Recent Submissions

  • Bone-Marrow-Derived Mesenchymal Stem Cells, Their Conditioned Media, Protect against Cyclophosphamide-Induced Infertility in Rats

    Ibrabim, Dalia; Abozied, Nadia; Maboud, Samar Abdel; Alzamami, Ahmad; Alturki, Norah; Jaremko, Mariusz; Alanazi, Maram Khalil; Seddek, Asmaa (Frontiers in Pharmacology, Frontiers Media, 2023-03-22) [Article]
    Cancer is a deadly disease characterized by abnormal cell proliferation. Chemotherapy is one tech-nique of cancer treatment. Cyclophosphamide (CYP) is the most powerful chemotherapy medication, yet it has serious adverse effects. It is an antimitotic medicine that regulates cell proliferation and primarily targets quickly dividing cells, and it has been related to varying levels of infertility in hu-mans. In the current study, we assessed the biochemical, histological, and microscopic evaluations of testicular damage following CYP administration. Further, we have explored the potential protective impact of mesenchymal stem cell (MSCs) transplantation. The biochemical results revealed that ad-ministration of CYP increased serum concentrations of follicle-stimulating hormone (FSH) and lu-teinizing hormone (LH), while it decreased serum concentrations of free testosterone hormone (TH), testicular FSH, LH, and free TH concentrations, testicular total antioxidant capacity (TAC), and testicular activity of superoxide dismutase (SOD) enzyme. The histology and sperm examinations revealed that CYP induced destruction to the architectures of several tissues in the testes, which drastically reduced the Johnsen score as well as the spermatogenesis process. Surprisingly, trans-plantation of MSCs after CYP administration altered the deterioration effect of CYP injury on the testicular tissues, as demonstrated by biochemical and histological analysis. Our results indicated alleviation of serum and testicular sex hormones, as well as testicular oxidative stress markers (TAC and SOD activity), and nearly restored the normal appearance of the testicular tissues, Johnsen score, and spermatogenesis process. In conclusion, our work emphasizes the protective pharmacological use of MSCs to mitigate the effects of CYP on testicular tissues that impair the spermatogenesis process following chemotherapy. These findings indicate that transferring MSCs to chemotherapy patients could significantly improve spermatogenesis
  • Tuning anticancer properties and DNA-binding of Pt(ii) complexes via alteration of nitrogen softness/basicity of tridentate ligands

    Al-Rashdi, Kamelah S.; Babgi, Bandar A.; Ali, Ehab M. M.; Jedidi, Abdesslem; Emwas, Abdul-Hamid M.; Davaasuren, Bambar; Jaremko, Mariusz; Humphrey, Mark G. (RSC Advances, Royal Society of Chemistry (RSC), 2023-03-21) [Article]
    Nine tridentate Schiff base ligands of the type (N^N^O) were synthesized from reactions of primary amines {2-picolylamine (Py), N-phenyl-1,2-diaminobenzene (PhN), and N-phenyl-1,2-diaminoethane(EtN)} and salicylaldehyde derivatives {3-ethoxy (OEt), 4-diethylamine (NEt2) and 4-hydroxy (OH)}. Complexes with the general formula Pt(N^N^O)Cl were synthesized by reacting K2PtCl4 with the ligands in DMSO/ethanol mixtures. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. The DNA-binding behaviours of the platinum(II) complexes were investigated by two techniques, indicating good binding affinities and a two-stage binding process for seven complexes: intercalation followed by switching to a covalent binding mode over time. The other two complexes covalently bond to ct-DNA without intercalation. Theoretical calculations were used to shed light on the electronic and steric factors that lead to the difference in DNA-binding behavior. The reactions of some platinum complexes with guanine were investigated experimentally and theoretically. The binding of the complexes with bovine serum albumin (BSA) indicated a static interaction with higher binding affinities for the ethoxy-containing complexes. The half maximal inhibitory concentration (IC50) values against MCF-7 and HepG2 cell lines suggest that platinum complexes with tridentate ligands of N-phenyl-o-phenylenediamine or pyridyl with 3-ethoxysalicylimine are good chemotherapeutic candidates. Pt-Py-OEt and Pt-PhN-OEt have IC50 values against MCF-7 of 13.27 and 10.97 μM, respectively, compared to 18.36 μM for cisplatin, while they have IC50 values against HepG2 of 6.99 and 10.15 μM, respectively, compared to 19.73 μM for cisplatin. The cell cycle interference behaviour with HepG2 of selected complexes is similar to that of cisplatin, suggesting apoptotic cell death. The current work highlights the impact of the tridentate ligand on the biological properties of platinum complexes.
  • 3D-Printed disposable nozzles for cost-efficient extrusion-based 3D bioprinting

    Albalawi, Hamed I.; Khan, Zainab N.; H. Rawas, Ranim; U. Valle-Pérez, Alexander; Abdelrahman, Sherin; Hauser, Charlotte (Materials Science in Additive Manufacturing, AccScience Publishing, 2023-03-21) [Article]
    3D bioprinting has significantly impacted tissue engineering with its capability to create intricate structures with complex geometries that were difficult to replicate through traditional manufacturing techniques. Extrusion-based 3D bioprinting methods tend to be limited when creating complex structures using bioinks of low viscosity. However, the capacity for creating multi-material structures that have distinct properties could be unlocked through the mixture of two solutions before extrusion. This could be used to generate architectures with varying levels of stiffness and hydrophobicity, which could be utilized for regenerative medicine applications. Moreover, it allows for combining proteins and other biological materials in a single 3D-bioprinted structure. This paper presents a standardized fabrication method of disposable nozzle connectors (DNC) for 3D bioprinting with hydrogel-based materials. This method entails 3D printing connectors with dual inlets and a single outlet to mix the material internally. The connectors are compatible with conventional Luer lock needles, offering an efficient solution for nozzle replacement. IVZK (Ac-Ile-Val-Cha-Lys-NH2) peptide-based hydrogel materials were used as a bioink with the 3D-printed DNCs. Extrusion-based 3D bioprinting was employed to print shapes of varying complexities, demonstrating potential in achieving high print resolution, shape fidelity, and biocompatibility. Post-printing of human neonatal dermal fibroblasts, cell viability, proliferation, and metabolic activity were observed, which demonstrated the effectiveness of the proposed design and process for 3D bioprinting using low-viscosity bioinks.
  • Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma.

    Larrayoz, Marta; Garcia-Barchino, Maria J; Celay, Jon; Etxebeste, Amaia; Jimenez, Maddalen; Perez, Cristina; Ordoñez, Raquel; Cobaleda, Cesar; Botta, Cirino; Fresquet, Vicente; Roa, Sergio; Goicoechea, Ibai; Maia, Catarina; Lasaga, Miren; Chesi, Marta; Bergsagel, P Leif; Larrayoz, Maria J; Calasanz, Maria J; Campos-Sanchez, Elena; Martinez-Cano, Jorge; Panizo, Carlos; Rodriguez-Otero, Paula; Vicent, Silvestre; Roncador, Giovanna; Gonzalez, Patricia; Takahashi, Satoru; Katz, Samuel G; Walensky, Loren D; Ruppert, Shannon M; Lasater, Elisabeth A; Amann, Maria; Lozano, Teresa; Llopiz, Diana; Sarobe, Pablo; Lasarte, Juan J; Planell, Nuria; Gomez-Cabrero, David; Kudryashova, Olga; Kurilovich, Anna; Revuelta, Maria V; Cerchietti, Leandro; Agirre, Xabier; San Miguel, Jesus; Paiva, Bruno; Prosper, Felipe; Martinez-Climent, Jose A (Nature medicine, Springer Science and Business Media LLC, 2023-03-16) [Article]
    The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK–MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.
  • Efficient in planta production of amidated antimicrobial peptides that are active against drug-resistant ESKAPE pathogens

    Chaudhary, Shahid; Ali, Zahir; Tehseen, Muhammad; Haney, Evan F.; Pantoja Angles, Aarón; Alshehri, Salwa; Wang, Tiannyu; Clancy, Gerard Jude; Ayach, Maya; Hauser, Charlotte; Hong, Pei-Ying; Hamdan, Samir; Hancock, Robert E. W.; Mahfouz, Magdy M. (Nature Communications, Springer Science and Business Media LLC, 2023-03-16) [Article]
    Antimicrobial peptides (AMPs) are promising next-generation antibiotics that can be used to combat drug-resistant pathogens. However, the high cost involved in AMP synthesis and their short plasma half-life render their clinical translation a challenge. To address these shortcomings, we report efficient production of bioactive amidated AMPs by transient expression of glycine-extended AMPs in Nicotiana benthamiana line expressing the mammalian enzyme peptidylglycine α-amidating mono-oxygenase (PAM). Cationic AMPs accumulate to substantial levels in PAM transgenic plants compare to nontransgenic N. benthamiana. Moreover, AMPs purified from plants exhibit robust killing activity against six highly virulent and antibiotic resistant ESKAPE pathogens, prevent their biofilm formation, analogous to their synthetic counterparts and synergize with antibiotics. We also perform a base case techno-economic analysis of our platform, demonstrating the potential economic advantages and scalability for industrial use. Taken together, our experimental data and techno-economic analysis demonstrate the potential use of plant chassis for large-scale production of clinical-grade AMPs.
  • The Influence of Prenatal Exposure to Methamphetamine on the Development of Dopaminergic Neurons in the Ventral Midbrain

    Alsanie, Walaa F.; Abdelrahman, Sherin; Felimban, Raed I.; Alkhatabi, Heba A.; Gaber, Ahmed; Alosimi, Ebtisam Abdulah; Alhomrani, Majid; Habeeballah, Hamza; Hauser, Charlotte; Alamri, Abdulhakeem S.; Althobaiti, Aiysha; Alsharif, Abdulaziz; Alzahrani, Ahmed S.; Al-Ghamdi, Mohammad S.; Raafat, Bassem M.; Alswat, Khaled A.; Althobaiti, Yusuf S.; Asiri, Yousif A. (International Journal of Molecular Sciences, MDPI AG, 2023-03-16) [Article]
    Methamphetamine, a highly addictive central nervous system (CNS) stimulant, is used worldwide as an anorexiant and attention enhancer. Methamphetamine use during pregnancy, even at therapeutic doses, may harm fetal development. Here, we examined whether exposure to methamphetamine affects the morphogenesis and diversity of ventral midbrain dopaminergic neurons (VMDNs). The effects of methamphetamine on morphogenesis, viability, the release of mediator chemicals (such as ATP), and the expression of genes involved in neurogenesis were evaluated using VMDNs isolated from the embryos of timed-mated mice on embryonic day 12.5. We demonstrated that methamphetamine (10 µM; equivalent to its therapeutic dose) did not affect the viability and morphogenesis of VMDNs, but it reduced the ATP release negligibly. It significantly downregulated Lmx1a, En1, Pitx3, Th, Chl1, Dat, and Drd1 but did not affect Nurr1 or Bdnf expression. Our results illustrate that methamphetamine could impair VMDN differentiation by altering the expression of important neurogenesis-related genes. Overall, this study suggests that methamphetamine use may impair VMDNs in the fetus if taken during pregnancy. Therefore, it is essential to exercise strict caution for its use in expectant mothers.
  • Molecular insights into the Darwin paradox of coral reefs from the sea anemone Aiptasia

    Cui, Guoxin; Konciute, Migle; Ling, Lorraine; Esau, Luke; Raina, Jean-Baptiste; Han, Baoda; Salazar Moya, Octavio Ruben; Presnell, Jason S.; Rädecker, Nils; Zhong, Huawen; Menzies, Jessica; Cleves, Phillip A.; Liew, Yi Jin; Krediet, Cory J.; Sawiccy, Val; Cziesielski, Maha Joana; Guagliardo, Paul; Bougoure, Jeremy; Pernice, Mathieu; Hirt, Heribert; Voolstra, Christian R.; Weis, Virginia M.; Pringle, John R.; Aranda, Manuel (Science Advances, American Association for the Advancement of Science (AAAS), 2023-03-15) [Article]
    Symbiotic cnidarians such as corals and anemones form highly productive and biodiverse coral reef ecosystems in nutrient-poor ocean environments, a phenomenon known as Darwin’s paradox. Resolving this paradox requires elucidating the molecular bases of efficient nutrient distribution and recycling in the cnidarian-dinoflagellate symbiosis. Using the sea anemone Aiptasia, we show that during symbiosis, the increased availability of glucose and the presence of the algae jointly induce the coordinated up-regulation and relocalization of glucose and ammonium transporters. These molecular responses are critical to support symbiont functioning and organism-wide nitrogen assimilation through glutamine synthetase/glutamate synthase–mediated amino acid biosynthesis. Our results reveal crucial aspects of the molecular mechanisms underlying nitrogen conservation and recycling in these organisms that allow them to thrive in the nitrogen-poor ocean environments.
  • LEP-AD: Language Embedding of Proteins and Attention to Drugs predicts drug target interactions

    Daga, Anuj; Khan, Sumeer Ahmad; Gomez-Cabrero, David; Hoehndorf, Robert; Kiani, Narsis A.; Tegner, Jesper (Cold Spring Harbor Laboratory, 2023-03-15) [Preprint]
    Predicting drug-target interactions is a tremendous challenge for drug development and lead optimization. Recent advances include training algorithms to learn drug-target interactions from data and molecular simulations. Here we utilize Evolutionary Scale Modeling (ESM-2) models to establish a Transformer protein language model for drug-target interaction predictions. Our architecture, LEP- AD, combines pre-trained ESM-2 and Transformer-GCN models predicting bind-ing affinity values. We report new best-in-class state-of-the-art results compared to competing methods such as SimBoost, DeepCPI, Attention-DTA, GraphDTA, and more using multiple datasets, including Davis, KIBA, DTC, Metz, ToxCast, and STITCH. Finally, we find that a pre-trained model with embedding of proteins (the LED-AD) outperforms a model using an explicit alpha-fold 3D representation of proteins (e.g., LEP-AD supervised by Alphafold). The LEP-AD model scales favorably in performance with the size of training data.
  • Palidis: fast discovery of novel insertion sequences.

    Carr, Victoria R; Pissis, Solon P; Mullany, Peter; Shoaie, Saeed; Gomez-Cabrero, David; Moyes, David L (Microbial genomics, Cold Spring Harbor Laboratory, 2023-03-10) [Article]
    The diversity of microbial insertion sequences, crucial mobile genetic elements in generating diversity in microbial genomes, needs to be better represented in current microbial databases. Identification of these sequences in microbiome communities presents some significant problems that have led to their underrepresentation. Here, we present a bioinformatics pipeline called Palidis that recognizes insertion sequences in metagenomic sequence data rapidly by identifying inverted terminal repeat regions from mixed microbial community genomes. Applying Palidis to 264 human metagenomes identifies 879 unique insertion sequences, with 519 being novel and not previously characterized. Querying this catalogue against a large database of isolate genomes reveals evidence of horizontal gene transfer events across bacterial classes. We will continue to apply this tool more widely, building the Insertion Sequence Catalogue, a valuable resource for researchers wishing to query their microbial genomes for insertion sequences.
  • In vitro and in silico evaluations of actinomycin X2and actinomycin D as potent anti-tuberculosis agents

    Qureshi, Kamal Ahmad; Azam, Faizul; Fatmi, Muhammad Qaiser; Imtiaz, Mahrukh; Prajapati, Dinesh Kumar; Rai, Pankaj Kumar; Jaremko, Mariusz; Emwas, Abdul-Hamid M.; Elhassan, Gamal Osman (PeerJ, PeerJ, 2023-03-08) [Article]
    Background: Multidrug-resistant tuberculosis (MDR-TB) is one of the world’s most devastating contagious diseases and is caused by the MDR-Mycobacterium tuberculosis (MDR-Mtb) bacteria. It is therefore essential to identify novel anti-TB drug candidates and target proteins to treat MDR-TB. Here, in vitro and in silico studies were used to investigate the anti-TB potential of two newly sourced actinomycins, actinomycin-X2 (act-X2) and actinomycin-D (act-D), from the Streptomyces smyrnaeus strain UKAQ_23 (isolated from the Jubail industrial city of Saudi Arabia). Methods: The anti-TB activity of the isolated actinomycins was assessed in vitro using the Mtb H37Ra, Mycobacterium bovis (BCG), and Mtb H37Rv bacterial strains, using the Microplate Alamar Blue Assay (MABA) method. In silico molecular docking studies were conducted using sixteen anti-TB drug target proteins using the AutoDock Vina 1.1.2 tool. The molecular dynamics (MD) simulations for both actinomycins were then performed with the most suitable target proteins, using the GROningen MAchine For Chemical Simulations (GROMACS) simulation software (GROMACS 2020.4), with the Chemistry at HARvard Macromolecular Mechanics 36m (CHARMM36m) forcefield for proteins and the CHARMM General Force Field (CGenFF) for ligands. Results: In vitro results for the Mtb H37Ra, BCG, and Mtb H37Rv strains showed that act-X2 had minimum inhibitory concentration (MIC) values of 1.56 ± 0.0, 1.56 ± 0.0, and 2.64 ± 0.07 µg/mL and act-D had MIC values of 1.56 ± 0.0, 1.56 ± 0.0, and 1.80 ± 0.24 µg/mL respectively. The in silico molecular docking results showed that protein kinase PknB was the preferred target for both actinomycins, while KasA and pantothenate synthetase were the least preferred targets for act-X2and act-D respectively. The molecular dynamics (MD) results demonstrated that act-X2 and act-D remained stable inside the binding region of PknB throughout the simulation period. The MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) binding energy calculations showed that act-X2 was more potent than act-D. Conclusion: In conclusion, our results suggest that both actinomycins X2 and D are highly potent anti-TB drug candidates. We show that act-X2is better able to antagonistically interact with the protein kinase PknB target than act-D, and thus has more potential as a new anti-TB drug candidate.
  • Salts as Additives: A Route to Improve Performance and Stability of n-Type Organic Electrochemical Transistors

    Ohayon, David; Flagg, Lucas Q.; Giugni, Andrea; Wustoni, Shofarul; Li, Ruipeng; Hidalgo, Tania C.; Emwas, Abdul-Hamid M.; Sheelamanthula, Rajendar; McCulloch, Iain; Richter, Lee J.; Inal, Sahika (ACS Materials Au, American Chemical Society (ACS), 2023-03-06) [Article]
    Organic electrochemical transistors (OECTs) are becoming increasingly ubiquitous in various applications at the interface with biological systems. However, their widespread use is hampered by the scarcity of electron-conducting (n-type) backbones and the poor performance and stability of the existing n-OECTs. Here, we introduce organic salts as a solution additive to improve the transduction capability, shelf life, and operational stability of n-OECTs. We demonstrate that the salt-cast devices present a 10-fold increase in transconductance and achieve at least one year-long stability, while the pristine devices degrade within four months of storage. The salt-added films show improved backbone planarity and greater charge delocalization, leading to higher electronic charge carrier mobility. These films show a distinctly porous morphology where the interconnectivity is affected by the salt type, responsible for OECT speed. The salt-based films display limited changes in morphology and show lower water uptake upon electrochemical doping, a possible reason for the improved device cycling stability. Our work provides a new and easy route to improve n-type OECT performance and stability, which can be adapted for other electrochemical devices with n-type films operating at the aqueous electrolyte interface.
  • Intelligent and smart biomaterials for sustainable 3D printing applications

    de León, Elena Herrera Ponce; Valle Pérez, Alexander Uriel; Khan, Zainab N.; Hauser, Charlotte (Current Opinion in Biomedical Engineering, Elsevier BV, 2023-03-04) [Article]
    Smart and intelligent biomaterials can be designed to carry out special tasks in modern medicine and sustainability, and engineered to identify and respond to environmental stimuli. Therefore, intelligent biomaterials have a large number of applications that can go from health (e.g. tissue engineering, drug delivery and biosensors), to more recently explored environmental applications involving ecosystem restoration (e.g. coral reefs and environmental remediation). The use of 3D printing technology opens the vision towards automated biomanufacturing with more precision and definition. With this broad range of applications, smart and intelligent biomaterials are used separately or in combination with 3D printing to enable the design of eco-friendly and sustainable solutions that can be used to overcome challenges for both; modern medicine and the environment.
  • Ideas and perspectives. The fluctuating nature of oxygen shapes the ecology of aquatic habitats and their biogeochemical cycles: the aquatic oxyscape

    Fusi, Marco; Rigaud, Sylvain; Guadagnini, Giovanna; Barausse, Alberto; Marasco, Ramona; Daffonchio, Daniele; Régis, Julie; Huchet, Louison; Camin, Capucine; Pettit, Laura; Vina-Herbon, Cristina; Giomi, Folco (Copernicus GmbH, 2023-03-03) [Preprint]
    Oxygen availability is a pivotal factor for ecosystem functioning and the resistance of organisms to the effect of climate change in aquatic habitats. Although extensive work has been made to assess the effect of oxygen on marine and freshwater biota, many studies did not capture the ecological importance of oxygen variations. Overlooking the fluctuating nature of oxygen may cause potential biases in the design and implementation of management policies of aquatic habitats. Conceptual perspectives on the dynamic nature of oxygen fluctuations have been raised in the scientific community to enhance the understanding of the effect of oxygen on the physiology and the ecology of aquatic species and the biogeochemical functioning of the ecosystems. A growing number of empirical works are outlining a novel conceptual framework that considers the magnitude of oxygen fluctuation as a key variable that explains adaptation to stress conditions. Oxygen in productive aquatic habitats shows large fluctuations at diel and seasonal scales, exposing aquatic species from conditions of extreme supersaturation to anoxia. Recent research indicates that such fluctuation tunes the physiological plasticity of the animal in response to thermal stresses. In this contribution, we provide compelling evidence based on current research that the fluctuating oxygen landscape, here defined as “oxyscape”, has an important role in aquatic animal physiology and adaptation and the ecosystem biogeochemistry. We propose that the oxyscape should be considered in the modelling and managing policies of aquatic ecosystems.
  • Computational network analysis of host genetic risk variants of severe COVID-19.

    Alsaedi, Sakhaa B; Mineta, Katsuhiko; Gao, Xin; Gojobori, Takashi (Human genomics, Springer Science and Business Media LLC, 2023-03-02) [Article]
    Background: Genome-wide association studies have identified numerous human host genetic risk variants that play a substantial role in the host immune response to SARS-CoV-2. Although these genetic risk variants significantly increase the severity of COVID-19, their influence on body systems is poorly understood. Therefore, we aim to interpret the biological mechanisms and pathways associated with the genetic risk factors and immune responses in severe COVID-19. We perform a deep analysis of previously identified risk variants and infer the hidden interactions between their molecular networks through disease mapping and the similarity of the molecular functions between constructed networks. Results: We designed a four-stage computational workflow for systematic genetic analysis of the risk variants. We integrated the molecular profiles of the risk factors with associated diseases, then constructed protein–protein interaction networks. We identified 24 protein–protein interaction networks with 939 interactions derived from 109 filtered risk variants in 60 risk genes and 56 proteins. The majority of molecular functions, interactions and pathways are involved in immune responses; several interactions and pathways are related to the metabolic and cardiovascular systems, which could lead to multi-organ complications and dysfunction. Conclusions: This study highlights the importance of analyzing molecular interactions and pathways to understand the heterogeneous susceptibility of the host immune response to SARS-CoV-2. We propose new insights into pathogenicity analysis of infections by including genetic risk information as essential factors to predict future complications during and after infection. This approach may assist more precise clinical decisions and accurate treatment plans to reduce COVID-19 complications.
  • A thermophilic chemolithoautotrophic bacterial consortium suggests a mutual relationship between bacteria in extreme oligotrophic environments

    Pinheiro, Yuri; Faria da Mota, Fabio; Peixoto, Raquel S; van Elsas, Jan Dirk; Lins, Ulysses; Rodrigues, Jorge L. Mazza; Rosado, Alexandre S. (Communications Biology, Springer Science and Business Media LLC, 2023-03-01) [Article]
    A thermophilic, chemolithoautotrophic, and aerobic microbial consortium (termed carbonitroflex) growing in a nutrient-poor medium and an atmosphere containing N2, O2, CO2, and CO is investigated as a model to expand our understanding of extreme biological systems. Here we show that the consortium is dominated by Carbonactinospora thermoautotrophica (strain StC), followed by Sphaerobacter thermophilus, Chelatococcus spp., and Geobacillus spp. Metagenomic analysis of the consortium reveals a mutual relationship among bacteria, with C. thermoautotrophica StC exhibiting carboxydotrophy and carbon-dioxide storage capacity. C. thermoautotrophica StC, Chelatococcus spp., and S. thermophilus harbor genes encoding CO dehydrogenase and formate oxidase. No pure cultures were obtained under the original growth conditions, indicating that a tightly regulated interactive metabolism might be required for group survival and growth in this extreme oligotrophic system. The breadwinner hypothesis is proposed to explain the metabolic flux model and highlight the vital role of C. thermoautotrophica StC (the sole keystone species and primary carbon producer) in the survival of all consortium members. Our data may contribute to the investigation of complex interactions in extreme environments, exemplifying the interconnections and dependency within microbial communities.
  • Genetic Variants in Protein Tyrosine Phosphatase Non-Receptor Type 23 Are Responsible for Mesiodens Formation

    Adisornkanj, Ploy; Chanprasit, Rajit; Eliason, Steven; Fons, Juan M.; Intachai, Worrachet; Tongsima, Sissades; Olsen, Bjorn; Arold, Stefan T.; Ngamphiw, Chumpol; Amendt, Brad A.; Tucker, Abigail S.; Kantaputra, Piranit (Biology, MDPI AG, 2023-03-01) [Article]
    A mesiodens is a supernumerary tooth located in the midline of the premaxilla. In order to investigate the genetic etiology of mesiodens, clinical and radiographic examination and whole exome sequencing (WES) were performed in 24 family members of a two-generation Hmong family and additionally in two unrelated Thai patients with mesiodens. WES in the Hmong family revealed a missense mutation (c.1807G>A;p.Glu603Lys) in PTPN23 in seven affected members and six unaffected members. The mode of inheritance was autosomal dominance with incomplete penetrance (53.84%). Two additional mutations in PTPN23, c.2248C>G;p.Pro750Ala and c.3298C>T;p.Arg1100Cys were identified in two unrelated patients with mesiodens. PTPN23 is a regulator of endosomal trafficking functioning to move activated membrane receptors, such as EGFR, from the endosomal sorting complex towards the ESCRT-III complex for multivesicular body biogenesis, lysosomal degradation, and subsequent downregulation of receptor signaling. Immunohistochemical study and RNAscope on developing mouse embryos showed broad expression of PTPN23 in oral tissues, while immunofluorescence showed that EGFR was specifically concentrated in the midline epithelium. Importantly, PTPN23 mutant protein was shown to have reduced phosphatase activity. In conclusion, mesiodens were associated with genetic variants in PTPN23, suggesting that mesiodens may form due to defects in endosomal trafficking, leading to disrupted midline signaling.
  • Medicinal chemistry perspective of pyrido[2,3-d]pyrimidines as anticancer agents

    Kumar, Adarsh; Bhagat, Kuber Kumar; Singh, Ankit Kumar; Singh, Harshwardhan; Angre, Tanuja; Verma, Amita; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid M.; Kumar, Pradeep (RSC advances, Royal Society of Chemistry (RSC), 2023-02-28) [Article]
    Cancer is a major cause of deaths across the globe due to chemoresistance and lack of selective chemotherapy. Pyrido[2,3-d]pyrimidine is an emerging scaffold in medicinal chemistry having a broad spectrum of activities, including antitumor, antibacterial, CNS depressive, anticonvulsant, and antipyretic activities. In this study, we have covered different cancer targets, including tyrosine kinase, extracellular regulated protein kinases – ABL kinase, phosphatidylinositol-3 kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinases, BCR-ABL, dihydrofolate reductase, cyclin-dependent kinase, phosphodiesterase, KRAS and fibroblast growth factor receptors, their signaling pathways, mechanism of action and structure–activity relationship of pyrido[2,3-d]pyrimidine derivatives as inhibitors of the above-mentioned targets. This review will represent the complete medicinal and pharmacological profile of pyrido[2,3-d]pyrimidines as anticancer agents, and will help scientists to design new selective, effective and safe anticancer agents.
  • Does zaxinone counteract strigolactones in shaping rice architecture?

    Wang, Jian You; Braguy, Justine; Al-Babili, Salim (Plant signaling & behavior, 2023-02-28) [Article]
    The cleavage of plant carotenoids leads to apocarotenoids, a group of metabolites including precursors of the hormones strigolactones (SLs) and abscisic acid, regulatory and signaling molecules. Zaxinone is a recently discovered apocarotenoid growth regulator that improves growth and suppress SL biosynthesis in rice (Oryza sativa). To test if zaxinone also counteracts the growth regulatory effects of SLs in rice, we co-supplied zaxinone and the synthetic SL analog rac-GR24 to the rice SL-deficient DWARF17 (d17) mutant. Results showed that co-application of GR24 and zaxinone still rescued d17 phenotype, indicating that zaxinone and GR24 act independently in regulating root and shoot growth and development in rice.
  • Mycobiome structure does not affect field litter decomposition in Eucalyptus and Acacia plantations

    Rachid, Caio T C C; Balieiro, Fabiano C; Peixoto, Raquel S; Fonseca, Eduardo S; Jesus, Hugo E; Novotny, Etelvino H; Chaer, Guilherme M; Santos, Felipe M; Tiedje, James M; Rosado, Alexandre S. (Frontiers in microbiology, Frontiers Media SA, 2023-02-28) [Article]
    Mixed tree plantations have been studied because of their potential to improve biomass production, ecosystem diversity, and soil quality. One example is a mixture of Eucalyptus and Acacia trees, which is a promising strategy to improve microbial diversity and nutrient cycling in soil. We examined how a mixture of these species may influence the biochemical attributes and fungal community associated with leaf litter, and the effects on litter decomposition. We studied the litter from pure and mixed plantations, evaluating the effects of plant material and incubation site on the mycobiome and decomposition rate using litterbags incubated in situ. Our central hypothesis was litter fungal community would change according to incubation site, and it would interfere in litter decomposition rate. Both the plant material and the incubation locale significantly affected the litter decomposition. The origin of the litter was the main modulator of the mycobiome, with distinct communities from one plant species to another. The community changed with the incubation time but the incubation site did not influence the mycobiome community. Our data showed that litter and soil did not share the main elements of the community. Contrary to our hypothesis, the microbial community structure and diversity lacked any association with the decomposition rate. The differences in the decomposition pattern are explained basically as a function of the exchange of nitrogen compounds between the litter.
  • miR-34c-3p Regulates Protein Kinase A Activity Independent of cAMP by Dicing prkar2b Transcripts in Theileria annulata-Infected Leukocytes

    Haidar, Malak; Tajeri, Shahin; Momeux, Laurence; Mourier, Tobias; Ben Rached, Fathia; Mfarrej, Sara; Rchiad, ‍Zineb; Pain, Arnab; Langsley, Gordon (mSphere, American Society for Microbiology, 2023-02-27) [Article]
    MicroRNAs (miRNAs) are small noncoding RNAs that can play critical roles in regulating various cellular processes, including during many parasitic infections. Here, we report a regulatory role for miR-34c-3p in cAMP-independent regulation of host cell protein kinase A (PKA) activity in Theileria annulata-infected bovine leukocytes. We identified prkar2b (cAMP-dependent protein kinase A type II-beta regulatory subunit) as a novel miR-34c-3p target gene and demonstrate how infection-induced upregulation of miR-34c-3p repressed PRKAR2B expression to increase PKA activity. As a result, the disseminating tumorlike phenotype of T. annulata-transformed macrophages is enhanced. Finally, we extend our observations to Plasmodium falciparum-parasitized red blood cells, where infection-induced augmentation in miR-34c-3p levels led to a drop in the amount of prkar2b mRNA and increased PKA activity. Collectively, our findings represent a novel cAMP-independent way of regulating host cell PKA activity in infections by Theileria and Plasmodium parasites.

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