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2025
Abstract
Allosteric regulation is a powerful mechanism for controlling the efficiency of enzymes. Deciphering the evolutionary mechanisms by which allosteric properties have been acquired in enzymes is of fundamental importance. We used the malate (MalDH) and lactate deydrogenases (LDHs) superfamily as model to elucidate this phenomenon. By introducing a few of mutations associated to the emergence of allosteric LDHs into the non-allosteric MalDH from Methanopyrus kandleri, we have gradually shifted its enzymatic profile toward that typical of allosteric LDHs. We first investigated the process triggering homotropic activation. The structures of the resulting mutants show the typical compact organization of the R-active state of LDHs, but a distorted (T-like) catalytic site demonstrating that they corresponds to hybrid states. Molecular dynamics simulations and free energy calculations confirmed the capability of these mutants to sample the T-inactive state. By adding a final single mutation to fine-tune the flexibility of the catalytic site, we obtained an enzyme with both sigmoid (homotropic) and hyperbolic (heterotropic) substrate activation profiles. Its structure shows a typical extended T-state as in LDHs, whereas its catalytic state has as a restored configuration favorable for catalysis. Free energy calculations indicate that the T and R catalytic site configurations are in an equilibrium that depends on solvent conditions. We observed long-range communication between monomers as required for allosteric activation. Our work links the evolution of allosteric regulation in the LDH/MDH superfamily to the ensemble model of allostery at molecular level, and highlights the important role of the underlying protein dynamics.- Book : 42(1)
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2025
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2025
- Book : 13(01)
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- Page : pp.132-144
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2025
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2025
Abstract
Bi2Te3/PbTe thermophotovoltaic cells are prepared by vacuum evaporation. This kind of cells can convert radiation of low temperature (below 500 K) into electricity. The short-circuit current, open-circuit voltage and conversion efficiency of the cells increase with temperature under 300-480 K. The experimental results show that the heat-electricity conversion at low temperature is feasible. The characteristics of the thermophotovoltaic cells are discussed in this paper.- Book : 2937(1)
- Pub. Date : 2025
- Page : pp.012002-012002
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2025
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2025
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2025
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2025
ABSTRACTPrimary frontal sinus squamous cell carcinoma (PFSSCC) represents a rare disease in dogs, and there is a general paucity of information in the current veterinary literature regarding its presentation and response to radiation therapy.The objective of this retrospective observational study was to describe a series of dogs diagnosed with PFSSCC and report their response to radiation therapy.Medical records of dogs with a diagnosis of PFSSCC were reviewed. Data collected included signalment, presenting complaint, clinicopathologic and diagnostic imaging findings, treatment, therapeutic response, and date of death or last follow‐up.Eight cases of PFSSCC in dogs were treated with radiation therapy at the authors' institution. Three of these dogs were treated with coarse‐fractionated radiation therapy. One dog was euthanized due to an unrelated cause 36 months after completing the radiation therapy. The second and third dogs survived 18 and 3 months, respectively, from the end of treatment to death due to PFSCC. Five further dogs were treated with a more fractionated protocol (Monday–Wednesday–Friday schedule). The median survival time for all patients was 7.5 months (range 2–36 months).Despite the small number of cases and variation in the radiation protocols used, the treatment outcomes in these eight dogs suggest that radiation therapy is potentially a viable treatment option for dogs with PFSSCC and that coarse fractionation might be an appropriate approach if more finely fractionated protocols are not possible.- Book : 66(1)
- Pub. Date : 2025
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2025
Antibody–drug conjugates (ADCs) have emerged as a transformative approach in cancer therapy by enhancing tumor targeting and minimizing systemic toxicity compared to traditional chemotherapy. Initially developed with chemotherapy agents as payloads, ADCs have now incorporated alternative payloads, such as immune-stimulating agents, natural toxins, and radionuclides, to improve therapeutic efficacy and specificity. A significant advancement in ADC technology is the integration of Proteolysis Targeting Chimeras (PROTACs), which enable the precise degradation of cellular targets involved in tumorigenesis. This strategy enhances the specificity and precision of cancer therapies, addressing key mechanisms in cancer cell survival. Moreover, incorporating radioactive isotopes into ADCs is an emerging strategy aimed at further improving therapeutic outcomes. By delivering localized radiation, this approach offers the potential to enhance the efficacy of treatment and expand the therapeutic arsenal. Despite these innovations, challenges remain, including dysregulated immune activation, severe adverse effects, and intrinsic immunogenicity of some agents. These emerging issues highlight the ongoing need for optimization in ADC therapy. This review summarizes the latest developments in ADC technology, focusing on novel payloads, PROTAC integration, and the potential for combining ADCs with other therapeutic modalities to refine cancer treatment and improve patient outcomes. - Book : 17()
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