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1.
Stem Cell Reports ; 19(5): 689-709, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38701778

RESUMO

Embryo size, specification, and homeostasis are regulated by a complex gene regulatory and signaling network. Here we used gene expression signatures of Wnt-activated mouse embryonic stem cell (mESC) clones to reverse engineer an mESC regulatory network. We identify NKX1-2 as a novel master regulator of preimplantation embryo development. We find that Nkx1-2 inhibition reduces nascent RNA synthesis, downregulates genes controlling ribosome biogenesis, RNA translation, and transport, and induces severe alteration of nucleolus structure, resulting in the exclusion of RNA polymerase I from nucleoli. In turn, NKX1-2 loss of function leads to chromosome missegregation in the 2- to 4-cell embryo stages, severe decrease in blastomere numbers, alterations of tight junctions (TJs), and impairment of microlumen coarsening. Overall, these changes impair the blastocoel expansion-collapse cycle and embryo cavitation, leading to altered lineage specification and developmental arrest.


Assuntos
Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio , Animais , Camundongos , Desenvolvimento Embrionário/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/genética , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Blastocisto/metabolismo , Blastocisto/citologia , Via de Sinalização Wnt , Proteínas Wnt/metabolismo , Junções Íntimas/metabolismo , Nucléolo Celular/metabolismo
2.
Am J Clin Pathol ; 161(1): 60-70, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-37658775

RESUMO

OBJECTIVES: Fluorescence in situ hybridization (FISH) for plasma cell neoplasms (PCNs) requires plasma cell (PC) identification or purification strategies to optimize results. We compared the efficacy of cytoplasmic immunoglobulin FISH (cIg-FISH) and fluorescence-activated cell sorting FISH (FACS-FISH) in a clinical laboratory setting. METHODS: The FISH analysis results of 14,855 samples from individuals with a suspected PCN subjected to cytogenetic evaluation between 2019 and 2022 with cIg-FISH (n = 6917) or FACS-FISH (n = 7938) testing were analyzed. RESULTS: Fluorescence-activated cell sorting-FISH increased the detection rate of abnormalities in comparison with cIg-FISH, with abnormal results documented in 54% vs 50% of cases, respectively (P < .001). It improved the detection of IGH::CCND1 (P < .001), IGH::MAF (P < .001), IGH::MAFB (P < .001), other IGH rearrangements (P < .001), and gains/amplifications of 1q (P < .001), whereas the detection rates of IGH::FGFR3 fusions (P = .3), loss of 17p (P = .3), and other abnormalities, including hyperdiploidy (P = .5), were similar. Insufficient PC yield for FISH analysis was decreased between cIg-FISH and FACS-FISH (22% and 3% respectively, P < .001). Flow cytometry allowed establishment of ploidy status in 91% of cases. In addition, FACS-FISH decreased analysis times, workload efforts, and operating costs. CONCLUSIONS: Fluorescence-activated cell sorting-FISH is an efficient PC purification strategy that affords significant improvement in diagnostic yield and decreases workflow requirements in comparison with cIg-FISH.


Assuntos
Mieloma Múltiplo , Neoplasias de Plasmócitos , Humanos , Plasmócitos , Hibridização in Situ Fluorescente/métodos , Mieloma Múltiplo/diagnóstico , Anticorpos , Aberrações Cromossômicas
3.
ACS Omega ; 8(41): 38288-38300, 2023 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-37867651

RESUMO

Commercial lubricant industries use a complex pipeline network for the sequential processing of thousands of unique products annually. Flushing is conducted between changeovers to ensure the integrity of each production batch. An upcoming product is used for cleaning the residues of the previous batch, resulting in the formation of a commingled/mixed oil that does not match the specifications of either of the two batches. The existing operations are based on the operator's experience and trial and error. After a selected flush time, the samples are tested for their viscosity to determine the success of a flush. The approach results in long downtime, the generation of large commingled oil volumes, and huge economic losses. Hence, to overcome the drawback, our work introduces a solution strategy for systematically optimizing flushing operations and making more informed decisions to improve the resource-management footprint of these industries. We use the American Petroleum Institute-Technical Data Book (API-TDB) blending correlations for calculating the mixture viscosities in real-time. The blending correlations are combined with our first-principles models and validated against well-designed experimental data from the partnered lubricant facility. Next, we formulate an optimal control problem for predicting the optimum flushing times. We solve the problem using two solution techniques viz. Pontryagin's maximum principle and discrete-time nonlinear programming. The results from both approaches are compared with well-designed experimental data, and the economic and environmental significance are discussed. The results illustrate that with the application of a discrete-time nonlinear programming solution approach, the flushing can be conducted at a customized flow rate, and the necessary flushing volume can be reduced to over 30% as compared to the trial-and-error mode of operation.

4.
Materials (Basel) ; 16(15)2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37570172

RESUMO

The discovery and validation of new adjuvants are critical areas for vaccinology. Mineral materials (e.g., alum microparticles) have been used for a long time as adjuvants in human vaccine formulations. Nonetheless, the use of nanosized materials is a promising approach to diversify the properties of adjuvants. Nanoclays are potential adjuvants proposed by some research groups. However, their adjuvant mechanisms and safety have not been fully elucidated. Herein, we aimed at expanding the knowledge on the potential adjuvanticity of layered double hydroxide (LDH) nanoparticles by reporting a detailed method for the synthesis and characterization of LDHs and the adsorption of a model antigen (bovine serum albumin, BSA). LDHs varying in diameter (from 56 to 88 nm) were obtained, and an in vitro evaluation revealed that the LDHs are not inherently toxic. BSA was passively adsorbed onto the LDHs, and the immunogenicity in mice of the conjugates obtained was compared to that of free BSA and BSA co-administered with alum (Alum-BSA). The LDH-BSA conjugates induced a higher humoral response that lasted for a longer period compared with that of free BSA and Alum-BSA, confirming that LDH exerts adjuvant effects. The 56 nm LDH particles were deemed as the more efficient carrier since they induced a higher and more balanced Th1/Th2 response than the 88 nm particles. This study is a contribution toward expanding the characterization and use of nanoclays in vaccinology and justifies further studies with pathogen-specific antigens.

5.
PLoS One ; 18(4): e0277389, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37018180

RESUMO

The southern Central Andes-or Puna-now contains specialized plant communities adapted to life in extreme environments. During the middle Eocene (~40 Ma), the Cordillera at these latitudes was barely uplifted and global climates were much warmer than today. No fossil plant remains have been discovered so far from this age in the Puna region to attest to past scenarios. Yet, we assume that the vegetation cover must have been very different from what it looks today. To test this hypothesis, we study a spore-pollen record from the mid Eocene Casa Grande Formation (Jujuy, northwestern Argentina). Although sampling is preliminary, we found ~70 morphotypes of spores, pollen grains and other palynomorphs, many of which were produced by taxa with tropical or subtropical modern distributions (e.g., Arecaceae, Ulmaceae Phyllostylon, Malvaceae Bombacoideae). Our reconstructed scenario implies the existence of a vegetated pond surrounded by trees, vines, and palms. We also report the northernmost records of a few unequivocal Gondwanan taxa (e.g., Nothofagus, Microcachrys), about 5,000 km north from their Patagonian-Antarctic hotspot. With few exceptions, the discovered taxa-both Neotropical and Gondwanan-became extinct from the region following the severe effects of the Andean uplift and the climate deterioration during the Neogene. We found no evidence for enhanced aridity nor cool conditions in the southern Central Andes at mid Eocene times. Instead, the overall assemblage represents a frost-free and humid to seasonally-dry ecosystem that prevailed near a lacustrine environment, in agreement with previous paleoenvironmental studies. Our reconstruction adds a further biotic component to the previously reported record of mammals.


Assuntos
Arecaceae , Ecossistema , Animais , Argentina , Clima , Pólen , Plantas , Fósseis , Esporos , Mamíferos
6.
J Behav Health Serv Res ; 50(3): 348-364, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36599990

RESUMO

Behavioral health disorders such as mental disorders (MD) and substance use disorders (SUD) are epidemics in the US; however, the availability of treatment and prevention services remains low. This study assessed neighborhood-level sociodemographic attributes to characterize the availability of behavioral health treatment facilities in Florida. The American Community Survey and SAMHSA's Behavioral Health Treatment Locator were used to identify behavioral health treatment facilities in Florida and calculate their density by census tract. Spatial lag regression models were used to assess census tract-level correlates of facility density for 390 MD treatment facilities, 518 SUD facilities, and subsets of affordable MD and SUD facilities. Behavioral health treatment facility density was negatively associated with rurality and positively associated with the proportion of non-Latino Black, Latino, insured, and college-educated populations. Stark rural-urban disparities in behavioral health treatment availability present opportunities to prioritize telehealth and mobile interventions and improve treatment utilization.


Assuntos
Acessibilidade aos Serviços de Saúde , Transtornos Relacionados ao Uso de Substâncias , Humanos , Estudos Transversais , Florida , Hispânico ou Latino , Características de Residência , Transtornos Relacionados ao Uso de Substâncias/terapia , Negro ou Afro-Americano
7.
Nat Cancer ; 4(2): 257-275, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36585452

RESUMO

Inhibiting individual histone deacetylase (HDAC) is emerging as well-tolerated anticancer strategy compared with pan-HDAC inhibitors. Through preclinical studies, we demonstrated that the sensitivity to the leading HDAC6 inhibitor (HDAC6i) ricolinstat can be predicted by a computational network-based algorithm (HDAC6 score). Analysis of ~3,000 human breast cancers (BCs) showed that ~30% of them could benefice from HDAC6i therapy. Thus, we designed a phase 1b dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in patients with metastatic BC (MBC) (NCT02632071). Study results showed that the two agents can be safely combined, that clinical activity is identified in patients with HR+/HER2- disease and that the HDAC6 score has potential as predictive biomarker. Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6i's. Mechanistically, we have linked the anticancer activity of HDAC6i's to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Desacetilase 6 de Histona/metabolismo , Neoplasias da Mama/tratamento farmacológico , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico
8.
Cancer Discov ; 13(2): 386-409, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36374194

RESUMO

Prioritizing treatments for individual patients with cancer remains challenging, and performing coclinical studies using patient-derived models in real time is often unfeasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework that predicts drug sensitivity in human tumors and their preexisting high-fidelity (cognate) model(s) by leveraging drug perturbation profiles. As a proof of concept, we applied OncoLoop to prostate cancer using genetically engineered mouse models (GEMM) that recapitulate a broad spectrum of disease states, including castration-resistant, metastatic, and neuroendocrine prostate cancer. Interrogation of human prostate cancer cohorts by Master Regulator (MR) conservation analysis revealed that most patients with advanced prostate cancer were represented by at least one cognate GEMM-derived tumor (GEMM-DT). Drugs predicted to invert MR activity in patients and their cognate GEMM-DTs were successfully validated in allograft, syngeneic, and patient-derived xenograft (PDX) models of tumors and metastasis. Furthermore, OncoLoop-predicted drugs enhanced the efficacy of clinically relevant drugs, namely, the PD-1 inhibitor nivolumab and the AR inhibitor enzalutamide. SIGNIFICANCE: OncoLoop is a transcriptomic-based experimental and computational framework that can support rapid-turnaround coclinical studies to identify and validate drugs for individual patients, which can then be readily adapted to clinical practice. This framework should be applicable in many cancer contexts for which appropriate models and drug perturbation data are available. This article is highlighted in the In This Issue feature, p. 247.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Camundongos , Animais , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Medicina de Precisão , Antagonistas de Receptores de Andrógenos , Transcriptoma , Perfilação da Expressão Gênica , Nitrilas , Receptores Androgênicos/genética
9.
Curr Protoc ; 2(9): e544, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36083100

RESUMO

The current Achilles heel of cancer drug discovery is the inability to forge precise and predictive connections among mechanistic drivers of the cancer cell state, therapeutically significant molecular targets, effective drugs, and responsive patient subgroups. Although advances in molecular biology have helped identify molecular markers and stratify patients into molecular subtypes, these associational strategies typically fail to provide a mechanistic rationale to identify cancer vulnerabilities. Recently, integrative systems biology methodologies have been used to reverse engineer cellular networks and identify master regulators (MRs), proteins whose activity is both necessary and sufficient to implement phenotypic states under physiological and pathological conditions, which are organized into highly interconnected regulatory modules called tumor checkpoints. Because of their functional relevance, MRs represent ideal pharmacological targets and biomarkers. Here, we present a six-step patient-to-model-to-patient protocol that employs computational and experimental methodologies to reconstruct and interrogate the regulatory logic of human cancer cells for identifying and therapeutically targeting the tumor checkpoint with novel as well as existing pharmacological agents. This protocol systematically identifies, from specific patient tumor samples, the MRs that comprise the tumor checkpoint. Then, it identifies in vitro and in vivo models that, by recapitulating the patient's tumor checkpoint, constitute the appropriate cell lines and xenografts to further elucidate the tissue context-specific drug mechanism of action (MOA) and permit precise, biomarker-based preclinical validations of drug efficacy. The combination of determination of a drug's context-specific MOA and precise identification of patients' tumor checkpoints provides a personalized, mechanism-based biomarker to enrich prospective clinical trials with patients likely to respond. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Biomarcadores , Descoberta de Drogas , Humanos , Neoplasias/tratamento farmacológico , Estudos Prospectivos
10.
Vaccines (Basel) ; 10(9)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36146630

RESUMO

Clay materials and nanoclays have gained recent popularity in the vaccinology field, with biocompatibility, simple functionalization, low toxicity, and low-cost as their main attributes. As elements of nanovaccines, halloysite nanotubes (natural), layered double hydroxides and hectorite (synthetic) are the nanoclays that have advanced into the vaccinology field. Until now, only physisorption has been used to modify the surface of nanoclays with antigens, adjuvants, and/or ligands to create nanovaccines. Protocols to covalently attach these molecules have not been developed with nanoclays, only procedures to develop adsorbents based on nanoclays that could be extended to develop nanovaccine conjugates. In this review, we describe the approaches evaluated on different nanovaccine candidates reported in articles, the immunological results obtained with them and the most advanced approaches in the preclinical field, while describing the nanomaterial itself. In addition, complex systems that use nanoclays were included and described. The safety of nanoclays as carriers is an important key fact to determine their true potential as nanovaccine candidates in humans. Here, we present the evaluations reported in this field. Finally, we point out the perspectives in the development of vaccine prototypes using nanoclays as antigen carriers.

11.
Commun Biol ; 5(1): 714, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35854100

RESUMO

SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of Master Regulators enriched in physical interactions with SARS-CoV-2 proteins, suggesting their mechanistic role in maintaining a host cell state refractory to virus replication. To test their functional relevance, we measured SARS-CoV-2 replication in epithelial cells treated with drugs predicted to activate the entire repertoire of repressed Master Regulators, based on their experimentally elucidated, context-specific mechanism of action. Overall, 15 of the 18 drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 replication, without affecting cell viability. This model for host-directed pharmacological therapy is fully generalizable and can be deployed to identify drugs targeting host cell-based Master Regulator signatures induced by virtually any pathogen.


Assuntos
Tratamento Farmacológico da COVID-19 , Viroses , Humanos , SARS-CoV-2 , Transcriptoma , Replicação Viral
12.
Food Funct ; 13(7): 4184-4193, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35322820

RESUMO

An imbalanced gut microbiota predisposes the development of nutritional disorders and chronic gastrointestinal diseases. Several studies have shown improvements on the host's health by enhancing the microbiota with prebiotics that stimulate probiotic microorganisms. This study describes the prebiotic effect of fructans from Agave salmiana consumed by children as a supplement for malnutrition. We report the extraction and degree of polymerization of fructans from A. salmiana, food safety and inflammatory analyses, and their effect in vitro on probiotic lactic acid bacteria (LAB). These fructans were included in the diet of 5-year-old normal-weight and malnourished children in double-blind, two-week interventions that compared the effects on their weight, bacterial count, and volatile organic compounds (VOCs). The extracted powdered fructans from A. salmiana had a composition comparable to inulin, were safe for human consumption, and stimulated the growth in vitro of three characteristic LAB. The children who consumed these fructans had a considerable weight gain, an increased number of LAB, and a decreased concentration of VOCs (indicative of less dysbiosis), demonstrating positive effects of this prebiotic on their microbiota, which were more significant in malnourished children. Fructans from A. salmiana induced in malnourished children significant weight gain and improved the functionality of their gut microbiota.


Assuntos
Agave , Frutanos , Desnutrição , Pré-Escolar , Método Duplo-Cego , Frutanos/farmacologia , Humanos , Inulina/farmacologia , Lactobacillales , Prebióticos , Probióticos
13.
Res Sq ; 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35132404

RESUMO

Precise characterization and targeting of host cell transcriptional machinery hijacked by viral infection remains challenging. Here, we show that SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Specifically, analysis of Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of MRs enriched in physical interactions with SARS-CoV-2 proteins, suggesting their mechanistic role in maintaining a host cell state refractory to virus replication. To test their functional relevance, we measured SARS-CoV-2 replication in epithelial cells treated with drugs predicted to activate the entire repertoire of repressed MRs, based on their experimentally elucidated, context-specific mechanism of action. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 replication, without affecting cell viability. This model for host-directed pharmacological therapy is fully generalizable and can be deployed to identify drugs targeting host cell-based MR signatures induced by virtually any pathogen.

14.
Clin Cancer Res ; 28(3): 452-460, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34728525

RESUMO

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7-291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79-35.9], 7.7% (95% CI, 1.17-50.6), and 17% (95% CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0-27.0); C: 7.7% (95% CI, 0.2-36.0); D: 10% (95% CI, 2.1-26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88). CONCLUSIONS: At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Hidrazinas/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Encéfalo/metabolismo , Neoplasias Encefálicas/cirurgia , Procedimentos Cirúrgicos de Citorredução , Feminino , Glioblastoma/cirurgia , Humanos , Hidrazinas/efeitos adversos , Hidrazinas/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/metabolismo , Adulto Jovem
16.
Leuk Lymphoma ; 62(13): 3192-3203, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34323164

RESUMO

Selinexor, a selective inhibitor of nuclear export, has demonstrated promising activity in patients with acute myeloid leukemia (AML). This randomized, phase II study evaluated selinexor 60 mg twice weekly (n = 118) vs. physician's choice (PC) treatment (n = 57) in patients aged ≥60 years with relapsed/refractory (R/R) AML. The primary outcome was overall survival (OS). Median OS did not differ significantly for selinexor vs. PC (3.2 vs. 5.6 months; HR = 1.18 [95% CI: 0.79-1.75]; p = 0.422). Complete remission (CR) plus CR with incomplete hematologic recovery trending in favor of selinexor occurred in a minority of patients. Selinexor treated patients had an increased incidence of adverse events. The most common grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anemia, hyponatremia. Despite well-balanced baseline characteristics, there were numerically higher rates of TP53 mutations, prior myelodysplastic syndrome, and lower absolute neutrophil counts in the selinexor group; warranting further investigation of selinexor in more carefully stratified R/R AML patients.Registered trial: NCT02088541.


Assuntos
Leucemia Mieloide Aguda , Médicos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Hidrazinas/efeitos adversos , Triazóis/efeitos adversos
17.
Preprint em Inglês | bioRxiv | ID: ppbiorxiv-451001

RESUMO

Precise characterization and targeting of host cell transcriptional machinery hijacked by SARS-CoV-2 remains challenging. To identify therapeutically targetable mechanisms that are critical for SARS-CoV-2 infection, here we elucidated the Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2. The analysis revealed coordinated inactivation of MR-proteins linked to regulatory programs potentiating efficiency of viral replication (detrimental host MR-signature) and activation of MR-proteins governing innate immune response programs (beneficial MR-signature). To identify MR-inverting compounds capable of rescuing activity of inactivated host MR-proteins, with-out adversely affecting the beneficial MR-signature, we developed the ViroTreat algorithm. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 infection, without affecting cell viability. ViroTreat is fully generalizable and can be extended to identify drugs targeting the host cell-based MR signatures induced by virtually any pathogen.

18.
Nanomedicine ; 34: 102372, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33662593

RESUMO

The development of vaccines is a crucial response against the COVID-19 pandemic and innovative nanovaccines could increase the potential to address this remarkable challenge. In the present study a B cell epitope (S461-493) from the spike protein of SARS-CoV-2 was selected and its immunogenicity validated in sheep. This synthetic peptide was coupled to gold nanoparticles (AuNP) functionalized with SH-PEG-NH2 via glutaraldehyde-mediated coupling to obtain the AuNP-S461-493 candidate, which showed in s.c.-immunized mice a superior immunogenicity (IgG responses) when compared to soluble S461-493; and led to increased expression of relevant cytokines in splenocyte cultures. Interestingly, the response triggered by AuNP-S461-493 was similar in magnitude to that induced using a conventional strong adjuvant (Freund's adjuvant). This study provides a platform for the development of AuNP-based nanovaccines targeting specific SARS-CoV-2 epitopes.


Assuntos
Vacinas contra COVID-19 , Epitopos de Linfócito B , Ouro , Imunogenicidade da Vacina , Nanopartículas Metálicas , Peptídeos , Glicoproteína da Espícula de Coronavírus , Animais , Vacinas contra COVID-19/síntese química , Vacinas contra COVID-19/química , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/farmacologia , Ouro/química , Ouro/farmacologia , Células HEK293 , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos/síntese química , Peptídeos/química , Peptídeos/imunologia , Peptídeos/farmacologia , Ovinos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/farmacologia
19.
PLoS One ; 16(3): e0234587, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33705414

RESUMO

Citizen science (CS) currently refers to the participation of non-scientist volunteers in any discipline of conventional scientific research. Over the last two decades, nature-based CS has flourished due to innovative technology, novel devices, and widespread digital platforms used to collect and classify species occurrence data. For scientists, CS offers a low-cost approach of collecting species occurrence information at large spatial scales that otherwise would be prohibitively expensive. We examined the trends and gaps linked to the use of CS as a source of data for species distribution models (SDMs), in order to propose guidelines and highlight solutions. We conducted a quantitative literature review of 207 peer-reviewed articles to measure how the representation of different taxa, regions, and data types have changed in SDM publications since the 2010s. Our review shows that the number of papers using CS for SDMs has increased at approximately double the rate of the overall number of SDM papers. However, disparities in taxonomic and geographic coverage remain in studies using CS. Western Europe and North America were the regions with the most coverage (73%). Papers on birds (49%) and mammals (19.3%) outnumbered other taxa. Among invertebrates, flying insects including Lepidoptera, Odonata and Hymenoptera received the most attention. Discrepancies between research interest and availability of data were as especially important for amphibians, reptiles and fishes. Compared to studies on animal taxa, papers on plants using CS data remain rare. Although the aims and scope of papers are diverse, species conservation remained the central theme of SDM using CS data. We present examples of the use of CS and highlight recommendations to motivate further research, such as combining multiple data sources and promoting local and traditional knowledge. We hope our findings will strengthen citizen-researchers partnerships to better inform SDMs, especially for less-studied taxa and regions. Researchers stand to benefit from the large quantity of data available from CS sources to improve global predictions of species distributions.


Assuntos
Ciência do Cidadão/tendências , Animais , Biodiversidade , Bases de Dados Factuais , Modelos Lineares , Revisão da Pesquisa por Pares
20.
Sci Total Environ ; 773: 145055, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33592477

RESUMO

The aim of this work was to compare the concentration of glyphosate and AMPA in the PM10 and the actual PM10 emission from agricultural soils and unpaved roads, located inside and outside farm fields. To determine the actual PM10 emission by wind erosion, the actual wind erosion was estimated using the Wind Erosion Equation, and the PM10 emission efficiency was measured with the Easy Dust Generator. PM10 was collected in an electrostatic precipitator coupled to the Easy Dust Generator. Actual PM10 emission was 11.5 g ha-1 year-1 in agricultural soils and 4711.4 g ha-1 year-1 in unpaved roads. The high value of actual PM10 emission in unpaved roads was due to their high actual wind erosion and the high PM10 emission efficiency, while the low value in agricultural soils was due to their low actual wind erosion. Content of glyphosate in the PM10 ranged from 59 to 359 µg kg-1 in agricultural soils, from 382 to 454 µg kg-1 in unpaved roads inside farm fields, and from 39 to 639 µg kg-1 in unpaved roads outside farm fields. Content of AMPA in the PM10 ranged from 387 to 7228 µg kg-1 in agricultural soils, from 900 to 4138 µg kg-1 in unpaved roads inside farm fields, and 98 to 500 µg kg-1 in unpaved roads outside farm fields. AMPA concentration in PM10 was higher than that of glyphosate due to the longer persistence of AMPA than glyphosate. Glyphosate and AMPA concentrations in PM10 were higher than in soil, which is an additional risk that should be considered when the effect of PM10 emitted by agricultural soils and unpaved roads on human health are evaluated. Our results show that the amount and chemical composition of PM10 emitted by wind erosion from unpaved roads should be studied in other regions.

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