Family Of Molecules Research Articles

Preparation and Photochemistry of Parent Triplet Vinylarsinidene.

Vinyl pnictinidenes are an elusive family of molecules that have been suggested as key intermediates in multiple chemical reactions and commonly display a predisposition toward open-shell electronic ground states (as is evident from quantum chemical computations). However, owing to their expected extremely high reactivity, no vinyl pnictinidene has ever been isolated and characterized spectroscopically. Here, we report the synthesis and spectroscopic characterization of vinylarsinidene, a higher congener of vinylnitrene. As we demonstrate, triplet vinylarsinidene can be prepared through the low-temperature photolysis of diazidovinylarsine at 10 K in an argon matrix. The title compound can also be generated through high-vacuum flash pyrolysis of the diazide at 700 °C and trapped analogously. Triplet vinylarsinidene was characterized by IR and UV/vis spectroscopy and displayed remarkably rich unimolecular photochemistry. Upon selective photoirradiation, it rearranges to vinylidenearsine, 2H-arsirene, triplet ethynylarsinidene or an arsinidene (H-As) acetylene complex. The formation mechanisms of these products were rationalized with DFT and CASPT2 computations.

Multifunctional Photoelectroactive Materials for Optoelectronic Applications Based on Thieno[3,4-b]pyrazines and Thieno[1,2,5]thiadiazoles.

In this study, we introduce a novel family of symmetrical thiophene-based small molecules with a Donor-Acceptor-Donor structure. These compounds feature three different acceptor units: benzo[c][1,2,5]thiadiazole (Bz), thieno[3,4-b]pyrazine (Pz), and thieno[1,2,5]thiadiazole (Tz), coupled with electron donor units based on a carbazole-thiophene derivative. Using Density Functional Theory (DFT), we investigate how the molecular geometry and strength of the central acceptor unit impact the redox and spectroscopic properties. Notably, the incorporation of Pz and Tz moieties induces a significant redshift in the absorption and emission spectra, which extend into the near-infrared (NIR) region, simultaneously reducing their energy gaps (~1.4-1.6 eV). This shift is attributed to the increased coplanarity of the oligomeric inner core, both in the ground (S0 ) and excited (S1 ) states, due to the enhanced quinoidal character as supported by bond-length alternation (BLA) analysis. These structural changes promote better π-electron delocalization and facilitate photoinduced charge transfer processes in optoelectronic devices. Notably, we show that Pz- and Tz-containing molecules exhibit NIR electrochromic behavior and present ambivalent character in bulk heterojunction (BHJ) solar cells. Finally, theoretical calculations suggest that these molecules could serve as effective two-photon absorption (2PA) probes, further expanding their potential in optoelectronic applications.

V-Shaped Tröger Oligothiophenes Boost Triplet Formation by CT Mediation and Symmetry Breaking.

A new family of molecules obtained by coupling Tröger's base unit with dicyanovinylene-terminated oligothiophenes of different lengths has been synthesized and characterized by steady-state stationary and transient time-resolved spectroscopies. Quantum chemical calculations allow us to interpret and recognize the properties of the stationary excited states as well as the time-dependent mechanisms of singlet-to-triplet coupling. The presence of the diazocine unit in Tröger's base derivatives is key to efficiently producing singlet-to-triplet intersystem crossing mediated by the role of the nitrogen atoms and of the almost orthogonal disposition of the two thiophene arms. Spin-orbit coupling-mediated interstate intersystem crossing (ISC) is activated by a symmetry-breaking process in the first singlet excited state with partial charge transfer character. This mechanism is a characteristic of these molecular triads since the independent dicyanovinylene-oligothiophene branches do not display appreciable ISC. These results show how Tröger's base coupling of organic chromophores can be used to improve the ISC efficiency and tune their photophysics.

SLAMF3 promotes Th17 differentiation and is reversed by iguratimod through JAK1/STAT3 pathway in primary Sjögren's syndrome

ObjectiveThe signaling lymphocytic activation molecule family of receptors (SLAMF) is involved in the activation of T cells and plays important roles in the pathogenesis of autoimmune diseases. The purpose of this study is to observe the expression of SLAMF3 on CD4 + T cells and its effect on the differentiation of T helper 17 (Th17) in primary Sjögren's syndrome (pSS). Furthermore, we found iguratimod (IGU) could effectively reverse the aberrant Th17 differentiation through JAK1/STAT3 signaling. MethodsPeripheral blood mononuclear cells from 40 pSS and 40 healthy control subjects were enrolled for analysis of expression of SLAMF3 on CD4 + T and Th17 cells by flow cytometry. Serum IL-17 and SLAMF3 were detected by ELISA assay. Labial biopsies from 20 pSS patients and 20 non-pSS controls were performed immunohistochemical for staining expression of CD4, IL-17, and SLAMF3. Under the priming conditions with anti-CD3/CD28 or CD3/SLAMF3 antibodies on CD4 + T cells extracted from pSS and controls, the proportion of Th17 cells in CD4 + T cells and the amount of soluble IL-17A were assessed by flow cytometry and ELISA. Furthermore, RNA sequencing was performed for the transcriptomics study. Additionally, RNA level of RORγt and IL-17A and the protein level of RORγt, p-JAK1 and p-STAT3, were detected by real-time PCR and western blot. ResultsThe expression levels of SLAMF3 on CD4 + T and Th17 cells in the peripheral blood and salivary glands in pSS patients were significantly elevated than that in control groups. The serum IL-17A and SLAMF3 in pSS patients were much higher compared with the control group. Although co-stimulation of CD3/SLAMF3 could promote CD4 + T cells differentiate into Th17 cells both in pSS and controls, the CD4 + T cells from pSS have a more sensitive response in Th17 differentiation with the SLAMF3 stimulation. Transcriptomics results showed the CD3/SLAMF3 stimulation caused the activation of Th17 signaling and JAK1/STAT3 pathway. Quantitative PCR and western blotting confirmed the IGU (iguratimod), which is a safe clinical drug in treatment of autoimmune diseases, effectively reversed the increased Th17 proportion, the expression levels of RORγt, pJAK1, and pSTAT3 caused by CD3/SLAMF3 stimulation. ConclusionSLAMF3 upregulates Th17 cell differentiation of CD4 + T cells and IL-17A secretion through enriching RORγt and activating the transcriptomics participating in the pathogenesis of primary Sjögren's syndrome. IGU could inhibit the process through this therapeutic target in pSS.

Inhibition of Rho-Associated Coiled-Coil Containing Protein Kinases with Belumosudil Mesylate Shows Anti-Tumor and Immune Modulatory Properties in Models of Multiple Myeloma

Background: Myeloma patient outcomes have continuously improved with the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs) recognizing cell surface proteins and, most recently, B-cell maturation antigen (BCMA)-targeted bispecifics and chimeric antigen receptor (CAR)-guided T-cells. However, the prognosis in triple-class refractory (TCR) disease that is refractory to PIs, IMiDs, and CD38 mAbs remains poor and, since BCMA-targeted CAR-Ts and bispecifics are not curative, quadruple-class refractory (QCR) disease that progresses during or after these therapies is an emerging challenge, indicating a persistent need for novel agents. Rho-associated coiled-coil containing protein kinases (ROCK1 and ROCK2) may represent novel potential targets since ROCK1 has been associated with a plasma cell leukemia-like transcriptional profile and as a myeloma dependency. Moreover, ROCK2 mediates expression of Interferon regulatory factor 4 (IRF4) and c-MYC, as well as Th17 responses that may contribute to an immune suppressive microenvironment. Methods: To examine the central hypothesis that targeting ROCK1/2 could be a novel and effective approach to myeloma therapy, we performed pre-clinical studies with the ROCK1/2 inhibitor belumosudil mesylate using drug-naïve and drug-resistant myeloma cell lines in vitro. Also, in vivo studies with immune correlates were performed in the Vk*MYC immune-competent syngeneic myeloma model, which has been reported to have a 67% positive predictive value for clinical efficacy in humans. Results: Belumosudil mesylate as a single agent reduced the viability of a panel of myeloma cell lines representing different molecular subtypes in a time- and concentration-dependent manner, with median inhibitory concentrations from 618 to 1,114 nM at 72 hours. These represent clinically relevant concentrations as the mean steady state C max for belumosudil mesylate given with food in studies of chronic graft-versus-host disease patients was 4.36 mM. Staining of myeloma cells with Annexin V and propidium iodide (PI) demonstrated that belumosudil induced appearance first of Annexin +/PI - (early apoptotic) cells, followed later by Annexin +/PI + (late apoptotic) and Annexin -/PI + (necrotic) cells, in a concentration-dependent manner. Studies of myeloma resistance mechanisms showed belumosudil largely overcame adhesion-mediated drug resistance, and was active against MM.1S and RPMI 8226 cells that are considered daratumumab-resistant. Moreover, belumosudil showed equal or even, in some cases, higher potency against bortezomib-, carfilzomib-, dexamethasone-, iberdomide-, lenalidomide-, melphalan-, and mezigdomide-resistant cell lines compared to their drug-naïve counterparts. Belumosudil induced in vitro killing of myeloma cells in a time- and dose-dependent manner independent of the presence of natural killer (NK) cells. Notably, when used in combination with the CD38 mAb isatuximab and in the presence of NK cells, belumosudil enhanced myeloma cell killing and prevented isatuximab-induced loss of CD38 expression. Mechanistically, belumosudil induced a reduction in c-MYC, IRF4, and phospho-STAT3 levels, consistent with its action on the IRF4/c-MYC axis. Dosing of belumosudil in vivo at 50 mg/kg twice weekly for three weeks in Vk*MYC mice with paraprotein levels consistent with active myeloma produced a consistent decline in disease burden as determined by serum protein electrophoresis monitoring ( A) compared to vehicle controls. NanoString analysis of tumor samples from these mice ( B) found down-regulation of XBP1 (X-box binding protein 1) and SLAMF7 (Signaling lymphocytic activation molecule family member 7), consistent with the anti-tumor efficacy of belumosudil mesylate. In addition, up-regulation was seen of c- JUN and c- FOS, consistent with promotion of T-cell activation and clonal expansion, as well as effector differentiation of antigen-activated CD8 + T cells. Conclusions: These pre-clinical in vitro and in vivo data support the hypothesis that targeting of ROCK1 and ROCK2 with belumosudil mesylate may be a promising strategy for relapsed/refractory myeloma and provide a rationale for its translation to the clinic. Currently, clinical trials of belumosudil are planned.

Overexpression of Integrin β7 in Newly Diagnosed Multiple Myeloma with High Risk Cytogenetic Abnormality and Poorer Prognosis

Introduction The second most prevalent malignant blood malignancy is multiple myeloma (MM), but the condition is still incurable. In the interaction between MM cells and the bone marrow microenvironment, adhesion molecules are known to mediate adhesion and promote the survival and proliferation of MM cells. Integrin β7 (ITGB7) is a member of the adhesion molecule family. However, there are few clinical studies on ITGB7 in MM and there is no prognostic analysis. By analyzing the relationship between ITGB7 expression and clinical signs and prognosis, this study thus provides a basis for evaluating the clinical and prognostic importance of ITGB7 expression in MM patients. Methods In 39 patients with newly diagnosed multiple myeloma from 2021.1 to 2022.9, we assessed the expression of ITGB7 in relation to clinical characteristics and prognosis. Flow cytometry was used to detect the median fluorescence of ITGB7, detecting that ITGB7 median fluorescence intensity (MFI) in abnormal plasma cell was significantly higher than that in mature B cells (18.76 vs 5.62, P<0.001). ROC curve defines that ITGB7 best indicator for predicting MM disease is the abnormal plasma cell to mature B cells median fluorescence intensity ratio (MFI P/B), with a cut-off value of 4.025. Results Compared to patients with low expression of ITGB7, patients with high expression of ITGB7 showed a significant increase in mSMART stratification risk (82.60% vs 50.00%, P=0.041), while those with IgH/FGFR3 showed a significant increase (38.9% vs 6.30%, P=0.043). Patients with high expression of ITGB7 had poorer prognostic trends in PFS and OS, (PFS: P=0.071; OS: P=0.070). Conclusion Overexpression of ITGB7 is prone to merging with high risk cytogenetic abnormality and poorer prognosis in newly diagnosed MM patients.

Synthesis of 2'-O-Methyl/2'-O-MOE-L-Nucleoside Derivatives and Their Applications: Preparation of G-Quadruplexes, Their Characterization, and Stability Studies.

Nucleosides and their analogues constitute an important family of molecules with potential antiviral and antiproliferative activity. The enantiomers of natural nucleosides, l-nucleoside derivatives, which have comparable biological activity but more favorable toxicological properties and greater metabolic stability than d-nucleosides, have emerged as a new class of therapeutic agents. Furthermore, l-nucleosides can be used as a building block to prepare l-oligonucleotides, which have identical physical properties in terms of solubility, hybridization kinetics, and duplex thermal stability as d-oligonucleotides but completely orthogonal in nature. Consequently, they are resistant to nuclease degradation, nontoxic, and immunologically passive, which are desirable properties for biomedical applications. Herein, we describe the synthesis of several 2'-O-methyl/2'-O-MOE-l-nucleoside pyrimidine derivatives and their incorporation into G-rich oligonucleotides. Finally, we evaluated the stability and resistance against nucleases of these new G-quadruplexes, demonstrating the potential of the l-nucleosides described in this work in providing enhanced nuclease resistance with a minimal impact in the nucleic acid structural properties.

DDDR-19. FIRST-IN-CLASS CANCER THERAPEUTICS TARGETING THE DNA DAMAGE RESPONSE

Abstract Hemispherian is advancing first-in-class therapeutics for cancers that are historically difficult to treat. Glioblastoma multiforme (GBM) is the primary indication for our lead compound GLIX1, which is currently in late-stage preclinical development. GLIX1 is developed together with a biomarker-based companion diagnostic assay to pair diagnostics and optimal treatment. It is Hemispherian’s mission to provide superior treatment options for brain cancer patients. Hemispherian’s proprietary molecules selectively target the DNA damage response in cancer cells. These molecules take advantage of a pre-existing condition of all cancer cells – nearly all cancer cells have a reduction in levels of the DNA base modification, 5-hydroxymethylcytosine. Hemispherian scientists have found that restoration of this base modification to normal cells activates the DNA damage response resulting in cancer cell death. Targeting of the enzyme responsible for maintaining genomic 5-hydroxymethylcytosine, TET2, led to the discovery of the GLIX family of molecules. Hemispherian’s lead GLIX molecules, GLIX1 and GLIX5, show excellent efficacy in vivo in xenograft models, have a superior safety profile, are orally bioavailable and are blood brain barrier penetrant. GLIX efficacy against a panel of patient-derived cell lines representing a broad spectrum of pediatric and adult brain tumor diagnoses will be discussed. Taken together, these molecules have an exceptional profile for treating a broad range of cancers including cancers of the brain.

Improving the Conductivity of Amide-Based Small Molecules through Enhanced Molecular Packing and Their Application as Hole Transport Mediators in Perovskite Solar Cells.

Organic-inorganic hybrid halide perovskite solar cells (PSCs) have attracted substantial attention from the photovoltaic research community, with the power conversion efficiency (PCE) already exceeding 26%. Current state-of-the-art devices rely on Spiro-OMeTAD as the hole-transporting material (HTM); however, Spiro-OMeTAD is costly due to its complicated synthesis and expensive product purification, while its low conductivity ultimately limits the achievable device efficiency. In this work, we build upon our recently introduced family of low-cost amide-based small molecules and introduce a molecule (termed TPABT) that results in high conductivity values (∼10-5 S cm-1 upon addition of standard ionic additives), outperforming our previous amide-based material (EDOT-Amide-TPA, ∼10-6 S cm-1) while only costing an estimated $5/g. We ascribe the increased optoelectronic properties to favorable molecular packing, as shown by single-crystal X-ray diffraction, which results in close spacing between the triphenylamine blocks. This, in turn, results in a short hole-hopping distance between molecules and therefore good mobility and conductivity. In addition, TPABT exhibits a higher bandgap and is as a result more transparent in the visible range of the solar spectrum, leading to lower parasitic absorption losses than Spiro-OMeTAD, and has increased moisture stability. We applied the molecule in perovskite solar cells and obtained good efficiency values in the ∼15% range. Our approach shows that engineering better molecular packing may be the key to developing high-efficiency, low-cost HTMs for perovskite solar cells.

Role of signaling lymphocytic activation molecule family of receptors in the pathogenesis of rheumatoid arthritis: insights and application.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and joint damage. The signaling lymphocytic activation molecule (SLAMF) family of receptors are expressed on various hematopoietic and non-hematopoietic cells and can regulate both immune cell activation and cytokine production. Altered expression of certain SLAMF receptors contributes to aberrant immune responses in RA. In RA, SLAMF1 is upregulated on T cells and may promote inflammation by participating in immune cell-mediated responses. SLAMF2 and SLAMF4 are involved in regulating monocyte tumor necrosis factor production and promoting inflammation. SLAMF7 activates multiple inflammatory pathways in macrophages to drive inflammatory gene expression. SLAMF8 inhibition can reduce inflammation in RA by blocking ERK/MMPs signaling. Of note, there are differences in SLAMF receptor (SFR) expression between normal and arthritic joint tissues, suggesting a role as potential diagnostic biomarkers. This review summarizes recent advances on the roles of SLAMF receptors 1, 2, 4, 7, and 8 in RA pathogenesis. However, further research is needed to elucidate the mechanisms of SLAMF regulation of immune cells in RA. Understanding interactions between SLAMF receptors and immune cells will help identify selective strategies for targeting SLAMF signaling without compromising normal immunity. Overall, the SLAMF gene family holds promise as a target for precision medicine in RA, but additional investigation of the underlying immunological mechanisms is needed. Targeting SLAMF receptors presents opportunities for new diagnostic and therapeutic approaches to dampen damaging immune-mediated inflammation in RA.

Targeting HDAC9 Contributes to Degradation of MLL Fusion Oncoproteins in KMT2A-Rearranged Acute Myeloid Leukemia

Acute myeloid leukemia with MLL rearrangement (MLLr-AML) is a highly aggressive subtype of AML. Existing treatment strategies are nonspecific and ineffective. The MLL fusion gene is one of the driver oncogenes in leukemia and is central to the pathogenesis of MLLr-AML, and more research has recently begun to focus on targeting MLL fusion proteins. Targeting MLL fusion proteins has been shown to have a tumor suppressor effect, demonstrating efficacy in preclinical models of MLLr-AML, and in 2022 Scott A Armstrong ‘s team suggested that degradation of MLL-AF9 can cause an increase in cell differentiation and apoptosis, confirming the efficacy of targeting MLL fusions. However, specific targets that degrade MLL fusion proteins as well as clinically translatable targeted therapies are still lacking and need to be further explored. Study confirmed that MLL-rearranged ALL cells are highly sensitive to the broad-spectrum HDAC inhibitor panobinostat. A recent clinical study by Mireia Camós’ team proposed that HDAC9 has a significantly high expression in childhood MLL-rearranged B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and AML, but that article did not address any mechanistic studies. The potential value of HDAC9 in adult lymphoid hematologic diseases has been gradually revealed, however, the expression profile and precise molecular mechanisms of HDAC9 in adult myeloid hematologic tumors, have not been reported, which deserves to be further explored. In order to investigate the expression and role of HDAC9 in MLLr-AML, we analyzed the second-generation sequencing data from the Beat AML dataset and found that HDAC9 has a significantly high expression in MLLr-AML, while only HDAC9 is characterized by this feature in HDAC family molecules. Further we analyzed the data of 300 adult AML specimens in our hospital (including 20 MLLr-AML patients), and the results further confirmed that only HDAC9 among the HDAC family had a significantly higher expression level in the MLLr-AML patient group than that in the Non-MLLr-AML patient group (P<0.001), and the high expression of HDAC9 in the MLLr-AML patient group was a common phenomenon and not limited to a particular class of MLL chaperone molecules. Further studies revealed that overexpression of MLL fusion proteins in HEK293T could cause up-regulation of HDAC9 protein levels, and this experiment clarified the direct correlation between the MLL fusion genes and the high expression of HDAC9. The HDAC IIa inhibitor (TMP-269), which can target HDAC9, was significantly more sensitive in MLLr-AML cell lines than in Non-MLLr-AML cell lines, and also that MLLr-AML cell survival was dependent on HDAC9, and that knockdown of HDAC9 induced an increase in apoptosis and a slowdown in proliferation in MLLr-AML cells. We subsequently demonstrated that knockdown of HDAC9 downregulates the expression of MLL fusion proteins through degradation of MLL proteins. Furthermore, when exploring therapeutic options for targeting MLLr-AML, we found that combining the BCL-2 inhibitor Venetoclax (VEN) with an MLL-Menin specific inhibitor (MEN1i) specifically downregulated the expression of HDAC9 and had a favorable synergistic killing effect on MLLr-AML in both in vitro and in vivo models, further suggesting an important role of HDAC9 in the treatment of MLLr-AML. To sum up, through this study, we can shed light on the role of specific HDAC molecules in MLLr-AML and provide a new potential target for the degradation of MLL fusion protein to eradicate MLLr-AML.

A Systematic Immune and Prognostic Analysis of CD48 Interaction with Tumor Microenvironment in Pan-Cancer.

The cluster of differentiation 48 (CD48) is a member of the signaling lymphocyte activation molecule family, constitutively expressed on most hematopoietic cells. CD48 was reported to affect immune regulation in certain tumors, thereby influencing tumor development and prognosis, but its impact on the prognosis and immune infiltration in pan-cancer remains unclear. We systematically analyzed the raw data from The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), and Tumor Immune Dysfunction and Exclusion (TIDE) databases. Initially, we investigated the differences in CD48 expression between pan-cancer and adjacent normal tissues. Then, the correlation analysis of CD48 with tumor mutational burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), and immune-related genes was evaluated. Moreover, bioinformatics tools: ESTIMATE and gene set enrichment analysis (GSEA) were used for tumor immunology analysis in pan-cancer. We performed validation studies including quantitative real-time PCR (qPCR) and Western blotting. Differential analysis revealed that CD48 was significantly altered in pan-cancer as compared with normal tissues. Meanwhile, the survival analysis demonstrated that CD48 strongly correlated with overall survival (OS), disease-free interval (DFI), progression-free interval (PFI), and disease-specific survival (DSS), indicating its crucial role in the tumor patients' prognosis. CD48 expression was also associated with TMB and MSI levels in 17 and 14 types of pan-cancers, respectively. Moreover, CD48 was linked to immune infiltrating cells and stromal components in the TME. Concludingly, patients with pan-cancer may benefit from evaluating CD48 as a prognostic and immunotherapy response biomarker.

Anion optimization for bifunctional surface passivation in perovskite solar cells.

Pseudo-halide (PH) anion engineering has emerged as a surface passivation strategy of interest for perovskite-based optoelectronics; but until now, PH anions have led to insufficient defect passivation and thus to undesired deep impurity states. The size of the chemical space of PH anions (>106 molecules) has so far limited attempts to explore the full family of candidate molecules. We created a machine learning workflow to speed up the discovery process using full-density functional theory calculations for training the model. The physics-informed machine learning model allowed us to pinpoint promising molecules with a head group that prevents lattice distortion and anti-site defect formation, and a tail group optimized for strong attachment to the surface. We identified 15 potential bifunctional PH anions with the ability to passivate both donors and acceptors, and through experimentation, discovered that sodium thioglycolate was the most effective passivant. This strategy resulted in a power-conversion efficiency of 24.56% with a high open-circuit voltage of 1.19 volts (24.04% National Renewable Energy Lab-certified quasi-steady-state) in inverted perovskite solar cells. Encapsulated devices maintained 96% of their initial power-conversion energy during 900 hours of one-sun operation at the maximum power point.

Higher expression of programmed cell death 4 (PDCD4) in acute myeloid leukemia is associated with better prognosis after chemotherapy.

Acute myeloid leukemia (AML) is a common heterogeneous malignancy. Novel molecular markers aid diagnosis, patient sub-categorization, and optimal clinical decisions. Here, we explored the prognostic implications associated with the expression of the programmed cell death (PDCD) family of molecules in AML patients. Based on the findings from the TCGA and OHSU cohorts, we observed that the mRNA abundance of PDCD4 is significantly higher compared to other molecules within the PDCD family. Furthermore, high expression of PDCD4 was associated with predicted long-term patient survival in diagnosed AML patients. In the chemotherapy group, patients with high PDCD4 expression showed a tendency toward longer overall survival (OS) (P = 0.0266) and event-free survival (EFS) (P = 0.0008). High PDCD4 levels served as a favorable independent predictor for both OS and EFS in AML patients. However, subgroup analyses in the hematopoietic stem cell transplantation (HSCT) group revealed no significant difference in OS or EFS between individuals with high and low PDCD4 expression. Furthermore, in the low PDCD4 expression group, AML patients who underwent HSCT experienced improved survival outcomes (P = 0.0015), helping to mitigate the unfavorable prognosis associated with PDCD4 downregulation. Conversely, in the high PDCD4 expression group, HSCT offered a notable short-term survival advantage, while patients with high PDCD4 expression responded favorably to long-term survival through chemotherapy. Biological function enrichment showed that the expression of PDCD4 was correlated with complement and coagulation cascades, cell receptor signaling pathways, and cholesterol metabolism. The findings from this study will aid in better categorizing heterogeneous AML patients and guiding more appropriate clinical decision-making.

Study of Air Pollution by NOx from Petrol Fuels at Four Stations in Dakar–Senegal by Determining Nitrogen Content

NOX emissions are a health hazard, and are increasingly regulated in cars. NOx also contributes to the formation of acid rain and the eutrophication of ecosystems. Nitrogen oxides are a family of molecules including nitrogen monoxide (NO) and nitrogen dioxide (NO2). These gases are formed in the engine during high-temperature fuel combustion, and play a role in the formation of fine particles in ambient air. In this article, the aim is to determine the nitrogen content of gasoline samples taken at four gasoline stations of the most representative groups in terms of distribution of light petroleum products in order to assess the environmental impact due to greenhouse gas emissions resulting from the use of gasoline by vehicles and to reduce the nitrogen content in the form of nitrogen oxides NOx. After an introduction, we presented the material and the method used, followed by the results of our analyses and a discussion of the results obtained before concluding.

Yeast-based heterologous production of the Colletochlorin family of fungal secondary metabolites

Transcriptomic studies have revealed that fungal pathogens of plants activate the expression of numerous biosynthetic gene clusters (BGC) exclusively when in presence of a living host plant. The identification and structural elucidation of the corresponding secondary metabolites remain challenging. The aim was to develop a polycistronic system for heterologous expression of fungal BGCs in Saccharomyces cerevisiae. Here we adapted a polycistronic vector for efficient, seamless and cost-effective cloning of biosynthetic genes using in vivo assembly (also called transformation-assisted recombination) directly in Escherichia coli followed by heterologous expression in S. cerevisiae. Two vectors were generated with different auto-inducible yeast promoters and selection markers. The effectiveness of these vectors was validated with fluorescent proteins. As a proof-of-principle, we applied our approach to the Colletochlorin family of molecules. These polyketide secondary metabolites were known from the phytopathogenic fungus Colletotrichum higginsianum but had never been linked to their biosynthetic genes. Considering the requirement for a halogenase, and by applying comparative genomics, we identified a BGC putatively involved in the biosynthesis of Colletochlorins in C. higginsianum. Following the expression of those genes in S. cerevisiae, we could identify the presence of the precursor Orsellinic acid, Colletochlorins and their non-chlorinated counterparts, the Colletorins. In conclusion, the polycistronic vectors described herein were adapted for the host S. cerevisiae and allowed to link the Colletochlorin compound family to their corresponding biosynthetic genes. This system will now enable the production and purification of infection-specific secondary metabolites of fungal phytopathogens. More widely, this system could be applied to any fungal BGC of interest.

Ruthenium-Based Photoactivated Chemotherapy.

Ruthenium(II) polypyridyl complexes form a vast family of molecules characterized by their finely tuned photochemical and photophysical properties. Their ability to undergo excited-state deactivation via photosubstitution reactions makes them quite unique in inorganic photochemistry. As a consequence, they have been used, in general, for building dynamic molecular systems responsive to light but, more particularly, in the field of oncology, as prodrugs for a new cancer treatment modality called photoactivated chemotherapy (PACT). Indeed, the ability of a coordination bond to be selectively broken under visible light irradiation offers fascinating perspectives in oncology: it is possible to make poorly toxic agents in the dark that become activated toward cancer cell killing by simple visible light irradiation of the compound inside a tumor. In this Perspective, we review the most important concepts behind the PACT idea, the relationship between ruthenium compounds used for PACT and those used for a related phototherapeutic approach called photodynamic therapy (PDT), and we discuss important questions about real-life applications of PACT in the clinic. We conclude this Perspective with important challenges in the field and an outlook.

A novel method for the extraction and characterization of metabolites from Basidiomycota: Pleurotus ostreatus (Jacq.) P. Kumm., 1871 as a case study

AbstractIn recent years, the interest in the exploitation of fungal metabolites has grown considerably, given their application in numerous sectors involving human health. However, their identification and characterization by conventional analytical approaches is generally limited to single families of molecules per method of analysis. This constitutes a limiting factor of primary importance in the study of both the metabolic pattern of a single fungal sample and the discovery of its possible applications. In this work, a reverse‐phase high‐performance liquid chromatography coupled with mass spectrometry method for the profile determination of primary and secondary metabolites produced by the oyster‐mushroom Pleurotus ostreatus (Jacq.) P. Kumm., 1871, has been developed. By using a concomitant extraction in three different polarity‐decreasing solvents, namely methanol, ethanol, and acetonitrile, this method allowed the simultaneous analysis of all extracted metabolites belonging to the widest possible range of chemical families, giving an advantage for both qualitative and quantitative determination of known and unknown compounds. The method appears to be valuable and robust for the study of complex matrices like raw fungi extract such as those of Pleurotus ostreatus cultivated on different substrates and/or exposed to multiple stressors.

Cell lipid biology in infections: an overview.

Lipids are a big family of molecules with a vast number of functions in the cell membranes, within the cytoplasm, and extracellularly. Lipid droplets (LDs) are the most common storage organelles and are present in almost every tissue type in the body. They also have structural functions serving as building blocks of cellular membranes and may be precursors of other molecules such as hormones, and lipoproteins, and as messengers in signal transduction. Fatty acids (FAs), such as sterol esters and triacylglycerols, are stored in LDs and are used in β-oxidation as fuel for tricarboxylic acid cycle (TCA) and adenosine triphosphate (ATP) generation. FA uptake and entrance in the cytoplasm are mediated by membrane receptors. After a cytoplasmic round of α- and β-oxidation, FAs are guided into the mitochondrial matrix by the L-carnitine shuttle system, where they are fully metabolized, and enter the TCA cycle. Pathogen infections may lead to impaired lipid metabolism, usage of membrane phospholipids, and LD accumulation in the cytoplasm of infected cells. Otherwise, bacterial pathogens may use lipid metabolism as a carbon source, thus altering the reactions and leading to cellular and organelles malfunctioning. This review aims to describe cellular lipid metabolism and alterations that occur upon infections.

Peptide derived from SLAMF1 prevents TLR4-mediated inflammation in vitro and in vivo.

Inflammation plays a crucial role in the development and progression of many diseases, and is often caused by dysregulation of signalling from pattern recognition receptors, such as TLRs. Inhibition of key protein-protein interactions is an attractive target for treating inflammation. Recently, we demonstrated that the signalling lymphocyte activation molecule family 1 (SLAMF1) positively regulates signalling downstream of TLR4 and identified the interaction interface between SLAMF1 and the TLR4 adaptor protein TRIF-related adapter molecule (TRAM). Based on these findings, we developed a SLAMF1-derived peptide, P7, which is linked to a cell-penetrating peptide for intracellular delivery. We found that P7 peptide inhibits the expression and secretion of IFNβ and pro-inflammatory cytokines (TNF, IL-1β, IL-6) induced by TLR4, and prevents death in mice subjected to LPS shock. The mechanism of action of P7 peptide is based on interference with several intracellular protein-protein interactions, including TRAM-SLAMF1, TRAM-Rab11FIP2, and TIRAP-MyD88 interactions. Overall, P7 peptide has a unique mode of action and demonstrates high efficacy in inhibiting TLR4-mediated signalling in vitro and in vivo.