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1.
Neural Regen Res ; 20(1): 209-223, 2025 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38767486

RESUMEN

JOURNAL/nrgr/04.03/01300535-202501000-00029/figure1/v/2024-05-14T021156Z/r/image-tiff Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory. Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1; however, whether KIF21A modulates dendritic structure and function in neurons remains unknown. In this study, we found that KIF21A was distributed in a subset of dendritic spines, and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines. Furthermore, the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity. Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching, and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1, but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1. Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals' cognitive abilities. Taken together, our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.

2.
Emerg Microbes Infect ; 13(1): 2364744, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38935839

RESUMEN

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.


Asunto(s)
Huésped Inmunocomprometido , Inmunoterapia Adoptiva , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Inmunoterapia Adoptiva/métodos , Antígenos HLA/inmunología , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Resultado del Tratamiento , Infecciones Oportunistas Relacionadas con el SIDA/inmunología , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Trasplante Homólogo , Linfocitos T CD4-Positivos/inmunología , Recuento de Linfocito CD4
4.
Animals (Basel) ; 14(11)2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38891682

RESUMEN

Crytosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi are important diarrheal pathogens with a global distribution that threatens the health of humans and animals. Despite cattle being potential transmission hosts of these protozoans, the associated risks to public health have been neglected. In the present study, a total of 1155 cattle fecal samples were collected from 13 administrative regions of Heilongjiang Province. The prevalence of Cryptosporidium spp., G. duodenalis, and E. bieneusi were 5.5% (64/1155; 95% CI: 4.2-6.9), 3.8% (44/1155; 95% CI: 2.7-4.9), and 6.5% (75/1155; 95% CI: 5.1-7.9), respectively. Among these positive fecal samples, five Cryptosporidium species (C. andersoni, C. bovis, C. ryanae, C. parvum, and C. occultus), two G. duodenalis assemblages (E and A), and eight E. bieneusi genotypes (BEB4, BEB6, BEB8, J, I, CHS7, CHS8, and COS-I) were identified. Phylogenetic analysis showed that all eight genotypes of E. bieneusi identified in the present study belonged to group 2. It is worth noting that some species/genotypes of these intestinal protozoans are zoonotic, suggesting a risk of zoonotic disease transmission in endemic areas. The findings expanded our understanding of the genetic composition and zoonotic potential of Cryptosporidium spp., G. duodenalis, and E. bieneusi in cattle in Heilongjiang Province.

5.
bioRxiv ; 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38746394

RESUMEN

NanoLuc luciferase and its derivatives are attractive bioluminescent reporters recognized for their efficient photon production and ATP independence. However, utilizing them for in vivo imaging poses notable challenges. Low substrate solubility has been a prominent problem, limiting in vivo brightness, while substrate instability hampers consistent results and handling. To address these issues, we developed a range of caged PEGylated luciferins with improved stability and water solubility of up to 25 mM, resulting in substantial bioluminescence increases in mouse models. This advancement has created the brightest and most sensitive luciferase-luciferin combination, enabling high-speed video-rate imaging of freely moving mice with brain-expressed luciferase. Furthermore, we developed a bioluminescent Ca 2+ indicator with exceptional sensitivity to physiological Ca 2+ changes and paired it with a new substrate to showcase non-invasive, video-rate imaging of Ca 2+ activity in a defined brain region in awake mice. These innovative substrates and the Ca 2+ indicator are poised to become invaluable resources for biological and biomedical fields.

6.
J Am Chem Soc ; 146(19): 13406-13416, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38698549

RESUMEN

Bioluminescent indicators are power tools for studying dynamic biological processes. In this study, we present the generation of novel bioluminescent indicators by modifying the luciferin molecule with an analyte-binding moiety. Specifically, we have successfully developed the first bioluminescent indicator for potassium ions (K+), which are critical electrolytes in biological systems. Our approach involved the design and synthesis of a K+-binding luciferin named potassiorin. Additionally, we engineered a luciferase enzyme called BRIPO (bioluminescent red indicator for potassium) to work synergistically with potassiorin, resulting in optimized K+-dependent bioluminescence responses. Through extensive validation in cell lines, primary neurons, and live mice, we demonstrated the efficacy of this new tool for detecting K+. Our research demonstrates an innovative concept of incorporating sensory moieties into luciferins to modulate luciferase activity. This approach has great potential for developing a wide range of bioluminescent indicators, advancing bioluminescence imaging (BLI), and enabling the study of various analytes in biological systems.


Asunto(s)
Luciferasas , Mediciones Luminiscentes , Potasio , Potasio/metabolismo , Potasio/química , Animales , Mediciones Luminiscentes/métodos , Ratones , Luciferasas/química , Luciferasas/metabolismo , Humanos , Ingeniería de Proteínas , Sustancias Luminiscentes/química , Luciferina de Luciérnaga/química , Luciferina de Luciérnaga/metabolismo
7.
Ann Med ; 56(1): 2346537, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38696817

RESUMEN

BACKGROUND: To investigate the effectiveness of the intervention with critical value management and push short messaging service (SMS), and to determine improvement in the referral rate of patients with positive hepatitis C antibody (anti-HCV). METHODS: No intervention was done for patients with positive anti-HCV screening results from 1 January 2015 to 31 October 2021. Patients with positive anti-HCV results at our hospital from 1 November 2021 to 31 July 2022 were informed vide critical value management and push SMS. For inpatients, a competent physician was requested to liaise with the infectious disease physician for consultation, and patients seen in the OPD (outpatient department) were asked to visit the liver disease clinic. The Chi-square correlation test, one-sided two-ratio test and linear regression were used to test the relationship between intervention and referral rate. RESULTS: A total of 638,308 cases were tested for anti-hepatitis C virus (HCV) in our hospital and 5983 of them were positive. 51.8% of the referred patients were aged 18-59 years and 10.8% were aged ≥75 years. The result of Chi-square correlation test between intervention and referral was p = .0000, p < .05. One-sided two-ratio test was performed for statistics of pre-intervention referral rate (p1) and post-intervention referral rate (p2). Normal approximation and Fisher's exact test for the results obtained were 0.000, p < .05, and the alternative hypothesis p1 - p2 < 0 was accepted. The linear regression equation was referral = 0.1396 × intervention + 0.3743, and the result model p = 8.79e - 09, p < .05. The model was significant, and the coefficient of intervention was 0.1396. CONCLUSIONS: The interventions of critical value management and push SMS were correlated with the referral rate of patients with positive anti-HCV.


Asunto(s)
Hepatitis C , Derivación y Consulta , Humanos , Derivación y Consulta/estadística & datos numéricos , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Adolescente , Hepatitis C/tratamiento farmacológico , Hepatitis C/diagnóstico , Adulto Joven , Anticuerpos contra la Hepatitis C/sangre , Envío de Mensajes de Texto , Mejoramiento de la Calidad
8.
bioRxiv ; 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38559024

RESUMEN

Bioluminescent indicators are power tools for studying dynamic biological processes. In this study, we present the generation of novel bioluminescent indicators by modifying the luciferin molecule with an analyte-binding moiety. Specifically, we have successfully developed the first bioluminescent indicator for potassium ions (K+), which are critical electrolytes in biological systems. Our approach involved the design and synthesis of a K+-binding luciferin named potassiorin. Additionally, we engineered a luciferase enzyme called BRIPO (bioluminescent red indicator for potassium) to work synergistically with potassiorin, resulting in optimized K+-dependent bioluminescence responses. Through extensive validation in cell lines, primary neurons, and live mice, we demonstrated the efficacy of this new tool for detecting K+. Our research demonstrates an innovative concept of incorporating sensory moieties into luciferins to modulate luciferase activity. This approach has great potential for developing a wide range of bioluminescent indicators, advancing bioluminescence imaging (BLI), and enabling the study of various analytes in biological systems.

9.
iScience ; 27(4): 109513, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38600975

RESUMEN

Early detection of left ventricular remodeling (LVR) is crucial. While cardiac magnetic resonance (CMR) provides valuable information, it has limitations. Coronary angiography-derived fractional flow reserve (caFFR) and index of microcirculatory resistance (caIMR) offer viable alternatives. 157 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention were prospectively included. 23.6% of patients showed LVR. Machine learning algorithms constructed three LVR prediction models: Model 1 incorporated clinical and procedural parameters, Model 2 added CMR parameters, and Model 3 included echocardiographic and functional parameters (caFFR and caIMR) with Model 1. The random forest algorithm showed robust performance, achieving AUC of 0.77, 0.84, and 0.85 for Models 1, 2, and 3. SHAP analysis identified top features in Model 2 (infarct size, microvascular obstruction, admission hemoglobin) and Model 3 (current smoking, caFFR, admission hemoglobin). Findings indicate coronary physiology and echocardiographic parameters effectively predict LVR in patients with STEMI, suggesting their potential to replace CMR.

10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 546-555, 2024 Apr.
Artículo en Chino | MEDLINE | ID: mdl-38660865

RESUMEN

OBJECTIVE: To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). METHODS: Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. RESULTS: Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). CONCLUSION: NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales , Leucemia Mieloide Aguda , Trasplante Homólogo , Humanos , Leucemia Mieloide Aguda/terapia , Estudios Retrospectivos , Citarabina , Supervivencia sin Enfermedad , Masculino , Femenino , Pronóstico , Inducción de Remisión , Factor Estimulante de Colonias de Granulocitos , Adulto , Persona de Mediana Edad
11.
Proc Natl Acad Sci U S A ; 121(18): e2314541121, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38657049

RESUMEN

Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin-2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABAA receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9-dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity.


Asunto(s)
Moléculas de Adhesión Celular Neuronal , Proteínas del Tejido Nervioso , Sinapsis , Transmisión Sináptica , Animales , Ratones , Moléculas de Adhesión Celular Neuronal/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatología , Epilepsia/patología , Hipocampo/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteolisis , Receptores de GABA-A/metabolismo , Sinapsis/metabolismo , Transmisión Sináptica/fisiología
12.
Eur Heart J Open ; 4(2): oeae009, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38544919

RESUMEN

Aims: With an aging population and better survival rates, coronary artery disease (CAD) with multimorbidity has become more prevalent, complicating treatment and impacting life quality and longevity. This study identifies multimorbidity patterns in CAD patients and their effect on clinical outcomes, emphasizing treatment strategies. Methods and results: The study analysed data from the DCEM registry (173 459 patients) and BleeMACS cohort (15 401 patients) to categorize CAD patients into three multimorbidity patterns. The focus was on how these patterns influence outcomes, especially concerning the efficacy and safety of dual antiplatelet therapy (DAPT). The study identified three distinct multimorbidity patterns: Class 1 encompassed cardiovascular-kidney-metabolic comorbidities indicating the highest risk; Class 2 included hypertension-dyslipidaemia comorbidities, reflecting intermediate risk; and Class 3 involved non-specific comorbidities, indicating the lowest risk. Class 1 patients demonstrated a six-fold increase in in-hospital mortality and a four-fold increase in severe in-hospital complications compared with Class 3. Over a 1-year period, Class 1 was associated with the highest risk, displaying a significant increase in all-cause mortality [adjusted hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.52-2.31, P < 0.001] and a notable risk for major bleeding (adjusted HR 1.74, 95% CI 1.36-2.24, P < 0.001) compared with Class 3. The use of DAPT, particularly aspirin combined with clopidogrel, significantly reduced the 1-year all-cause mortality in Class 1 patients (adjusted HR 0.60, 95% CI 0.37-0.98, P = 0.04) without increasing in major bleeding. Conclusion: Coronary artery disease patients with a cardiovascular-kidney-metabolic profile face the highest mortality risk. Targeted DAPT, especially aspirin and clopidogrel, effectively lowers mortality without significantly raising bleeding risks. Registration: DCEM registry (NCT05797402) and BleeMACS registry (NCT02466854).

13.
Adv Mater ; 36(23): e2400655, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38373742

RESUMEN

Ultrathin 2D ferroelectrics with high Curie temperature are critical for multifunctional ferroelectric devices. However, the ferroelectric spontaneous polarization is consistently broken by the strong thermal fluctuations at high temperature, resulting in the rare discovery of high-temperature ferroelectricity in 2D materials. Here, a chemical vapor deposition method is reported to synthesize 2D CuCrSe2 nanosheets. The crystal structure is confirmed by scanning transmission electron microscopy characterization. The measured ferroelectric phase transition temperature of ultrathin CuCrSe2 is about ≈800 K. Significantly, the switchable ferroelectric polarization is observed in ≈5.2 nm nanosheet. Moreover, the in-plane and out-of-plane ferroelectric response are modulated by different maximum bias voltage. This work provides a new insight into the construction of 2D ferroelectrics with high Curie temperature.

15.
Biosensors (Basel) ; 14(1)2024 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-38275307

RESUMEN

Introducing 3-aminotyrosine (aY), a noncanonical amino acid (ncAA), into green fluorescent protein (GFP)-like chromophores shows promise for achieving red-shifted fluorescence. However, inconsistent results, including undesired green fluorescent species, hinder the effectiveness of this approach. In this study, we optimized expression conditions for an aY-derived cpGFP (aY-cpGFP). Key factors like rich culture media and oxygen restriction pre- and post-induction enabled high-yield, high-purity production of the red-shifted protein. We also engineered two variants of aY-cpGFP with enhanced brightness by mutating a few amino acid residues surrounding the chromophore. We further investigated the sensitivity of the aY-derived protein to metal ions, reactive oxygen species (ROS), and reactive nitrogen species (RNS). Incorporating aY into cpGFP had minimal impact on metal ion reactivity but increased the response to RNS. Expanding on these findings, we examined aY-cpGFP expression in mammalian cells and found that reductants in the culture media significantly increased the red-emitting product. Our study indicates that optimizing expression conditions to promote a reduced cellular state proved effective in producing the desired red-emitting product in both E. coli and mammalian cells, while targeted mutagenesis-based protein engineering can further enhance brightness and increase method robustness.


Asunto(s)
Aminoácidos , Escherichia coli , Tirosina/análogos & derivados , Animales , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/química , Escherichia coli/genética , Medios de Cultivo , Mamíferos
16.
J Atheroscler Thromb ; 31(5): 603-615, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38148032

RESUMEN

AIM: A close relationship exists between resting heart rate (RHR) and obstructive sleep apnea (OSA). Still, the prognostic importance of nighttime RHR in patients with acute coronary syndrome (ACS) with or without OSA remains unclear. METHODS: In this prospective cohort study, OSA was defined as an apnea-hypopnea index of ≥ 15 events/h, and the high nighttime RHR (HNRHR) was defined as a heart rate of ≥ 70 bpm. The primary endpoint was a major adverse cardiovascular and cerebrovascular event (MACCE), including cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization, or hospitalization for heart failure. RESULTS: Among the 1875 enrolled patients, the mean patient age was 56.3±10.5 years, 978 (52.2%) had OSA, and 425 (22.7%) were in HNRHR. The proportion of patients with HNRHR is higher in the OSA population than in the non-OSA population (26.5% vs. 18.5%; P<0.001). During 2.9 (1.5, 3.5) years of follow-up, HNRHR was associated with an increased risk of MACCE in patients with OSA (adjusted HR: 1.56, 95% CI: 1.09-2.23, P=0.014), but not in patients without OSA (adjust HR: 1.13, 95% CI: 0.69-1.84, P=0.63). CONCLUSIONS: In patients with ACS, a nighttime RHR of ≥ 70 bpm was associated with a higher risk of MACCE in those with OSA but not in those without it. This identifies a potential high-risk subgroup where heart rate may interact with the prognosis of OSA. Further research is needed to determine causative relationships and confirm whether heart rate control impacts cardiovascular outcomes in patients with ACS-OSA.


Asunto(s)
Síndrome Coronario Agudo , Frecuencia Cardíaca , Apnea Obstructiva del Sueño , Humanos , Síndrome Coronario Agudo/fisiopatología , Síndrome Coronario Agudo/complicaciones , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/complicaciones , Persona de Mediana Edad , Masculino , Femenino , Frecuencia Cardíaca/fisiología , Pronóstico , Estudios Prospectivos , Estudios de Seguimiento , Anciano , Factores de Riesgo , Descanso/fisiología
17.
World J Psychiatry ; 13(11): 912-918, 2023 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-38073906

RESUMEN

BACKGROUND: The psychological state of patients with post stroke limb movement disorders undergoes a series of changes that affect rehabilitation training and recovery of limb motor function. AIM: To determine the correlation between motor rehabilitation and the psychological state of patients with limb movement disorders after stroke. METHODS: Eighty patients with upper and lower limb dysfunction post stroke were retrospectively enrolled in our study. Based on Hospital Anxiety and Depression Scale (HADS) scores measured before rehabilitation, patients with HADS scores ≥ 8 were divided into the psychological group; otherwise, the patients were included in the normal group. Motor function and daily living abilities were compared between the normal and psychological groups. Correlations between the motor function and psychological status of patients, and between daily living ability and psychological status of patients were analyzed. RESULTS: After 1, 2, and 3 wk of rehabilitation, both the Fugl-Meyer assessment and Barthel index scores improved compared to their respective baseline scores (P < 0.05). A greater degree of improvement was observed in the normal group compared to the psychological group (P < 0.05). There was a negative correlation between negative emotions and limb rehabilitation (-0.592 ≤ r ≤ -0.233, P < 0.05), and between negative emotions and daily living ability (-0.395 ≤ r ≤ -0.199, P < 0.05). CONCLUSION: There is a strong correlation between motor rehabilitation and the psychological state of patients with post stroke limb movement disorders. The higher the negative emotions, the worse the rehabilitation effect.

18.
Cell Rep ; 42(12): 113573, 2023 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-38096054

RESUMEN

Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca2+ release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.


Asunto(s)
Enfermedad de Huntington , Ratones , Animales , Enfermedad de Huntington/genética , Plasticidad Neuronal/fisiología , Neuronas/patología , Hipocampo/patología , Sinapsis/patología , Lisosomas/patología , Dendritas/patología , Espinas Dendríticas/patología
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 31(6): 1852-1859, 2023 Dec.
Artículo en Chino | MEDLINE | ID: mdl-38071072

RESUMEN

OBJECTIVE: To retrospectively analyze the efficacy and complications of our institution's modified nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) in treating intermediate-risk acute myeloid leukemia (AML) - first complete remission (CR1) and prognostic factors. METHODS: Clinical data of 50 intermediate-risk AML-CR1 patients who underwent matched related NST at the Fifth Medical Center of Chinese People's Liberation Army General Hospital from August 2004 to April 2021 were collected, the hematopoietic recovery, donor engraftment and complications were observed, and overall survival (OS) rate, leukemia-free survival (LFS) rate, treatment-related mortality (TRM), and cumulative relapse rate were calculated. Statistical analysis of factors affecting prognosis was also preformed. RESULTS: The median times for neutrophil and platelet recovery after transplantation were 10 (6-16) and 13 (6-33) days, respectively. One month after transplantation, 22 patients (44%) achieved full donor chimerism (FDC), and 22 patients (44%) achieved mixed chimerism (MC), among whom 18 cases gradually transited to FDC during 1-11 months, 4 cases maintained MC status. The overall incidence of acute graft-versus-host disease (aGVHD) was 36%, with a rate of 18% for grade II-IV aGVHD and a median onset time of 45 (20-70) days after transplantation. The overall incidence of chronic GVHD (cGVHD) was 34%, with 20% and 14% of patients having limited or extensive cGVHD, respectively. The incidence rates of infections, interstitial pneumonia, and hemorrhagic cystitis were 30%, 10%, and 16%, respectively. The 5-year OS rate, LFS rate, TRM, and cumulative relapse rate were 68%, 64%, 16%, and 20%, respectively. The increase of the number of CD34+ cells infused had shortened the recovery time for neutrophils and platelets (r =0.563, r =0.350). The number of CD34+ cells infused significantly influenced the occurrence of extensive cGVHD (OR =1.36, 95%CI : 1.06-1.84, P =0.024). CONCLUSION: Modified NST is effective in treating intermediate-risk AML-CR1 patients, however, further expansion of sample size is needed to study prognostic factors.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/complicaciones , Pronóstico , Recurrencia , Estudios Retrospectivos
20.
Respir Res ; 24(1): 313, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38098080

RESUMEN

BACKGROUND: Sporadic studies have examined the impact of OSA on ACS patients by homocysteine (Hcy) level. This study attempted to comprehensively evaluate the effects of the interaction between Hcy and OSA on long-term cardiovascular outcomes in ACS patients. METHODS: In this prospective, large-scale cohort study, 2160 patients admitted for ACS were recruited to undergo overnight sleep monitoring. OSA was diagnosed when apnea-hypopnea index ≥ 15 events/h. Patients with normohomocysteinemia (NHcy) were defined as having serum Hcy ≤ 15 µmol/L, and the others had hyperhomocysteinemia (HHcy). The primary endpoint was major adverse cerebrocardiovascular event (MACCE), a composite of cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization and hospitalization for unstable angina and heart failure. RESULTS: A total of 1553 eligible ACS patients (average age: 56.3 ± 10.5 years) were enrolled, among which 819 (52.7%) had OSA, and 988 (63.6%) were with NHcy. OSA did not significantly affect the level of Hcy. During a median follow-up of 2.9 (1.6, 3.5) years, after adjustment for clinical confounders, OSA was associated with increased risk for MACCE occurrence versus non-OSA ones in ACS patients with NHcy (adjusted hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.02-1.83, P = 0.039), but not in those with HHcy (adjusted HR = 0.92, 95%CI 0.62-1.36, P = 0.668). There was an absence of interaction between homocysteine level and OSA in relation to MACCE (interaction P = 0.106). CONCLUSIONS: OSA was independently associated with worse prognosis in ACS patients with NHcy. Our study emphasized the necessity to identify potential presence of OSA in such a population. TRIAL REGISTRATION: ClinicalTrials.gov; Number: NCT03362385; URL: www. CLINICALTRIALS: gov .


Asunto(s)
Síndrome Coronario Agudo , Apnea Obstructiva del Sueño , Humanos , Persona de Mediana Edad , Anciano , Pronóstico , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/epidemiología , Estudios Prospectivos , Estudios de Cohortes , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/complicaciones , Homocisteína , Factores de Riesgo
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