In this phase 3 trial, among infants with spinal muscular atrophy, those who received nusinersen were more likely to achieve major motor milestones and less likely to need permanent assisted ...ventilation than those who underwent a sham procedure.
RESUMO Este relato descreve o caso do Cladosporium cladosporioides isolado de uma lesão periocular de um felino atendido no Hospital Veterinário da Universidade Federal de Mato Grosso, em Cuiabá. A ...principal queixa do proprietário era uma lesão periocular, com piora no decorrer do tempo, havia aproximadamente quatro meses. Foi descrita a tentativa de tratamento da lesão com anti-inflamatórios e antibióticos, sem sucesso. Na anamnese foi relatado que o animal tinha acesso à rua e a hábitos de caça e que não havia outros animais da casa com lesão semelhante. O animal foi submetido à biópsia e citologia para um diagnóstico mais preciso do caso. Um fragmento foi encaminhado para o Laboratório de Patologia Veterinária e outro para o de Microbiologia Veterinária. Nas análises histopatológicas, houve compatibilidade com carcinoma de células escamosas e, nas lâminas de citologia, foi evidenciado um processo inflamatório agudo. Nas características macroscópicas e microscópicas da colônia, houve compatibilidade com Cladosporium sp. Posteriormente, o DNA foi extraído e sequenciado, confirmando a espécie Cladosporium cladosporioides. O objetivo deste relato foi descrever o isolamento dessa espécie em um felino com carcinoma de células escamosas.
In this single-group, phase 2 study, the use of trastuzumab deruxtecan resulted in a response in 60% of women with HER2-positive advanced breast cancer who had received a median of six previous lines ...of therapy. The drug was associated with myelosuppression and gastrointestinal toxicity; interstitial lung disease was reported in 13.6% of the patients.
Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid ...substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.
Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, ...facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3' end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin.
Objective
IgG4‐related disease (IgG4‐RD) is a fibro‐inflammatory condition that can affect multiple organs. We previously demonstrated that TLR7‐transgenic C57BL/6 mice showed elevated serum IgG1 ...levels and inflammation with fibrosis in the salivary glands (SGs), lungs, and pancreas. Moreover, we observed extensive Toll‐like receptor 7 (TLR‐7)–positive CD163+ M2 macrophage infiltration in SGs from IgG4‐RD patients. We undertook this study to examine the fibrotic mechanism via the TLR‐7 pathway.
Methods
Gene expression in SGs from human TLR7‐transgenic mice and IgG4‐RD patients was analyzed using DNA microarrays. We extracted the common up‐regulated TLR‐7–related genes in SGs from TLR7‐transgenic mice and IgG4‐RD patients. Finally, we investigated the interaction between CD163+ M2 macrophages and fibroblasts before and after stimulation with the TLR‐7 agonist loxoribine.
Results
In TLR7‐transgenic mice and IgG4‐RD patients, IRAK3 and IRAK4 were significantly overexpressed. Real‐time polymerase chain reaction validated the up‐regulation of only IRAK4 in IgG4‐RD patients compared with the other groups (P < 0.05). Interleukin‐1 receptor–associated kinase 4 (IRAK4) was strongly detected in and around germinal centers in SGs from patients with IgG4‐related dacryoadenitis and sialadenitis alone. Double immunofluorescence staining showed that IRAK4‐positive cells were mainly colocalized with CD163+ M2 macrophages in SGs (P < 0.05). After stimulation with loxoribine, CD163+ M2 macrophages exhibited significantly enhanced expression of IRAK4 and NF‐κB and increased supernatant concentrations of fibrotic cytokines. Finally, we confirmed that the number of fibroblasts was increased by culture with the supernatant of CD163+ M2 macrophages following stimulation with loxoribine (P < 0.05).
Conclusion
CD163+ M2 macrophages promote fibrosis in IgG4‐RD by increasing the production of fibrotic cytokines via TLR‐7/IRAK4/NF‐κB signaling.
It has been hypothesized that the therapeutic effects of artepillin C, a natural compound derived from Brazilian green propolis, are likely related to its partition in the lipid bilayer component of ...biological membranes. To test this hypothesis, we investigated the effects of the major compound of green propolis, artepillin C, on model membranes (small and giant unilamelar vesicles) composed of ternary lipid mixtures containing cholesterol, which display liquid-ordered (lo) and liquid-disordered (ld) phase coexistence. Specifically, we explored potential changes in relevant membrane parameters upon addition of artepillin C presenting both neutral and deprotonated states by means of small angle X-ray scattering (SAXS), differential scanning calorimetry (DSC), and confocal and multiphoton excitation fluorescence microscopy. Thermotropic analysis obtained from DSC experiments indicated a loss in the lipid cooperativity of lo phase at equilibrium conditions, while at similar conditions spontaneous formation of unilamellar vesicles from SAXS experiments showed that deprotonated artepillin C preferentially located at the surface of the membrane. Time-resolved experiments using fluorescence microscopy showed that at doses above 100 µM, artepillin C in its neutral state interacted with both liquid-ordered and liquid-disordered phases, inducing curvature stress and promoting dehydration at the membrane interface.
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