We report on the existence and nature of Holocene solar and climatic variations on centennial to millennial timescales. We introduce a new solar activity proxy, based on nitrate (NO3−) concentration ...from the Talos Dome ice core, East Antarctica. We also use a new algorithm for computing multiple-cross wavelet spectra in time–frequency space that is generalized for multiple time series (beyond two). Our results provide a new interpretive framework for relating Holocene solar activity variations on centennial to millennial timescales to co-varying climate proxies drawn from a widespread area around the globe. Climatic proxies used represent variation in the North Atlantic Ocean, Western Pacific Warm Pool, Southern Ocean and the East Asian monsoon regions. Our wavelet analysis identifies fundamental solar modes at 2300-yr (Hallstattzeit), 1000-yr (Eddy), and 500-yr (unnamed) periodicities, leaves open the possibility that the 1500–1800-yrcycle may either be fundamental or derived, and identifies intermediary derived cycles at 700-yr and 300-yr that may mark rectified responses of the Atlantic thermohaline circulation to external solar modulation and pacing. Dating uncertainties suggest that the 1500-yr and 1800-yrcycles described in the literature may represent either the same or two separate cycles, but in either case, and irrespective too of whether it is a fundamental or derived mode in the sense of Dima and Lohmann (2009), the 1500–1800-yr periodicity is widely represented in a large number of paleoclimate proxy records. It is obviously premature to reject possible links between changing solar activity at these multiple scales and the variations that are commonly observed in paleoclimatic records.
Botrytis cinerea is a fungal plant pathogen that causes significant economic losses in the agricultural industry worldwide. Fungicides that target microtubules, such as carbendazim (CBZ), ...diethofencarb (DEF), and zoxamide (ZOX), are widely used in crop protection against this pathogen. These groups of compounds exert their fungicidal activity by disrupting the microtubule assembly by binding to the β-tubulin subunit, provoking cell-cycle arrest and cell death. However, with the appearance of isolates resistant to these compounds, it is necessary to search for new alternatives to control this pathogenic fungus. In this work, we gained insight into the binding and stability of these fungicides in the benzimidazole binding site of B. cinerea β-tubulin through different computational approaches. Our molecular dynamics simulation replicas showed that R enantiomers of ZOX and its analog RH-4032 had better interaction profiles at the site compared to S enantiomers. The simulations also revealed that while the R-isomer fungicides formed H-bonds with the main chain carbonyl of V236 or the side chain residue of S314, only CBZ interacted with E198. Previous experimental data have identified key mutations in B. cinerea’s β-tubulin gene that lead to the development of resistance or, on the contrary, increased sensitivity for treatment with these fungicide compounds. In agreement with experimental findings, alchemical free energy calculations showed that E198A and E198V mutations in B. cinerea β-tubulin have high sensitivity to (R)-ZOX, whereas the E198K mutation decreased its affinity. Similarly, the results obtained explain the resistance to CBZ of B. cinerea isolates with E198A/V/K mutations and the insensitivity of the wild-type organism to DEF. Our work provides a deeper insight into the molecular mechanism of action of these fungicides, highlighting the importance of understanding the interaction profiles to develop more effective antifungal agents.
The data in clinical practice regarding the effectiveness and safety of brodalumab in psoriasis are scarce, especially at scalp and palmoplantar locations. The main objective was the percentage of ...patients achieving absolute PASI ≤3/ ≤1/ =0 for plaque psoriasis and the percentage of patients achieving an IGA 0-1/IGA 0 for the special locations at Week 52 of treatment.
Observational retrospective multicentre study in 28 Spanish Hospitals that included adult patients with plaque psoriasis treated with brodalumab, from September 2018 until March 2021.
A total of 200 patients were included. The mean baseline PASI was 10.97 (±6.28) with a mean basal scalp (n = 58) and palmoplantar (n = 40) IGA of 2.10 (±0.97) and 2.15 (±1.26), respectively. At Week 52, 93.98%/75.90%/68.67% of patients reached an absolute PASI ≤3/ ≤1/ =0 in plaque psoriasis (n = 83), with a percentage of patients achieving scalp (n = 27) and palmoplantar (n = 19) IGA 0-1/IGA 0 of 96.3%/88.9% and 100%/88.9%, respectively. Fifteen per cent of patients reported any adverse events with candidiasis being the most reported (6%), but only 6% of the adverse events required the withdrawal.
Brodalumab demonstrated high PASI and IGA responses and was well tolerated in clinical practice in plaque, scalp and palmoplantar psoriasis.
Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well ...known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the receptor kinase (RK) motif. The RK motif is accessible only upon TCR ligation, demonstrating how ligand binding leads to Lck recruitment. Binding of the Lck SH3 domain to the exposed RK motif resulted in local augmentation of Lck activity, CD3 phosphorylation, T cell activation and thymocyte development. Introducing the RK motif into a well-characterized 41BB-based chimeric antigen receptor enhanced its antitumor function in vitro and in vivo. Our findings underscore how a better understanding of the functioning of the TCR might promote rational improvement of chimeric antigen receptor design for the treatment of cancer.
We classify three dimensional evolution algebras over a field having characteristic different from 2 and in which there are roots of orders 2, 3 and 7.
The link between cancer and aberrant glycosylation has recently become evident. Glycans and their altered forms, known as tumour-associated carbohydrate antigens (TACAs), are diverse, complex and ...difficult to target therapeutically. Lectins are naturally occurring glycan-binding proteins that offer a unique opportunity to recognise TACAs. T cells expressing chimeric antigen receptors (CARs) have proven to be a successful immunotherapy against leukaemias, but so far have shown limited success in solid tumours. We developed a panel of lectin-CARs that recognise the glycosphingolipid globotriaosylceramide (Gb3), which is overexpressed in various cancers, such as Burkitt's lymphoma, colorectal, breast and pancreatic. We have selected the following lectins: Shiga toxin's B-subunit from
Shigella dysenteriae
, LecA from
Pseudomonas aeruginosa
, and the engineered lectin Mitsuba from
Mytilus galloprovincialis
as antigen-binding domains and fused them to a well-known second-generation CAR. The Gb3-binding lectin-CARs have demonstrated target-specific cytotoxicity against Burkitt's lymphoma-derived cell lines as well as solid tumour cells from colorectal and triple-negative breast cancer. Our findings reveal the big potential of lectin-based CARs as therapeutical applications to target Gb3 and other TACAs expressed in haematological malignancies and solid tumours.
PDF
