. Genomic DNA was extracted from 84 Formalin-Fixed Paraffin-Embedded samples of PC patients in Jordan, and then subjected to PCR and sequencing for the targeted exons. This study revealed the presence of two novel mutations (N53Y and Q59K) and a high frequency of mutations in exon 4, with a lack of mutations in the E17K hotspot. Nine missense and two synonymous mutations were detected in exon 4 (Phe27Tyr, Phe27Leu, Ala58Thr, Ser56Phe, Arg41Trp, Phe35Leu, Asp32Glu, Phe35Tyr, and Gln43Lys) and (Ser56 and Glu40), respectively. Two synonymous mutations were detected in exon 3 (Leu12 and Ser2). It is concluded that there is a high frequency of AKT1 mutation in PC patients in Jordan with two novel missense mutations in the Pleckstrin homology (PH) domain. E17K hotspot mutation was not detected in any tested samples, which underlined the significant role of mutations in other AKT1 exons in PC development. Full article

Hypertension is defined as a systolic blood pressure (SBP) of over 140 mmHg or diastolic blood pressure (DBP) of over 90 mmHg. Hypertension is widely known to be a factor affecting human health, so its prevention is considered important. We investigated the effect of casein-derived tripeptide Met-Lys-Pro (MKP) on blood pressure in a randomized, placebo-controlled, parallel-group study. Participants were healthy adults with SBP between 120 and 139 mmHg, and/or DBP between 80 and 89 mmHg. A total of 121 participants were randomly assigned to the MKP group or placebo group. Participants received either a test powder containing 100 μg of MKP or a placebo powder without MKP for 12 weeks. As a result, SBP and DBP were significantly lower in the MKP group than in the placebo group. No adverse events associated with the MKP intake were observed. This study showed that MKP has a beneficial effect on lowering blood pressure in healthy adults with high-normal and elevated blood pressure and can be safely used for continuous intake. Full article

Cathepsin S (CatS) is a proteolytic enzyme and a member of the cysteine protease family of proteolytic enzymes. Cathepsins S, K, and L are particularly similar in terms of their amino acid sequences and interactions with substrates, and this has made it difficult to develop inhibitors with specificity for either CatS, CatK, or CatL. The involvement of CatS in various disease pathophysiologies (autoimmune disorders, cardiovascular diseases, cancer, etc.) has made it a very important target in drug development. Efforts have been made since the early 1990s to develop a specific CatS inhibitor without any major success. Following many failed efforts to develop an inhibitor for CatS, it was discovered that interactions with the amino acid residues at the S2 and S3 pockets of CatS are critical for the identification of CatS-specific inhibitors. Amino acid residues at these pockets have been the target of recent research focused on developing a non-covalent, reversible, and specific CatS inhibitor. Methods applied in the identification of CatS inhibitors include molecular modeling, in-vitro screening, and in-vivo studies. The molecular modeling process has proven to be very successful in the identification of CatS-specific inhibitors, with R05459072 (Hoffmann-La Roche) and LY3000328 (Eli Lilly Company) which has completed phase 1 clinical trials. CatS inhibitors identified from 2011 to 2023 with promising prospects are discussed in this article. Full article

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy. Full article

Lung tumor-promoting environmental exposures and γherpesvirus infections are associated with Type 17 inflammation. To test the effect of γherpesvirus infection in promoting lung tumorigenesis, we infected mutant K-Ras-expressing (K-Ras^LA1) mice with the murine γherpesvirus MHV68 via oropharyngeal aspiration. After 7 weeks, the infected mice displayed a more than 2-fold increase in lung tumors relative to their K-Ras^LA1 uninfected littermates. Assessment of cytokines in the lung revealed that expression of Type 17 cytokines (Il-6, Cxcl1, Csf3) peaked at day 7 post-infection. These observations correlated with the post-infection appearance of known immune mediators of tumor promotion via IL-17A in the lungs of tumor-bearing mice. Surprisingly, Cd84, an immune cell marker mRNA, did not increase in MHV68-infected wild-type mice lacking lung tumors. Csf3 and Cxcl1 protein levels increased more in the lungs of infected K-Ras^LA1 mice relative to infected wild-type littermates. Flow cytometric and transcriptomic analyses indicated that the infected K-Ras^LA1 mice had increased Ly6G^dim/Ly6C^hi immune cells in the lung relative to levels seen in uninfected control K-Ras^LA1 mice. Selective methylation of adenosines (m⁶A modification) in immune-cell-enriched mRNAs appeared to correlate with inflammatory infiltrates in the lung. These observations implicate γherpesvirus infection in lung tumor promotion and selective accumulation of immune cells in the lung that appears to be associated with m⁶A modification of mRNAs in those cells. Full article

Variants in membrane trafficking proteins are known to cause rare disorders with severe symptoms. The highly conserved transport protein particle (TRAPP) complexes are key membrane trafficking regulators that are also involved in autophagy. Pathogenic genetic variants in specific TRAPP subunits are linked to neurological disorders, muscular dystrophies, and skeletal dysplasias. Characterizing these variants and their phenotypes is important for understanding the general and specialized roles of TRAPP subunits as well as for patient diagnosis. Patient-derived cells are not always available, which poses a limitation for the study of these diseases. Therefore, other systems, like the yeast Saccharomyces cerevisiae, can be used to dissect the mechanisms at the intracellular level underlying these disorders. The development of CRISPR/Cas9 technology in yeast has enabled a scar-less editing method that creates an efficient humanized yeast model. In this study, core yeast subunits were humanized by replacing them with their human orthologs, and TRAPPC1, TRAPPC2, TRAPPC2L, TRAPPC6A, and TRAPPC6B were found to successfully replace their yeast counterparts. This system was used for studying the first reported individual with an autosomal recessive disorder caused by biallelic TRAPPC1 variants, a girl with a severe neurodevelopmental disorder and myopathy. We show that the maternal variant (TRAPPC1 p.(Val121Alafs*3)) is non-functional while the paternal variant (TRAPPC1 p.(His22_Lys24del)) is conditional-lethal and affects secretion and non-selective autophagy in yeast. This parallels defects seen in fibroblasts derived from this individual which also showed membrane trafficking defects and altered Golgi morphology, all of which were rescued in the human system by wild-type TRAPPC1. This study suggests that humanized yeast can be an efficient means to study TRAPP subunit variants in the absence of human cells and can assign significance to variants of unknown significance (VUS). This study lays the foundation for characterizing further TRAPP variants through this system, rapidly contributing to disease diagnosis. Full article

In the present work, we report an update and extension of the previous ion-pair formation study of Hubers, M.M.; Los, J. Chem. Phys. 1975, 10, 235–259, noting new fragment anions from time-of-flight mass spectrometry. The branching ratios obtained from the negative ions formed in K + SF₆ collisions, in a wide energy range from 10.7 up to 213.1 eV in the centre-of-mass frame, show that the main anion is assigned to SF₅⁻ and contributing to more than 70% of the total ion yield, followed by the non-dissociated parent anion SF₆⁻ and F⁻. Other less intense anions amounting to <20% are assigned to SF₃⁻ and F₂⁻, while a trace contribution at 32u is tentatively assigned to S⁻ formation, although the rather complex intramolecular energy redistribution within the temporary negative ion is formed during the collision. An energy loss spectrum of potassium cation post-collision is recorded showing features that have been assigned with the help of theoretical calculations. Quantum chemical calculations for the lowest-lying unoccupied molecular orbitals in the presence of a potassium atom are performed to support the experimental findings. Apart from the role of the different resonances participating in the formation of different anions, the role of higher-lying electronic-excited states of Rydberg character are noted. Full article

The exponential growth of Knowledge Graphs necessitates effective and efficient methods for their exploration and understanding. Frequently Asked Questions (FAQ) is a service that typically presents a list of questions and answers related to a specific topic, and which is intended to help people understand that topic. Although FAQ has already shown its value on large websites and is widely used, to the best of our knowledge it has not yet been exploited for Knowledge Graphs. In this paper, we present ULYSSES, the first system for automatically constructing FAQ lists for large Knowledge Graphs. Our method consists of three key steps. First, we select the most frequent queries by exploiting the available query logs. Next, we answer the selected queries, using the original graph. Finally, we construct textual descriptions of both the queries and the corresponding answers, exploring state-of-the-art transformer models, i.e., ChatGPT 3.5 and Gemini 1.5 Pro. We evaluate the results of each model, using a human-constructed FAQ list, contributing a unique dataset to the domain and showing the benefits of our approach. Full article

This work aims at proposing an affordable, non-wearable system to detect falls of people in need of care. The proposal uses artificial vision based on deep learning techniques implemented on a Raspberry Pi4 4GB RAM with a High-Definition IR-CUT camera. The CNN architecture classifies detected people into five classes: fallen, crouching, sitting, standing, and lying down. When a fall is detected, the system sends an alert notification to mobile devices through the Telegram instant messaging platform. The system was evaluated considering real daily indoor activities under different conditions: outfit, lightning, and distance from camera. Results show a good trade-off between performance and cost of the system. Obtained performance metrics are: precision of $96.4\%$, specificity of $96.6\%$, accuracy of $94.8\%$, and sensitivity of $93.1\%$. Regarding privacy concerns, even though this system uses a camera, the video is not recorded or monitored by anyone, and pictures are only sent in case of fall detection. This work can contribute to reducing the fatal consequences of falls in people in need of care by providing them with prompt attention. Such a low-cost solution would be desirable, particularly in developing countries with limited or no medical alert systems and few resources. Full article

Solar cells convert light energy directly into electricity using semiconductor materials. The ternary system, composed of poly(3-hexylthiophene) (P3HT), fullerene (C₆₀), and phenyl-C₆₁-butyric-acid-methyl-ester (PCBM), expressed as P3HT-C₆₀-PCBM, is one of the most efficient organic solar cells. In the present study, the structures and electronic states of P3HT-C₆₀-PCBM have been investigated by means of the density functional theory (DFT) method to shed light on the mechanism of charge separation in semiconductor materials. The thiophene hexamer was used as a model of P3HT. Five geometrical conformers were obtained as the C₆₀-PCBM binary complexes. In the ternary system, P3HT wrapped around C₆₀ in the stable structure of P3HT-C₆₀-PCBM. The intermolecular distances for P3HT-(C₆₀-PCBM) and (P3HT-C₆₀)-PCBM were 3.255 and 2.885 Å, respectively. The binding energies of P3HT + (C₆₀-PCBM) and (P3HT-C₆₀) + PCBM were 27.2 and 19.1 kcal/mol, respectively. The charge transfer bands were found at the low-lying excited states of P3HT-C₆₀-PCBM. These bands strongly correlated with the carrier separation and electron transfer in solar cells. The electronic states at the ground and excited states of P3HT-C₆₀-PCBM were discussed on the basis of the calculated results. Full article

In forensics, one-third of sudden deaths remain unexplained after a forensic autopsy. A majority of these sudden unexplained deaths (SUDs) are considered to be caused by inherited cardiovascular diseases. In this study, we investigated 40 young SUD cases (<40 years), with non-diagnostic structural cardiac abnormalities, using Targeted NGS (next-generation sequencing) for 167 genes previously associated with inherited cardiomyopathies and channelopathies. Fifteen cases identified 17 variants on related genes including the following: AKAP9, CSRP3, GSN, HTRA1, KCNA5, LAMA4, MYBPC3, MYH6, MYLK, RYR2, SCN5A, SCN10A, SLC4A3, TNNI3, TNNI3K, and TNNT2. Of these, eight variants were novel, and nine variants were reported in the ClinVar database. Five were determined to be pathogenic and four were not evaluated. The novel and unevaluated variants were predicted by using in silico tools, which revealed that four novel variants (c.5187_5188dup, p.Arg1730llefsTer4 in the AKAP9 gene; c.1454A>T, p.Lys485Met in the MYH6 gene; c.2535+1G>A in the SLC4A3 gene; and c.10498G>T, p.Asp3500Tyr in the RYR2 gene) were pathogenic and three variants (c.292C>G, p.Arg98Gly in the TNNI3 gene; c.683C>A, p.Pro228His in the KCN5A gene; and c.2275G>A, p.Glu759Lys in the MYBPC3 gene) still need to be further verified experimentally. The results of our study contributed to the general understanding of the causes of SUDs. They provided a scientific basis for screening the risk of sudden death in family members of victims. They also suggested that the Targeted NGS method may be used to identify the pathogenic variants in SUD victims. Full article

Evidence-based research on the effects of rainfall, temperature, and relative humidity variability on maize yield is essential for understanding the climate dynamics of, and paving the way for informed adaptive solutions to future potential negative impacts in, Dschang-Cameroon. This study employed the non-parametric Mann–Kendall and Sen’s slope method to detect trends in climate variables and maize yield in the period between 1990 to 2018. Pearson correlation and multilinear regression (MLR) analyses were also used to establish the linear relationship between climate variables and maize yield, and to explore the behavior of the response variable (maize yield) with the predictor variables (climatic variables), respectively. In addition, perceptions of climate variability and its impact on maize yield from a hundred farmers were collected through a questionnaire and analyzed in SPSS. Twenty key informants’ interviews (KII) were conducted using a semi-structured interview and analyzed by thematic analysis. The results showed that the minimum temperature exhibited a decreasing trend at a rate of 0.039 °C per annum, whereas relative humidity had an increasing trend of 0.25% per annum with statistical significance at p = 0.001. In addition, a decreasing trend of rainfall, at a rate of 4.94 mm per annum, was observed; however, this had no statistical significance. Furthermore, the MLR analysis showed that mean temperature and relative humidity have an inversely proportional but statistically significant relationship with maize yield (p = 0.046 and p = 0.001, respectively). The analysis of farmers’ perceptions confirmed the results of trend analyses of decreasing rainfall and increasing maximum temperatures. Moreover, the farmers asserted that the vulnerability of farmers to climate variability is also linked to gender and locality, where women’s outputs are more assailable and farms in low-lying areas are more prone to floods. The high price of farm inputs was also reported as a key factor, other than climate variability, hindering the flourishing of the maize sector in Dschang. Finally, an analysis of the KII indicated the inadequate implementation of flagship agricultural programs in the locality. Full article