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"Jacob, Justin"
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Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently available treatments include the antifibrotic drugs nintedanib and pirfenidone, which effectively reduce fibrosis progression are, unfortunately, not effective in curing the disease. In recent years, the paradigm of IPF pathogenesis has shifted from a fibroblast-driven disease to an epithelium-driven disease, wherein, upon recurrent microinjuries, dysfunctional alveolar type II epithelial cells (ATII) are not only unable to sustain physiological lung regeneration but also promote aberrant epithelial–mesenchymal crosstalk. This creates a drift towards fibrosis rather than regeneration. In the context of this review article, we discuss the most relevant mechanisms involved in IPF pathogenesis with a specific focus on the role of dysfunctional ATII cells in promoting disease progression. In particular, we summarize the main causes of ATII cell dysfunction, such as aging, environmental factors, and genetic determinants. Next, we describe the known mechanisms of physiological lung regeneration by drawing a parallel between embryonic lung development and the known pathways involved in ATII-driven alveolar re-epithelization after injury. Finally, we review the most relevant interventional clinical trials performed in the last 20 years with the aim of underlining the urgency of developing new therapies against IPF that are not only aimed at reducing disease progression by hampering ECM deposition but also boost the physiological processes of ATII-driven alveolar regeneration.
Journal Article
A role for keratin 17 during DNA damage response and tumor initiation
High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.
Journal Article
Evaluation of probiotic properties of Lysinibacillus macroides under in vitro conditions and culture of Cyprinus carpio on growth parameters
Cyprinus carpio
is an important freshwater fish in aquaculture. It was used for the isolation of potential probiotic strain for aquaculture applications. The most dominant strain was isolated on MRS agar from the gastrointestinal (GI) of
C. carpio
and identified as
Lysinibacillus macroides
using molecular marker 16S rRNA gene
.
Various probiotic properties such as acid and bile tolerance and antibiotic susceptibility were analysed under in vitro conditions. Further, formulate pelletized feed using probiotic (
L. macroides
) in different concentrations (2, 4, 6 and 8%). Rearing of
C. carpio
was carried out 45 days and fed with formulated feed. The highest length (5.14 ± 0.07 cm) and weight (3.56 ± 0.07 g) of
C. carpio
fingerlings was recorded in the 8% LM probiotic pelletized feed, while in fingerlings fed with control showed lower in the length (3.02 ± 0.13 cm) and the weight (0.92 ± 0.04 g) on the 45th day of the experiment. Both percentage of weight gain (PWG) and specific growth rate (SGR) were significantly increased (
P
< 0.05) of
C. carpio
fingerlings fed with probiotic feed compared to control feed. Hence, the use of probiotic bacteria could be an encouraging alternative feed for future endeavours in the field of aquaculture. In conclusion,
L. macroides
can serve as probiotic for sustainable, competitive and promising beneficial bacteria to aquaculture industry.
Journal Article
Meiosis-Specific Cohesin Component, Stag3 Is Essential for Maintaining Centromere Chromatid Cohesion, and Required for DNA Repair and Synapsis between Homologous Chromosomes
Cohesins are important for chromosome structure and chromosome segregation during mitosis and meiosis. Cohesins are composed of two structural maintenance of chromosomes (SMC1-SMC3) proteins that form a V-shaped heterodimer structure, which is bridged by a α-kleisin protein and a stromal antigen (STAG) protein. Previous studies in mouse have shown that there is one SMC1 protein (SMC1β), two α-kleisins (RAD21L and REC8) and one STAG protein (STAG3) that are meiosis-specific. During meiosis, homologous chromosomes must recombine with one another in the context of a tripartite structure known as the synaptonemal complex (SC). From interaction studies, it has been shown that there are at least four meiosis-specific forms of cohesin, which together with the mitotic cohesin complex, are lateral components of the SC. STAG3 is the only meiosis-specific subunit that is represented within all four meiosis-specific cohesin complexes. In Stag3 mutant germ cells, the protein level of other meiosis-specific cohesin subunits (SMC1β, RAD21L and REC8) is reduced, and their localization to chromosome axes is disrupted. In contrast, the mitotic cohesin complex remains intact and localizes robustly to the meiotic chromosome axes. The instability of meiosis-specific cohesins observed in Stag3 mutants results in aberrant DNA repair processes, and disruption of synapsis between homologous chromosomes. Furthermore, mutation of Stag3 results in perturbation of pericentromeric heterochromatin clustering, and disruption of centromere cohesion between sister chromatids during meiotic prophase. These defects result in early prophase I arrest and apoptosis in both male and female germ cells. The meiotic defects observed in Stag3 mutants are more severe when compared to single mutants for Smc1β, Rec8 and Rad21l, however they are not as severe as the Rec8, Rad21l double mutants. Taken together, our study demonstrates that STAG3 is required for the stability of all meiosis-specific cohesin complexes. Furthermore, our data suggests that STAG3 is required for structural changes of chromosomes that mediate chromosome pairing and synapsis, DNA repair and progression of meiosis.
Journal Article
Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes
Pierre Coulombe and colleagues show that the autoimmune regulator Aire is induced in tumor keratinocytes in a keratin 17 (K17)-dependent manner and promotes skin tumorigenesis in mice. They further show that K17 and Aire colocalize in the nucleus and bind a subset of proinflammatory genes, providing a molecular explanation for the K17-dependent amplification of inflammatory responses in diseased epithelia.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia
1
,
2
,
3
. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of
Gli2
-induced skin tumorigenesis in mice. The induction of
Aire
mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K
4
. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.
Journal Article
Sustainable biodiesel from flex-mix feedstock and its combustion in a VCR-CRDI engine with variable exhaust gas recirculation and injection pressure
Biodiesel produced from single feedstocks has many challenges due to variations in the oil properties. The flex-mix approach is a long-term solution for turning mixed feedstock into high-quality biodiesels. In this investigation, a pre-mixed used cooking oil and animal fat (pig fat) mixture (from 20% to 80%) was transesterified to produce flex-mix methyl ester (FMME). The FMME fuel characteristics were tested and compared to biodiesel standards. Generally, biodiesel emits higher oxides of nitrogen (NO x ) gas due to the presence of highly unsaturated compounds and oxygen. The present study aims to address this issue by adopting the flex-mix approach in combination with fuel injection strategies (400, 500 and 600 bar), exhaust gas recirculation (EGR 10%, 20% and 30%) and variable compression ratio (CR 17.5:1, 20:1 and 22:1). At a CR of 22 and an injection pressure ( P inj ) of 600 bar, the FMME fuel without EGR shows a minimum reduction in brake thermal efficiency of 0.15% when compared to diesel. Nitric oxide gas emissions decreased by nearly 50% for all P inj and EGR values, but they rose when the compression ratio was increased to 20 and 22. Smoke and hydrocarbon emissions also increased with the exhaust gas proportion. The engine performance with FMME fuel was found to be equivalent to that with fossil diesel fuel. According to the findings, the flex-mix approach could be a long-term alternative to producing renewable fuel for off-road diesel engine application.
Journal Article
Equity Research Project - Johnson & Johnson
This equity research report, prepared as part of Nova SBE’s Field Lab by Justin Jacob and Rupert Schuler, evaluates Johnson & Johnson (JNJ). Our valuation estimates a share price of$183, indicating the stock is undervalued compared to its December 13, 2024 market price of $ 146.62. A detailed relative valuation and sensitivity analysis across four scenarios support this conclusion. The report considers JNJ’s operational resilience, ongoing litigations, and macroeconomic factors, providing a balanced assessment of internal and external influences on the company’s intrinsic value.
Dissertation
A green and facile approach for the synthesis of silver nanoparticles using aqueous extract of Ailanthus excelsa leaves, evaluation of its antibacterial and anticancer efficacy
Silver nanoparticles possess a wide range of applications especially in the field of medicine and this has stimulated the need for synthesizing them. Conventionally, chemical methods are used, which are hazardous and energy consuming. Therefore an eco-friendly and facile means of synthesizing nanoparticles is needed to replace the chemical method of synthesis. In the present study, silver nanoparticles were synthesized in a cost-effective and environment-friendly manner using aqueous leaf extract of
Ailanthus excelsa
—a medicinal tree used in the treatment of asthma, bronchitis, cold, abdominal pain, etc. The leaf extract helped in the bioreduction of silver ions yielding silver nanoparticles. The silver nanoparticles thus biosynthesized were characterized using UV–vis absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR) analysis and scanning electron microscopy (SEM). These biologically synthesized silver nanoparticles were also found to exhibit excellent antibacterial effect against
Staphylococcus aureus
,
Pseudomonas aeruginosa
,
Escherichia coli
,
Klebsiella pneumonia
and anticancer effect against MCF-7 cell line.
Journal Article
Nanoparticle analysis for various medicinal drugs and human body saliva at macromolecular level
The spectral bio-diagnosis of normal human body saliva sample shows the following functional compounds and it is related to various proteins and enzymes. Because of the presence of water in the saliva sample, the hydroxyl group is observed in the form of O–H at 3,305 cm
−1
, because of the presence of lipids, the functional group C–H is obtained from 2,928 to 2,856 cm
−1
, due to the presence of amide-I in the form of C=N and C=C obtained at 1,658 cm
−1
, the proteins are exhibited. Due to the presence of aliphatic CH
2
, the Lipids, Adenine, Cytosine, Collagen are observed at 1,455 cm
−1
, because of the presence of Carbohydrates, Phospholipids, Nucleic acids, the functional groups C=O and P=O from 1,159 to 1,064 cm
−1
are exhibited. Due to the presence of Phenylalanine, Tyrosine, Cystine and Hydroxyapatite C–C twist, C–C stretch, C–S stretch and PO
4
2−
are observed at 748 and 483 cm
−1
. Silver nanoparticle has attracted considerable interest due to their extensive applicability in various areas such as electronics, catalysis, chemistry, energy and medicine. To study the opto-electronics properties of the samples, it was mixed with silver nanoparticles and characterized.
Journal Article