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GABA(B) receptor-mediated stimulation of adenylyl cyclase activity in membranes of rat olfactory bulb.

Previous studies have shown that GABA(B) receptors facilitate cyclic AMP formation in brain slices likely through an indirect mechanism involving intracellular second messengers. In the present study, we have investigated whether a positive coupling of GABA(B) receptors to adenylyl cyclase could be detected in a cell-free preparation of rat olfactory bulb, a brain region where other Gi/Go-coupled neurotransmitter receptors have been found to stimulate the cyclase activity. The GABA(B) receptor agonist (-)-baclofen significantly increased basal adenylyl cyclase activity in membranes of the gran

NTP Toxicology and Carcinogenesis Studies of Dimethyl Hydrogen Phosphite (CAS No. 868-85-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Dimethyl hydrogen phosphite (DMHP) is used as an intermediate in the production of insecticides and herbicides, as an additive to lubricants, and as a stabilizer in oil and plaster and was considered for use as a chemical to simulate the physical (but not the biologic) properties of anticholinesterase agents. Results of 13-week gavage studies in F344/N rats (0-400 mg DMHP/kg body weight) and in B6C3F1 mice (0-1,500 mg DMHP/kg body weight) were used to identify short-term toxicity and to establish doses for the 2-year toxicology and carcinogenesis studies. In these studies, dimethyl hydrogen ph

Calcium microdomains near R-type calcium channels control the induction of presynaptic long-term potentiation at parallel fiber to purkinje cell synapses.

R-type calcium channels in postsynaptic spines signal through functional calcium microdomains to regulate a calcium/calmodulin-sensitive potassium channel that in turn regulates postsynaptic hippocampal long-term potentiation (LTP). Here, we ask whether R-type calcium channels in presynaptic terminals also signal through calcium microdomains to control presynaptic LTP. We focus on presynaptic LTP at parallel fiber to Purkinje cell synapses in the cerebellum (PF-LTP), which is mediated by calcium/calmodulin-stimulated adenylyl cyclases. Although most presynaptic calcium influx is through N-type

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

BackgroundMCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902).MethodsBinding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xen

Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain.

Severe head trauma causes widespread neuronal shear injuries and acute seizures. Shearing of neural processes might contribute to seizures by disrupting the transmembrane ion gradients that subserve normal synaptic signaling. To test this possibility, we investigated changes in intracellular chloride concentration ([Cl(-)](i)) associated with the widespread neural shear injury induced during preparation of acute brain slices. In hippocampal slices and intact hippocampal preparations from immature CLM-1 mice, increases in [Cl(-)](i) correlated with disruption of neural processes and biomarkers

Radiolabeled Peptides and Antibodies in Medicine.

Radiolabeled peptides are a relatively new, very specific radiotracer group, which is still expanding. This group is very diverse in terms of peptide size. It contains very small structures containing several amino acids and whole antibodies. Moreover, radiolabeled peptides are diverse in terms of the binding aim and therapeutic or diagnostic applications. The majority of this class of radiotracers is utilized in oncology, where the same structure can be used in therapy and diagnostic imaging by varying the radionuclide. In this study, we collected new reports of radiolabeled peptide applicati

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… an ortho trifluoromethyl group. 8 Direct labeling technique nowadays involves mostly radioiodination and in some cases technetium-labeling. 9 , 10 Technetium direct labeling requires a specific structure of labeled agent coordination sphere, for example, with thiol groups, and reducing agents like phosphines … J. ( 2005 ) Water-soluble phosphines for direct labeling of peptides with technetium and rhenium: Insights from electrospray mass spectrometry . Bioconjugate Chem. 16 ( 4 ), 939 – 948 . 10.1021/bc0500600 . 16029035 Wilbur D. …

Covalent targeting of PSMD14 by Eupalinolide B induces oncoprotein degradation and apoptosis in acute promyelocytic leukemia cells.

Treatment of acute promyelocytic leukemia (APL) remains challenged by toxicities associated with current regimens, highlighting the need for novel and safer therapeutic agents. Here, we identify Eupalinolide B (EB), a natural sesquiterpene lactone isolated from Eupatorium lindleyanum DC., as a potent anti-leukemic compound targeting the human APL-derived HL-60 cell line. Through integrated chemoproteomic profiling and functional validation, we demonstrate that EB covalently binds and inhibits 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a deubiquitinase enzyme (DUB) within the 19S

Intraglomerular inhibition: signaling mechanisms of an olfactory microcircuit.

Microcircuits composed of principal neuron and interneuron dendrites have an important role in shaping the representation of sensory information in the olfactory bulb. Here we establish the physiological features governing synaptic signaling in dendrodendritic microcircuits of olfactory bulb glomeruli. We show that dendritic gamma-aminobutyric acid (GABA) release from periglomerular neurons mediates inhibition of principal tufted cells, retrograde inhibition of sensory input and lateral signaling onto neighboring periglomerular cells. We find that L-type dendritic Ca(2+) spikes in periglomerul

Brigatinib и Alectinib for ALK Restruction-Positive Under-Spective Meta-Analysis с центральной нервной системой или без нее.

На сегодняшний день ни одно из испытаний не сравнивало эффективность бригатиниба и алектиниба с анапластической лимфатической киназой (АЛК) реструктуризацией положительной (ALK-p), АЛК-инбитор-наив, передовым раком легких немалых клеток (NSCLC) с метастазом центральной нервной системы (CNS). Мы провели непрямое сопоставление между бригатинибом и алектинибом с использованием кризотиниба в качестве общего компаратора, используя байезскую модель с неинформационным предварительным распределением, и провели оценку неоднородности исследований между исследованиями. Основным конечным показателем эффек

The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease.

Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone di

Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs).

Antibody-drug conjugates (ADCs) are emerging as effective tools in cancer therapy, combining the antibody's exquisite specificity for the target antigen-expressing cancer cell together with the cytotoxic potency of the payload. Much success stems from the rational design of "toxic warheads", chemically linked to antibodies, and from fine-tuning the intricate properties of chemical linkers. Here, we focus on the antibody moiety of ADCs, dissecting the impact of Fab, linkers, isotype and Fc structure on the anti-tumoral and immune-activating functions of ADCs. Novel design approaches informed by

Ведомые АПРЕЛЬ БКМА/ТАКИ двойные целевые лиганды-наркотики для селективной и мощной терапии множественной миеломы.

Антиген созревания клеток B (BCMA) в значительной степени проявляется в злокачественных плазменных клетках и является идеальной терапевтической целью в множестве миеломы (MM). Однако эффективность лечения, ориентированного на BCMA, часто ограничивается регулированием деградации антигенов и выходом из опухоли. В этой связи мы представляем информацию о разработке двухцелевого лиганда-наркотика (НРС), использующего подпитывающий распространение лиган (АПРИЛ), естественного лиганда как для BCMA, так и для трансмембранового активатора, а также кальция-модулятора и циклофилина лиганда (TACI). Такая

The research progress on radionuclides in osteoporosis diagnosis and drug efficacy monitoring.

Osteoporosis is a common metabolic bone disease that seriously affects the quality of life and health of patients. Traditional diagnostic methods, such as dual energy X-ray absorptiometry (DXA), have limitations in early detection and dynamic monitoring, making it difficult to meet clinical needs. This paper focuses on the potential of radionuclide imaging techniques, such as Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), in the early diagnosis of osteoporosis. The paper further elaborates on the importance of radionuclides in evaluating the therapeu

Discovery and validation of surface N-glycoproteins in MM cell lines and patient samples uncovers immunotherapy targets.

BackgroundMultiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow. While recent advances in treatment for MM have improved patient outcomes, the 5-year survival rate remains ~50%. A better understanding of the MM cell surface proteome could facilitate development of new directed therapies and assist in stratification and monitoring of patient outcomes.MethodsIn this study, we first used a mass spectrometry (MS)-based discovery-driven cell surface capture (CSC) approach to map the cell surface N-glycoproteome of MM cell lines. Next, we developed t

Кристальная структура и каталитический механизм дрименоловой синтазы, необычная двухфункциональная терпеновая киклаза-фосфатаза.

Дрименол синтаза из Aquimarina pongiae (ASDMS) — очень необычная химера, интегрирующая two - отдельные, последовательные операции по переработке изопреноидов в рамках единой полипептидной цепи. ASDMS катализирует циклизацию фарнесилового дифосфата (FPP) класса II для образования дрименилового дифосфата, который затем подвергается гидролизу энзим-катализу для получения дрименинола, биоактивного сескитерпенового спирта с антифунгальными и антираковыми свойствами. Здесь мы сообщаем рентгеновские кристаллы ASDMS и его комплекс с сескитерпен тиол. Структура ASDMS имеет дидомаиновую архитектуру, сос

Global ethylene oxide uses in foods and considerations for food safety.

Ethylene oxide (EtO) is a sterilant widely used for medical devices, but its use is controversial due to its carcinogenicity. In some countries, EtO is also used to fumigate food to eliminate foodborne pathogens, though this practice is banned in others. National regulations on EtO use in food vary widely; exporting countries prioritize trade facilitation and prevention of foodborne illness, while importing countries emphasize maintaining food safety and promoting domestic public health. These divergent public health priorities present challenges to establishing universal maximum residue limit

Proteomic analysis identifies pathways related to immune dysregulation in patients with hematologic malignancies after COVID-19 infection.

Patients with hematologic malignancies (HMs) are particularly vulnerable to coronavirus disease 2019 (COVID-19) because of underlying immune dysfunction and treatment-related immunosuppression. However, proteomic features associated with different clinical trajectories in this population remain insufficiently characterized. We performed serum proteomic analysis in 40 HM patients with COVID-19 and 15 healthy controls. Compared with controls, HM patients showed impaired immune-related responses during the acute phase of COVID-19. Acute-phase proteomic patterns differed across outcome groups; how

Unc-51 like kinase 3 (ULK3) contributes to autophagy and cell survival in multiple myeloma.

Despite effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. Analysis of RNA sequencing data from CD138 + MM patient cells (n = 813) across disease stages identifies an autophagy gene signature. Particularly elevated ULK3 expression is strongly associated with disease progression. Functional studies reveal that ULK3 supports MM cell survival via the ULK-ATG13-FIP200 complex. We generate small-molecule kinase inhibitors (SG3-014/MA9-060) exhibiting nanomolar potency against ULK3, with binding confirmed by co-crystallization. While ex

Роль антиоксидантов в множестве миеломы: диагностика, прогнозирование и терапевтическое применение: обзор сюжета.

Множественная миэлома (ММ) — злокачественная клетка B-клеток с моноклональными плазменными клетками, производящими нефункциональные иммуноглобулины. Она по-прежнему неизлечима из-за de novo или приобретенного сопротивления злокачественных клеток стандартным химиотерапиям. Таким образом, понимание механизма терапевтического сопротивления имеет важнейшее значение для разработки более эффективных мер вмешательства и определения новых целей лечения. MM - это разнородная болезнь, характеризующаяся сложными генетическими изменениями, которые имеют решающее значение для прогнозирования стратификации.

Клетки T-бет+CXCR3+B вызывают гиперреактивное взаимодействие клеток B-T в множестве склерозов.

Множественный склероз (MS) — аутоиммунное заболевание центральной нервной системы (CNS). Одним из ключевых механизмов в НР является автораспространение (АП) ячеек В и Т, основанное на самопропитании. Здесь мы показываем, что про-воспаление B-T-обогащенные клетки клеток (BTEC) формируются во время AP и зеркальные особенности реакции микроцентра. T-bet+CXCR3+B — основной подмножество клеток, усиливающих и поддерживающих свои параллельные клетки TH1 с помощью интерферона (IFN)-__, и присутствуют в сильно воспламенённой менингетной ткани. Фундаментальная сигнатура активации клеток В находит свое о