We review the theoretical and phenomenological aspects of the Next-to-Minimal Supersymmetric Standard Model: the Higgs sector including radiative corrections and the 2-loop
β
-functions for all ...parameters of the general NMSSM; the tadpole and domain wall problems, baryogenesis; NMSSM phenomenology at colliders,
B
physics and dark matter; specific scenarios as the constrained NMSSM, gauge mediated supersymmetry breaking,
U
(
1
)
′
-extensions, CP and R-parity violation.
Programmed Death-1 (PD-1) is a coinhibitory receptor expressed on activated T cells that suppresses T-cell signaling and effector functions. It has been previously shown that binding to its ligand ...PD-L1 induces a spatial reorganization of PD-1 receptors into microclusters on the cell membrane. However, the roles of the spatial organization of PD-L1 on PD-1 clustering and T-cell signaling have not been elucidated. Here, we used DNA origami flat sheets to display PD-L1 ligands at defined nanoscale distances and investigated their ability to inhibit T-cell activation in vitro. We found that DNA origami flat sheets modified with CD3 and CD28 activating antibodies (FS-α-CD3-CD28) induced robust T-cell activation. Co-treatment with flat sheets presenting PD-L1 ligands separated by ∼200 nm (FS-PD-L1-200), but not 13 nm (FS-PD-L1-13) or 40 nm (FS-PD-L1-40), caused an inhibition of T-cell signaling, which increased with increasing molar ratio of FS-PD-L1-200 to FS-α-CD3-CD28. Furthermore, FS-PD-L1-200 induced the formation of smaller PD-1 nanoclusters and caused a larger reduction in IL-2 expression compared to FS-PD-L1-13. Together, these findings suggest that the spatial organization of PD-L1 determines its ability to regulate T-cell signaling and may guide the development of future nanomedicine-based immunomodulatory therapies.
Antibiotic resistance is one of the greatest challenges in the health system nowadays, representing a serious problem for public health. Initially, antibiotic-resistant strains were restricted to the ...hospital environment, but now they can be found everywhere. Globalization, excessive use of antibiotics in animal husbandry and aquaculture, use of multiple broad-spectrum agents, and lack of good antimicrobial stewardship can be listed as the factors most responsible for the spread of antibiotic resistance. The increase in the prevalence of antibiotic-resistant pathogens implies having fewer antimicrobial agents to treat infections. The estimate is that by 2050, there will be no effective antibiotic available, if no new drug is developed or discovered. This raises the need to search for alternative methods of controlling antibiotic-resistant pathogens. Considering this problem, the objective of this review is to outline the most frequent antibiotic-resistant bacteria and describe the advantageous and limitations of alternative methods that have been proposed to control them.
Synthetic biology aims to contribute to the development of next-generation patient-specific cell-based therapies for chronic diseases especially through the construction of sophisticated synthetic ...gene switches to enhance the safety and spatiotemporal controllability of engineered cells. Indeed, switches that sense and process specific cues, which may be either externally administered triggers or endogenous disease-associated molecules, have emerged as powerful tools for programming and fine-tuning therapeutic outputs. Living engineered cells, often referred to as designer cells, incorporating such switches are delivered to patients either as encapsulated cell implants or by infusion, as in the case of the clinically approved CAR-T cell therapies. Here, we review recent developments in synthetic gene switches responsive to molecular stimuli, spanning regulatory mechanisms acting at the transcriptional, translational, and posttranslational levels. We also discuss current challenges facing clinical translation of cell-based therapies employing these devices.Synthetic biology aims to contribute to the development of next-generation patient-specific cell-based therapies for chronic diseases especially through the construction of sophisticated synthetic gene switches to enhance the safety and spatiotemporal controllability of engineered cells. Indeed, switches that sense and process specific cues, which may be either externally administered triggers or endogenous disease-associated molecules, have emerged as powerful tools for programming and fine-tuning therapeutic outputs. Living engineered cells, often referred to as designer cells, incorporating such switches are delivered to patients either as encapsulated cell implants or by infusion, as in the case of the clinically approved CAR-T cell therapies. Here, we review recent developments in synthetic gene switches responsive to molecular stimuli, spanning regulatory mechanisms acting at the transcriptional, translational, and posttranslational levels. We also discuss current challenges facing clinical translation of cell-based therapies employing these devices.
Cancer is a major public health problem, but despite the several treatment approaches available, patients develop resistance in short time periods, making overcoming resistance or finding more ...efficient treatments an imperative challenge. Silver nanoparticles (AgNPs) have been described as an alternative option due to their physicochemical properties. The scope of this review was to systematize the available scientific information concerning these characteristics in AgNPs synthesized according to green chemistry’s recommendations as well as their cytotoxicity in different cancer models. This is the first paper analyzing, correlating, and summarizing AgNPs’ main parameters that modulate their cellular effect, including size, shape, capping, and surface plasmon resonance profile, dose range, and exposure time. It highlights the strong dependence of AgNPs’ cytotoxic effects on their characteristics and tumor model, making evident the strong need of standardization and full characterization. AgNPs’ application in oncology research is a new, open, and promising field and needs additional studies.
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Synthetic biology aims to repurpose cells to sense a wide range of input signals and respond by conditionally expressing user-defined output genes. In this review, we highlight the ...latest developments in synthetic-biology-inspired in vitro and in vivo diagnostics and therapeutics employing engineered mammalian cells. Recent work has led to the creation of modular synthetic receptors with adaptable ligand-binding domains whose recognition specificity can be easily tailored to target various diseases. Engineered cells can now sense a great variety of soluble and surface-bound antigens with unprecedented selectivity and sensitivity, and implanted designer cells equipped with appropriate response modules can successfully treat diabetes, cancer and autoimmune diseases in animal models. Recently, the first immunotherapies using chimeric-antigen receptor (CAR)-T cells were approved to treat lymphoma patients. As this milestone paves the way for translating state-of-the-art synthetic biology approaches into clinical benefit, we also discuss the challenges facing engineered cell therapies.
A
bstract
An observation of any lepton number violating process will undoubtedly point towards the existence of new physics and indirectly to the clear Majorana nature of the exchanged fermion. In ...this work, we explore the potential of a minimal extension of the Standard Model via heavy sterile fermions with masses in the 0.1 − 10 GeV range concerning an extensive array of “neutrinoless” meson and tau decay processes. We assume that the Majorana neutrinos are produced on-shell, and focus on three-body decays. We conduct an update on the bounds on the active-sterile mixing elements,
U
ℓ
α
4
U
ℓ
β
4
, taking into account the most recent experimental bounds (and constraints) and new theoretical inputs, as well as the effects of a finite detector, imposing that the heavy neutrino decay within the detector. This allows to establish up-to-date comprehensive constraints on the sterile fermion parameter space. Our results suggest that the branching fractions of several decays are close to current sensitivities (likely within reach of future facilities), some being already in conflict with current data (as is the case of
K
+
→
ℓ
α
+
ℓ
β
+
π
−
, and
τ
−
→
μ
+
π
−
π
−
). We use these processes to extract constraints on all entries of an enlarged definition of a 3 × 3 “effective” Majorana neutrino mass matrix
m
ν
αβ
.
•Energy consumption is nearly 8 times lower for electric vehicles.•Electric vehicle can be currently feasible in Brazil for reducing CO2 emissions.•CO2 emissions from electric vehicles can be 10–12 ...times lower.•Substitution of 25% of a taxi fleet by electric vehicles reduce 1000 tons CO2/year.•Substitution of total taxi fleet by electric vehicles reduce 5600 tons CO2/year.
This paper evaluates the impacts on energy consumption and carbon dioxide (CO2) emissions from the introduction of electric vehicles into a smart grid, as a case study. The AVL Cruise software was used to simulate two vehicles, one electric and the other engine-powered, both operating under the New European Driving Cycle (NEDC), in order to calculate carbon dioxide (CO2) emissions, fuel consumption and energy efficiency. Available carbon dioxide data from electric power generation in Brazil were used for comparison with the simulated results. In addition, scenarios of gradual introduction of electric vehicles in a taxi fleet operating with a smart grid system in Sete Lagoas city, MG, Brazil, were made to evaluate their impacts. The results demonstrate that CO2 emissions from the electric vehicle fleet can be from 10 to 26 times lower than that of the engine-powered vehicle fleet. In addition, the scenarios indicate that even with high factors of CO2 emissions from energy generation, significant reductions of annual emissions are obtained with the introduction of electric vehicles in the fleet.
High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial ...deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.
Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4-10).
Echocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress.
Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.
A
bstract
Motivated by an explanation of the
R
K
*
anomalies, we propose a Standard Model extension via two scalar SU(2)
L
triplet leptoquarks and three generations of triplet Majorana fermions. The ...gauge group is reinforced by a
Z
2
symmetry, ensuring the stability of the lightest
Z
2
-odd particle, which is a potentially viable dark matter candidate. Neutrino mass generation occurs radiatively (at the three-loop level), and leads to important constraints on the leptoquark couplings to leptons. We consider very generic textures for the flavour structure of the
h
1
leptoquark Yukawa couplings, identifying classes which succeed in saturating the
R
K
*
anomalies. We subsequently carry a comprehensive analysis of the model’s contributions to numerous high-intensity observables such as meson oscillations and decays, as well as charged lepton flavour violating processes, which put severe constraints on the flavour structure of these leptoquark extensions. Our findings suggest that the most constraining observables are
K
+
→
π
+
ν
ν
¯
decays, and charged lepton flavour violating
μ
−
e
conversion in nuclei (among others). Nevertheless, for several classes of flavour textures and for wide mass regimes of the new mediators (within collider reach), this Standard Model extension successfully addresses neutrino mass generation, explains the current
R
K
*
tensions, and offers a viable dark matter candidate.
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