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1.
Sci Rep ; 14(1): 13199, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38851793

RESUMEN

The increasing global phenomenon of soil salinization has prompted heightened interest in the physiological ecology of plant salt and alkali tolerance. Halostachys caspica belonging to Amaranthaceae, an exceptionally salt-tolerant halophyte, is widely distributed in the arid and saline-alkali regions of Xinjiang, in Northwest China. Soil salinization and alkalinization frequently co-occur in nature, but very few studies focus on the interactive effects of various salt and alkali stress on plants. In this study, the impacts on the H. caspica seed germination, germination recovery and seedling growth were investigated under the salt and alkali stress. The results showed that the seed germination percentage was not significantly reduced at low salinity at pH 5.30-9.60, but decreased with elevated salt concentration and pH. Immediately after, salt was removed, ungerminated seeds under high salt concentration treatment exhibited a higher recovery germination percentage, indicating seed germination of H. caspica was inhibited under the condition of high salt-alkali stress. Stepwise regression analysis indicated that, at the same salt concentrations, alkaline salts exerted a more severe inhibition on seed germination, compared to neutral salts. The detrimental effects of salinity or high pH alone were less serious than their combination. Salt concentration, pH value, and their interactions had inhibitory effects on seed germination, with salinity being the decisive factor, while pH played a secondary role in salt-alkali mixed stress.


Asunto(s)
Álcalis , Amaranthaceae , Germinación , Plantas Tolerantes a la Sal , Semillas , Germinación/efectos de los fármacos , Plantas Tolerantes a la Sal/crecimiento & desarrollo , Amaranthaceae/crecimiento & desarrollo , Semillas/efectos de los fármacos , Semillas/crecimiento & desarrollo , Concentración de Iones de Hidrógeno , Plantones/crecimiento & desarrollo , Plantones/efectos de los fármacos , Salinidad , Estrés Fisiológico , Cloruro de Sodio/farmacología , Estrés Salino , Tolerancia a la Sal
2.
J Chem Phys ; 160(18)2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38716843

RESUMEN

Polycyclic aromatic hydrocarbons (PAHs) are common atmospheric pollutants, and they are also ubiquitous in the interstellar medium. Here, we report the study of a complex O-containing PAH anion, the deprotonated 2-hydroxytriphenylene (2-OtPh-), using high-resolution photoelectron imaging and photodetachment spectroscopy of cryogenically cooled anions. Vibrationally resolved photoelectron spectra yield the electron affinity of the 2-OtPh radical as 2.629(1) eV and several vibrational frequencies for its ground electronic state. Photodetachment spectroscopy reveals bound valence excited electronic states for the 2-OtPh- anion, with unprecedentedly rich vibronic features. Evidence is presented for a low-lying triplet state (T1) and two singlet states (S1 and S2) below the detachment threshold. Single-color resonant two-photon photoelectron spectroscopy uncovers rich photophysics for the 2-OtPh- anion, including vibrational relaxation in S1, internal conversion to the ground state of 2-OtPh-, intersystem crossing from S2 to T1, and a long-lived autodetaching shape resonance about 1.3 eV above the detachment threshold. The rich electronic structure and photophysics afforded by the current study suggest that 2-OtPh- would be an interesting system for pump-probe experiments to unravel the dynamics of the excited states of this complex PAH anion.

3.
J Med Chem ; 67(10): 7836-7858, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38695063

RESUMEN

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.


Asunto(s)
Antineoplásicos , Mutación , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Humanos , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Ratones , Línea Celular Tumoral , Sulfonamidas/farmacología , Sulfonamidas/química , Ratas , Descubrimiento de Drogas
4.
Int Immunopharmacol ; 134: 112149, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38692019

RESUMEN

Systemic lupus erythematosus (SLE) is a severe autoimmune disease with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal immune function, and disordered energy metabolism is increasingly recognized as an important contributor to the pathogenesis of SLE. Disorders of energy metabolism are characterized by increased reactive oxygen species, ATP deficiency, and abnormal metabolic pathways. Oxygen and mitochondria are critical for the production of ATP, and both mitochondrial dysfunction and hypoxia affect the energy production processes. In addition, several signaling pathways, including mammalian target of rapamycin (mTOR)/adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling and the hypoxia-inducible factor (HIF) pathway also play important regulatory roles in energy metabolism. Furthermore, drugs with clear clinical effects on SLE, such as sirolimus, metformin, and tacrolimus, have been proven to improve the disordered energy metabolism of immune cells, suggesting the potential of targeting energy metabolism for the treatment of SLE. Moreover, several metabolic modulators under investigation are expected to have potential therapeutic effects in SLE. This review aimed to gain insights into the role and mechanism of abnormal energy metabolism in the pathogenesis of SLE, and summarizes the progression of metabolic modulator in the treatment of SLE.


Asunto(s)
Metabolismo Energético , Lupus Eritematoso Sistémico , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/inmunología , Humanos , Animales , Mitocondrias/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal , Proteínas Quinasas Activadas por AMP/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adenosina Trifosfato/metabolismo
5.
Anaesthesiologie ; 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38575771

RESUMEN

BACKGROUND: Delayed extubation and transfer to the intensive care unit (ICU) in children undergoing major scoliosis surgery may increase postoperative complications, prolong hospital stay, and increase medical expenses; however, whether a child will require delayed extubation or transfer to the ICU after scoliosis orthopedic surgery is not fully understood. In this study, we reviewed the risk factors for delayed extubation and transfer to the ICU after scoliosis orthopedic surgery in children. METHOD: The electronic medical records of pediatric patients (≤ 18 years) who underwent posterior spinal fusion surgery between January 2018 and November 2021 were reviewed and analyzed. Patient characteristics (age, sex, body mass index, American Society of Anesthesiologists, ASA, grade, preoperative lung function, and congenital heart disease), preoperative Cobb angle, scoliosis type, correction rate, vertebral fusion segments, pedicle screws, surgical osteotomy, intraoperative bleeding, intraoperative allogeneic transfusion, intraoperative hemoglobin changes, intraoperative mean arterial pressure changes, intraoperative tidal volume (ml/kg predicted body weight), surgical time, postoperative extubation, and transfer to the ICU were collected. The primary outcomes were delayed extubation and transfer to the ICU. Multivariate logistic regression models were used to determine the risk factors for delayed extubation and ICU transfer. RESULTS: A total of 246 children who satisfied the inclusion criteria were enrolled in this study, of whom 23 (9.3%) had delayed extubation and 81 (32.9%) were transferred to the ICU after surgery. High ASA grade (odds ratio [OR] 5.42; 95% confidence interval [CI] 1.49-19.78; p = 0.010), high Cobb angle (OR 1.04; 95% CI 1.02-1.07; p < 0.001), moderate to severe pulmonary dysfunction (OR 10.9; 95% CI 2.00-59.08; p = 0.006) and prolonged surgical time (OR 1.01; 95% CI 1.00-1.03; p = 0.040) were risk factors for delayed extubation. A high Cobb angle (OR 1.02; 95% CI 1.01-1.04; p = 0.004), high intraoperative bleeding volume (OR 1.06; 95% CI 1.03-1.10; p = 0.001), allogeneic transfusion (OR 3.30; 95% CI 1.24-8.83; p = 0.017) and neuromuscular scoliosis (OR 5.38; 95% CI 1.59-18.25; p = 0.007) were risk factors for transfer to the ICU. A high Cobb angle was a risk factor for both delayed extubation and ICU transfer. Age, sex, body mass index, number of vertebral fusion segments, correction rate, and intraoperative tidal volume were not associated with delayed postoperative extubation and ICU transfer. CONCLUSION: The most common risk factor for delayed extubation and ICU transfer in pediatric patients who underwent posterior spinal fusion was a high Cobb angle. Determining risk factors for a poor prognosis may help optimize perioperative respiratory management strategies and planning of postoperative care for children undergoing complicated spinal surgery.

7.
J Phys Chem A ; 128(18): 3579-3586, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38662918

RESUMEN

We report a high-resolution photoelectron imaging study of cryogenically cooled BiB2- and BiB3- clusters. Vibrational features are completely resolved for the ground-state detachment transitions, providing critical information about the structures of the anionic clusters and their corresponding neutrals. The electron affinities of BiB2 and BiB3 are accurately measured to be 2.174(1) and 2.121(1) eV, respectively. The B-B and Bi-B stretching frequencies are measured to be 1262 and 476 cm-1, respectively, in the ground state of BiB2. Three vibrational frequencies are measured for the ground state of BiB3: 1194 cm-1 (B-B stretching), 782 cm-1 (B-B stretching), and 339 cm-1 (Bi-B stretching). Both BiB2- and BiB3- and their neutral ground states are found to have planar C2v structures in which the Bi atom bridges two B atoms. BiB2- is found to have a triplet spin state (3B2), consistent with its complicated photoelectron spectra, whereas BiB3- is a doublet (2B1) and neutral BiB3 is closed shell (1A1). Both BiB2 and BiB3 consist of peripheral localized Bi-B and B-B σ bonds and delocalized π and σ bonds.

8.
J Phys Chem A ; 128(18): 3564-3570, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38676655

RESUMEN

Spontaneous symmetry-breaking is common in chemical and physical systems. Here, we show that by adding an electron to the C7v PbB8 cluster, which consists of a planar B8 disk with the Pb atom situated along the C7 axis, the Pb atom spontaneously moves to the off-axis position in the PbB8- anion. Photoelectron spectroscopy of PbB8- reveals a broad ground-state transition and a large energy gap, suggesting a highly stable closed-shell PbB8 borozene complex and a significant geometry change upon electron detachment. Quantum chemistry calculations indicate that the lowest unoccupied molecular orbital of the C7v PbB8 cluster is a degenerate π orbital mainly consisting of the Pb 6px and 6py atomic orbitals. Occupation of one of the 6p orbitals spontaneously break the C7v symmetry in the anion due to the Jahn-Teller effect. The large amplitude of the position change of Pb in PbB8- relative to PbB8 is surprising owing to bonding interactions between the Pb 6p orbital with the π orbital of the B8 borozene.

9.
Angew Chem Int Ed Engl ; : e202406535, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38652809

RESUMEN

Borophenes have sparked considerable interest owing to their fascinating physical characteristics and diverse polymorphism. However, borophene nanoribbons (BNRs) with widths less than 2 nm have not been achieved. Herein, we report the experimental realization of supernarrow BNRs. Combining scanning tunneling microscopy imaging with density functional theory modeling and ab initio molecular dynamics simulations, we demonstrate that, under the applied growth conditions, boron atoms can penetrate the outermost layer of Au(111) and form BNRs composed of a pair of zigzag (2,2) boron rows. The BNRs have a width self-contained to ∼1 nm and dipoles at the edges to keep them separated. They are embedded in the outermost Au layer and shielded on top by the evacuated Au atoms, free of the need for post-passivation. Scanning tunneling spectroscopy reveals distinct edge states, primarily attributed to the localized spin at the BNRs' zigzag edges. This work adds a new member to the boron material family and introduces a new physical feature to borophenes.

10.
Pediatr Neurol ; 154: 20-25, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38452434

RESUMEN

BACKGROUND: The pathophysiology and the potential risks of placental transfusion (PT) differ substantially in preterm infants, necessitating specific studies in this population. This study aimed to evaluate the safety and efficacy of PT in preterm infants from the perspective of long-term neurodevelopmental outcomes. METHODS: We conducted a systematic literature search using placental transfusion, preterm infant, and its synonyms as search terms. Cochrane Central Register of Controlled Trials, Medline, and Embase were searched until March 07, 2023. Two reviewers independently identified, extracted relevant randomized controlled trials, and appraised the risk of bias. The extracted studies were included in the meta-analysis of long-term neurodevelopmental clinical outcomes using fixed-effects models. RESULTS: A total of 5612 articles were identified, and seven randomized controlled trials involving 2551 infants were included in our meta-analysis. Compared with immediate cord clamping (ICC), PT may not impact adverse neurodevelopment events. No clear evidence was found of a difference in the risk of neurodevelopmental impairment (risk ratio [RR]: 0.89, 95% confidence interval [CI]: 0.76 to 1.03, P = 0.13, I2 = 0). PT was not associated with the incidence of cerebral palsy (RR: 1.23, 95% CI: 0.59 to 2.57, P = 0.79, I2 = 0). Analyses showed no differences between the two interventions in cognitive, language, and motor domains of neurodevelopment. CONCLUSIONS: From the perspective of long-term neurodevelopment, PT at preterm birth may be as safe as ICC. Future studies should focus on standardized, high-quality clinical trials and individual participant data to optimize cord management strategies for preterm infants after birth.


Asunto(s)
Recien Nacido Prematuro , Nacimiento Prematuro , Lactante , Recién Nacido , Humanos , Femenino , Embarazo , Clampeo del Cordón Umbilical , Placenta , Ensayos Clínicos Controlados Aleatorios como Asunto
11.
Behav Brain Res ; 465: 114960, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38494129

RESUMEN

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer's disease and Parkinson's disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.


Asunto(s)
Miedo , Trastornos por Estrés Postraumático , Animales , Ratones , Quinasa de la Caseína II/metabolismo , Condicionamiento Clásico/fisiología , Extinción Psicológica/fisiología , Miedo/fisiología , Corteza Prefrontal/metabolismo , Trastornos por Estrés Postraumático/metabolismo
12.
Structure ; 32(5): 550-561.e5, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38460520

RESUMEN

TIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab_Fab and Tiragolumab_Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103HCDR3 and HIS76TIGIT explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment.


Asunto(s)
Modelos Moleculares , Unión Proteica , Receptores Inmunológicos , Concentración de Iones de Hidrógeno , Humanos , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/química , Cristalografía por Rayos X , Anticuerpos Monoclonales/química , Sitios de Unión , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/inmunología
13.
Phys Chem Chem Phys ; 26(17): 12928-12938, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38456623

RESUMEN

Copper has been shown to be an important substrate for the growth of borophenes. Copper-boron binary clusters are ideal platforms to study the interactions between copper and boron, which may provide insight about the underlying growth mechanisms of borophene on copper substrates. Here we report a joint photoelectron spectroscopy and theoretical study on two copper-doped boron clusters, CuB7- and CuB8-. Well resolved photoelectron spectra are obtained for the two clusters at different wavelengths and are used to understand the structures and bonding properties of the two CuBn- clusters. We find that CuB8- is a highly stable borozene complex, which possesses a half-sandwich structure with a Cu+ species interacting with the doubly aromatic η8-B82- borozene. The CuB7- cluster is found to consist of a terminal copper atom bonded to a double-chain B7 motif, but it has a low-lying isomer composed of a half-sandwich structure with a Cu+ species interacting with an open-shell η7-B72- borozene. Both ionic and covalent interactions are found to be possible in the binary Cu-B clusters, resulting in different structures.

14.
Funct Integr Genomics ; 24(2): 55, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38467948

RESUMEN

Huang Qin decoction (HQD) is a traditional Chinese medicine formula for treating colitis, but the effects and molecular mechanism of action of HQD in colitis-associated carcinogenesis (CAC) are still unclear. Therefore, we aimed to determine the beneficial effects of HQD on CAC in mice and to reveal the underlying mechanism involved. AOM/DSS was used to induce CAC in mice, and the effects of HQD on tumorigenesis in mice were examined (with mesalazine serving as a positive control). Mesalazine or HQD treatment alleviated body weight loss and decreased the disease activity index in mice induced by AOM/DSS. Mesalazine or HQD treatment also suppressed the shortening of colon tissue length, the number of tumors, and the infiltration of inflammatory cells. The genes targeted by HQD were predicted and verified, followed by knockout experiments. Elevated SLC6A4 and inhibited serotonin production and inflammation were observed in HQD-treated mice. HQD inhibited the NFκB and NLRP3/caspase1/GSDMD pathways. The therapeutic effect of HQD was diminished in SLC6A4-deficient AOM/DSS mice. Additionally, the downregulation of SLC6A4 mitigated the inhibitory effect of HQD-containing serum on MODE-K cell pyroptosis. Our findings suggest that SLC6A4 is a pivotal regulator of HQD-alleviated CAC via its modulation of the NLRP3/caspase1/GSDMD pathway.


Asunto(s)
Colitis , Scutellaria baicalensis , Ratones , Animales , Mesalamina , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/tratamiento farmacológico , Carcinogénesis/metabolismo , Ratones Endogámicos C57BL
15.
ACS Appl Mater Interfaces ; 16(8): 10996-11002, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38349800

RESUMEN

The integration of dissimilar semiconductor materials holds immense potential for harnessing their complementary properties in novel applications. However, achieving such combinations through conventional heteroepitaxy or wafer bonding techniques presents significant challenges. In this research, we present a novel approach involving the direct bonding of InGaAs-based p-i-n membranes with GaN, facilitated by van der Waals forces and microtransfer printing technology. The resulting n-InP/n-GaN heterojunction was rigorously characterized through electrical measurements, with a comprehensive investigation into the impact of various surface treatments on device performance. The obtained InGaAs/GaN photodetector demonstrates remarkable electrical properties and exhibits a high optical responsivity of 0.5 A/W at the critical wavelength of 1550 nm wavelength. This pioneering work underscores the viability of microtransfer printing technology in realizing large lattice-mismatched heterojunction devices, thus expanding the horizons of semiconductor device applications.

16.
Ann Med Surg (Lond) ; 86(2): 643-649, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38333301

RESUMEN

Introduction and importance: There is no expert consensus or guidance on perioperative anaesthesia management for spinal surgery of spinal muscular atrophy (SMA) patients with severe scoliosis (Cobb≧90°). We provide a comprehensive summary of the perioperative characteristics observed in patients with SMA and propose an optimized perioperative management strategy for anaesthesia. Methods: This study is a retrospective single-centre research. Twenty-six SMA patients with severe scoliosis underwent posterior spinal fusion surgery from September 2019 to September 2022 were enroled. The main outcomes were to show the patients' characteristics in anaesthesia, intra- and post-operative periods. Outcomes: Nineteen patients underwent awake transnasal/transairway intubation. The median anaesthesia time of 25 patients treated under total intravenous anaesthesia was 425 min. After operation, the Cobb angle and correction rate in the coronal plane were median 54.0° and 54.4%. The length of mechanical ventilation with endotracheal intubation in ICU was median 17.5 h in 8 patients. The ICU length of stay of postoperative hospital was median 19 days. Postoperative pneumonia developed in nine patients, atelectasis in two patients, and pleural effusion in six patients. All patients did not need special oxygen therapy after discharge. Conclusion: Multidisciplinary consultation, lung-protective ventilation strategy, appropriate anaesthetic drugs and reasonable blood transfusion scheme and postoperative monitoring were important in anaesthesia, intraoperative and postoperative periods in the patients of severe scoliosis with spinal muscular atrophy.

17.
Blood ; 143(18): 1825-1836, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38211332

RESUMEN

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.


Asunto(s)
Antineoplásicos , Compuestos Bicíclicos Heterocíclicos con Puentes , Resistencia a Antineoplásicos , Neoplasias Hematológicas , Proteínas Proto-Oncogénicas c-bcl-2 , Sulfonamidas , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sulfonamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Animales , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Mutación , Apoptosis/efectos de los fármacos
18.
Proc Natl Acad Sci U S A ; 121(6): e2314819121, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38285944

RESUMEN

SO2 (Sulfur dioxide) is the major precursor to the production of sulfuric acid (H2SO4), contributing to acid rain and atmospheric aerosols. Sulfuric acid formed from SO2 generates light-reflecting sulfate aerosol particles in the atmosphere. This property has prompted recent geoengineering proposals to inject sulfuric acid or its precursors into the Earth's atmosphere to increase the planetary albedo to counteract global warming. SO2 oxidation in the atmosphere by the hydroxyl radical HO to form HOSO2 is a key rate-limiting step in the mechanism for forming acid rain. However, the dynamics of the HO + SO2 → HOSO2 reaction and its slow rate in the atmosphere are poorly understood to date. Herein, we use photoelectron spectroscopy of cryogenically cooled HOSO2- anion to access the neutral HOSO2 radical near the transition state of the HO + SO2 reaction. Spectroscopic and dynamic calculations are conducted on the first ab initio-based full-dimensional potential energy surface to interpret the photoelectron spectra of HOSO2- and to probe the dynamics of the HO + SO2 reaction. In addition to the finding of a unique pre-reaction complex (HO⋯SO2) directly connected to the transition state, dynamic calculations reveal that the accessible phase space for the HO + SO2 → HOSO2 reaction is extremely narrow, forming a key reaction bottleneck and slowing the reaction rate in the atmosphere, despite the low reaction barrier. This study underlines the importance of understanding the full multidimensional potential energy surface to elucidate the dynamics of complex bimolecular reactions involving polyatomic reactants.

19.
Phys Chem Chem Phys ; 26(6): 5356-5367, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38269413

RESUMEN

Boron has been found to be able to form multiple bonds with lead. To probe Pb-B bonding, here we report an investigation of three Pb-doped boron clusters, PbB2-, PbB3O-, and PbB4O2-, which are produced by a laser ablation cluster source and characterized by photoelectron spectroscopy and ab initio calculations. The most stable structures of PbB2-, PbB3O-, and PbB4O2- are found to follow the formula, [PbB2(BO)n]- (n = 0-2), with zero, one, and two boronyl ligands coordinated to a triangular and aromatic PbB2 core, respectively. The PbB2- cluster contains a BB double bond and two Pb-B single bonds. The coordination of BO is observed to weaken Pb-B bonding but strengthen the BB bond in [PbB2(BO)n]- (n = 1, 2). The anionic [PbB2(BO)2]- and its corresponding neutral closed-shell [PbB2(BO)2] contain a BB triple bond. A low-lying Y-shaped isomer is also observed for PbB4O2-, consisting of a central sp2 hybridized B atom bonded to two boronyl ligands and a PbB unit.

20.
World J Pediatr ; 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38238638

RESUMEN

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) not only significantly improves survival rates in severely ill neonates but also is associated with long-term neurodevelopmental issues. To systematically review the available literature on the neurodevelopmental outcomes of neonates and infants who have undergone ECMO treatment, with a focus on motor deficits, cognitive impairments, sensory impairments, and developmental delays. This review aims to understand the incidence, prevalence, and risk factors for these problems and to explore current nursing care and management strategies. DATA SOURCES: A comprehensive literature search was performed across PubMed, EMBASE, and Web of Science using a wide array of keywords and phrases pertaining to ECMO, neonates, infants, and various facets of neurodevelopment. The initial screening involved reviewing titles and abstracts to exclude irrelevant articles, followed by a full-text assessment of potentially relevant literature. The quality of each study was evaluated based on its research methodology and statistical analysis. Moreover, citation searches were conducted to identify potentially overlooked studies. Although the focus was primarily on neonatal ECMO, studies involving children and adults were also included due to the limited availability of neonate-specific literature. RESULTS: About 50% of neonates post-ECMO treatment exhibit varying degrees of brain injury, particularly in the frontal and temporoparietal white matter regions, often accompanied by neurological complications. Seizures occur in 18%-23% of neonates within the first 24 hours, and bleeding events occur in 27%-60% of ECMO procedures, with up to 33% potentially experiencing ischemic strokes. Although some studies suggest that ECMO may negatively impact hearing and visual development, other studies have found no significant differences; hence, the influence of ECMO remains unclear. In terms of cognitive, language, and intellectual development, ECMO treatment may be associated with potential developmental delays, including lower composite scores in cognitive and motor functions, as well as potential language and learning difficulties. These studies emphasize the importance of early detection and intervention of potential developmental issues in ECMO survivors, possibly necessitating the implementation of a multidisciplinary follow-up plan that includes regular neuromotor and psychological evaluations. Overall, further multicenter, large-sample, long-term follow-up studies are needed to determine the impact of ECMO on these developmental aspects. CONCLUSIONS: The impact of ECMO on an infant's nervous system still requires further investigation with larger sample sizes for validation. Fine-tuned management, comprehensive nursing care, appropriate patient selection, proactive monitoring, nutritional support, and early rehabilitation may potentially contribute to improving the long-term outcomes for these infants.

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