The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community ...has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The performance of single‐atom electrocatalysts usually suffers from attenuation due to high energy states, especially in harsh environments. Therefore, as high‐efficiency electrocatalysts for ...hydrogen reduction reaction (HER), supported metal nanoclusters (NCs) with maximum metal atom efficiency are promising, yet the genuine mechanism involving rational orbital modulation is still arguable. Herein, the conjugating effect between electron‐donor boron (B)‐tethering engineering and iridium (Ir) that facilitates the electron capture of Ir atoms is explored, achieving highly dispersive Ir‐NCs confined in N, B co‐doped defective carbon (Ir@NBD‐C). The Ir@NBD‐C catalyst achieves displays remarkable high activity for HER in a pH‐universal range, in particular, with an ultralow overpotential of 7 mV (10 mA cm−2), high mass activity of 652.2 A gIr−1, and turnover frequency (TOF) of 1.90 H2 S−1 (100 mV) in 1.0 m KOH, outperforming almost all state‐of‐the‐art HER electrocatalysts. Operando characterizations and theoretical calculations unveil that the outstanding catalytic activity can attribute to the optimal binding to hydrogen intermediate species (H*) derived from the tunable and favorable electronic structure of the Ir site through the tethering of B heteroatoms. Undoubtedly, this work brings new insight into the design of catalysts with high intrinsic activity and thermodynamic stability.
Synergistic tethering of electron‐donor (B)/acceptor (N) heteroatoms regulates the electronic structure of Ir nanoclusters, resulting in high catalytic activity and optimal adsorption energy of hydrogen intermediate (H*) in HER.
In modular invariant models of flavor, observables must be modular invariant. The observables discussed so far in the literature are functions of the modulus τ and its conjugate, τ¯. We point out ...that certain combinations of observables depend only on τ, i.e. are meromorphic, and in some cases even holomorphic functions of τ. These functions, which we dub “invariants” in this Letter, are highly constrained, renormalization group invariant, and allow us to derive many of the models' features without the need for extensive parameter scans. We illustrate the robustness of these invariants in two existing models in the literature based on modular symmetries, Γ3 and Γ5. We find that, in some cases, the invariants give rise to robust relations among physical observables that are independent of τ. Furthermore, there are instances where additional symmetries exist among the invariants. These symmetries are relevant phenomenologically and may provide a dynamical way to realize symmetries of mass matrices.
Magnetic resonance imaging (MRI) offers the most detailed brain structure image available today; it can identify tiny lesions or cerebral cortical abnormalities. The primary purpose of the procedure ...is to confirm whether there is structural variation that causes epilepsy, such as hippocampal sclerotherapy, local cerebral cortical dysplasia, and cavernous hemangioma. Cerebrovascular disease, the second most common factor of death in the world, is also the fourth leading cause of death in Taiwan, with cerebrovascular disease having the highest rate of stroke. Among the most common are large vascular atherosclerotic lesions, small vascular lesions, and cardiac emboli. The purpose of this thesis is to establish a computer-aided diagnosis system based on small blood vessel lesions in MRI images, using the method of Convolutional Neural Network and deep learning to analyze brain vascular occlusion by analyzing brain MRI images. Blocks can help clinicians more quickly determine the probability and severity of stroke in patients. We analyzed MRI data from 50 patients, including 30 patients with stroke, 17 patients with occlusion but no stroke, and 3 patients with dementia. This system mainly helps doctors find out whether there are cerebral small vessel lesions in the brain MRI images, and to output the found results into labeled images. The marked contents include the position coordinates of the small blood vessel blockage, the block range, the area size, and if it may cause a stroke. Finally, all the MRI images of the patient are synthesized, showing a 3D display of the small blood vessels in the brain to assist the doctor in making a diagnosis or to provide accurate lesion location for the patient.
Macrophage infiltration and polarization during lumbar intervertebral disc herniation (LDH) have attracted increased attention but their role remains unclear. To explore macrophage polarization in ...herniated nucleus pulposus (NP) tissue of patients with LDH and investigate the association between cell frequency and different clinical characteristics or symptoms, we conducted a retrospective study by analyzing NP tissue samples from 79 patients. Clinical features and symptoms, using the visual analog scale (VAS) and Oswestry disability index (ODI), were collected. The macrophage markers CD68, CCR7, CD163, and CD206; pro‐inflammatory cytokine TNF‐α; and anti‐inflammatory factor IL‐4 were analyzed by immunohistochemistry. The frequency of polarized macrophages and positivity rate of pro‐ and anti‐inflammatory cytokines showed significant differences in some of clinical characteristics. Specifically, higher CCR7+ and TNF‐α + proportions were identified in the high‐intensity zone (HIZ) and the type of extrusion and sequestration NP tissue than in non‐HIZ and protrude NP tissue. Higher CD206+ and IL‐4+ proportion were detected in Modic changes. However, no differences in gender, age, smoking status, Pfirrmann grade, analgesic use, leg pain duration, and segments were found between groups. CD68+, CCR7+, and CD206+ cell proportions, and TNF‐α and IL‐4 showed positive associations with VAS scores preoperation. Associations between ODI and the macrophages markers were weak/insignificant. Our results indicated that macrophage polarization or macrophage‐like cells contribute to LDH pathological features. Macrophage populations displaying significant associations with VAS score reflected continuous M1/M2 transition contributing to pain during LDH. These findings may contribute to enhanced/personalized pharmacological interventions for patients with LDH considering pain heterogeneity.
The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the ...(S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.
Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 ...(10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC50 = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50 = 3.74–151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.
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•A next-generation orally selective type II TRK inhibitor was discovered.•Twenty-nine quinazoline-based analogues were designed and synthesized.•Property-driven strategy guided lead-to-candidate optimization.•39 is a potent TRK inhibitor against both wild-type and mutant TRKs.•39 demonstrated antitumor effectiveness in KM-12 xenograft model.
The catalytic oxidative desulfurization (ODS) technique is able to remove sulfur compounds from fuels, conducive to achieving deep desulfurization for the good of the ecological environment. Ti-based ...metalorganic frameworks (Ti-MOFs) possessing good affinity to organic reactants and considerable numbers of Ti active sites are promising catalysts for ODS. However, current Ti-MOFs suffer from severe diffusion limitations caused by the size mismatch between sole micropores and bulky sulfur compounds, leading to poor ODS performance. Here, a facile method of intraparticle ripening without any additive is developed to obtain hierarchically mesomicroporous Ti-MIL-125 single crystals (Meso-Ti-MIL-125) for the first time. Such Meso-Ti-MIL-125 shows a BET surface area of 1401 m
2
g
1
and a mesoporous volume that is 1.7 times as high as that of the conventional Ti-MIL-125. Our novel Meso-Ti-MIL-125 exhibits excellent catalytic performance in the ODS of a series of bulky thiophenic sulfur compounds, completely removing benzothiophene (BT), dibenzothiophene (DBT), and 4,6-dimethyldibenzothiophene (DMDBT) from model fuels, which is, respectively, 2.4 times, 1.5 times, and 6.7 times higher than the removal achieved with conventional Ti-MIL-125. Such a facile synthetic strategy is envisioned to be applied in many kinds of crystalline materials, such as zeolites, for industrial production.
For the first time, Ti-MOF single crystals featuring an intracrystal mesomicroporous hierarchy were prepared by a facile method of intraparticle ripening, and excellent deep catalytic oxidative desulfurization performance was achieved.
Excessive emission of CO2 into the atmosphere has severely impacted the global ecological environment. Converting CO2 into valuable chemicals and fuels is of great significance for sustainable ...development. However, low activity and undesirable selectivity often result from the inherent inertness of CO2. Herein, K- or/and Zn-modified Fe-based catalysts were prepared by an incipient-wetness impregnation method for CO2 hydrogenation via a cascade reaction. The results indicate that K species exist as K2O while Zn species exist as ZnFe2O4. In the CO2 hydrogenation pathway, K2O facilitates the adsorption of CO2 and restrains the adsorption of H2, accelerating the transformation of CO2 into C2–C4 olefins rather than paraffins while Zn species promote the dispersion of Fe species, leading to improved activity. Synergistically, a K- and Zn-modified Fe-based catalyst (2Zn–10K–Fe/Al) shows excellent catalytic CO2 hydrogenation activity, achieving a CO2 conversion of 77% which is 1.8 times that (42%) of the unmodified Fe-based catalyst (Fe/Al). Our catalyst also shows a significantly promoted selectivity to C2–C4 olefins of 17% in comparison with the Fe/Al catalyst (0%). It is envisioned that such a binary effect of elements might contribute to the low-cost and industrial production of Fe-based catalysts for selective CO2 conversion.
The study of precision medicine is flourishing in recent decades. Tumor‐agnostic therapy is one of the targeted therapies, which can treat the malignant cells regardless of where they grow. Herein we ...reviewed currently the U.S. FDA‐approved tumor‐agnostic therapies: one monoclonal antibody as a PD‐1 inhibitor called pembrolizumab and four small‐molecule kinase inhibitors, larotrectinib, entrectinib, selpercatinib, and pralsetinib. We also summarized the reported synthetic routes toward three drugs and some developing candidates under clinical trials as tumor‐agnostic therapy.
In this review, we introduced a novel cancer therapy for patients called tumor‐agnostic therapy, including five marketed drugs and several candidates. Pembrolizumab is a PD‐1 inhibitor, whereas larotrectinib, entrectinib, selpercatinib, and pralsetinib are small‐molecule kinase inhibitors. By introducing both marketed and currently developing therapies, we can further comprehend the concept of this breakthrough cancer therapy.
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