Background and purpose
The aim was to characterize the phenotypic and genotypic features of myelin protein zero (MPZ) related neuropathy and provide baseline data for longitudinal natural history ...studies or drug clinical trials.
Method
Clinical, neurophysiological and genetic data of 37 neuropathy patients with MPZ mutations were retrospectively collected.
Results
Nineteen different MPZ mutations in 23 unrelated neuropathy families were detected, and the frequency of MPZ mutations was 5.84% in total. Mutations c.103_104InsTGGTTTACACCG, c.513dupG, c.521_557del and c.696_699delCAGT had not been reported previously. Hot spot mutation p.Thr124Met was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile‐onset group included 12 families, the childhood‐onset group consisted of two families and the adult‐onset group included nine families. The Charcot–Marie–Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (p.Arg98Cys, p.Cys127Trp, p.Ser140Cys and p.Cys127Arg) in the extracellular region were more likely to cause severe early‐onset Charcot–Marie–Tooth disease type 1B (CMT1B) or Dejerine–Sottas syndrome. Nonsense‐mediated mRNA decay mutations p.Asp35delInsVVYTD, p.Leu174Argfs*66 and p.Leu172Alafs*63 were related to severe infantile‐onset CMT1B or Dejerine–Sottas syndrome; however, mutation p.Val232Valfs*19 was associated with a relatively milder childhood‐onset CMT1 phenotype.
Conclusion
Four novel MPZ mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile‐onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies.
To meet the cooling demands of high heat flow density hotspots in scenarios such as electronic chips, a novel three-dimensional stacked T-shaped thermoelectric cooler (STTEC) is designed in this ...study. Under steady-state conditions, a finite element method with coupled thermal–electrical–mechanical physical fields is utilized, and the temperature dependence of thermoelectric (TE) materials is considered. First, the cooling flux, coefficient of performance (COP), and minimum cooling temperature of STTEC under different input-current and thermal boundary conditions are investigated and compared to the traditional π-shaped thermoelectric cooler (π-TEC). Second, the effects of geometrical parameter variations under optimal currents on the cooling performance and reliability of STTEC are studied. Finally, the structural parameters are optimized. The results show that the STTEC altered the path of TE conversion and transfer, which significantly improved the optimal current. The STTEC has a remarkable advantage in cooling performance under low temperature differences or high cooling loads. Compared to the π-TEC, STTEC enhances cooling flux by 101.6%, rises COP by 358.5%, and lowers the cold-end temperature by 46.6 K. At optimal current conditions, by optimizing the thickness of the T-shaped copper slice and the height difference between the TE leg and the T-shaped copper slice, the thermal stress decreased by 18.4%. The STTEC’s novel design could inspire the manufacturing and commercialization of high-performance thermoelectric coolers.
Multi-agent reinforcement learning excels at addressing group intelligent decision-making problems involving sequential decision-making. In particular, in complex, high-dimensional state and action ...spaces, it imposes higher demands on the reliability, stability, and adaptability of decision algorithms. The reinforcement learning algorithm based on the multi-agent deep strategy gradient incorporates a function approximation method using discriminant networks. However, this can lead to estimation errors when agents evaluate action values, thereby reducing model reliability and stability and resulting in challenging convergence. With the increasing complexity of the environment, there is a decline in the quality of experience collected by the experience playback pool, resulting in low efficiency of the sampling stage and difficulties in algorithm convergence. To address these challenges, we propose an innovative approach called the empirical clustering layer-based multi-agent dual dueling policy gradient (ECL-MAD3PG) algorithm. Experimental results demonstrate that our ECL-MAD3PG algorithm outperforms other methods in various complex environments, demonstrating a remarkable 9.1% improvement in mission completion compared to MADDPG within the context of complex UAV cooperative combat scenarios.
Tamoxifen remains the most effective treatment for estrogen receptor α (ERα)‐positive breast cancer. However, many patients still develop resistance to tamoxifen in association with metastatic ...recurrence, which presents a tremendous clinical challenge. To better understand tamoxifen resistance from the perspective of the tumor microenvironment, the whole microenvironment landscape is charted by single‐cell RNA sequencing and a new cancer‐associated fibroblast (CAF) subset, CD63+ CAFs, is identified that promotes tamoxifen resistance in breast cancer. Furthermore, it is discovered that CD63+ CAFs secrete exosomes rich in miR‐22, which can bind its targets, ERα and PTEN, to confer tamoxifen resistance on breast cancer cells. Additionally, it is found that the packaging of miR‐22 into CD63+ CAF‐derived exosomes is mediated by SFRS1. Furthermore, CD63 induces STAT3 activation to maintain the phenotype and function of CD63+ CAFs. Most importantly, the pharmacological blockade of CD63+ CAFs with a CD63‐neutralizing antibody or cRGD‐miR‐22‐sponge nanoparticles enhances the therapeutic effect of tamoxifen in breast cancer. In summary, the study reveals a novel subset of CD63+ CAFs that induces tamoxifen resistance in breast cancer via exosomal miR‐22, suggesting that CD63+ CAFs may be a novel therapeutic target to enhance tamoxifen sensitivity.
Tamoxifen resistance is a severe clinical challenge in breast cancer treatment. In the present study, single‐cell RNA sequencing reveals a new subset of cancer‐associated fibroblast (CD63+ CAF) in the tumor microenvironment, which downregulates ERα and PTEN expression in breast cancer cells through exosomal miR‐22 and thus induces tamoxifen resistance.
FPR1: A critical gatekeeper of the heart and brain Zhangsun, Ziyin; Dong, Yushu; Tang, Jiayou ...
Pharmacological research,
April 2024, 2024-Apr, 2024-04-00, 20240401, 2024-04-01, Letnik:
202
Journal Article
Recenzirano
Odprti dostop
G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of ...intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.
Display omitted
The thermoelectric refrigeration system is an application of the Peltier effect, and good refrigeration performance is dependent on effective heat dissipation performance. To enhance the cooling ...performance of the thermoelectric system, this paper designs a new type of finned heat sink, which does not change the overall size of the thermoelectric system. The performance of the refrigeration system under the new fin is tested by experiments under various conditions. During the experiment, the cooling wind speed, the temperature of the hot and cold side of the TEC, the power consumption of the fan, and other parameters were directly recorded through the measuring instrument. The results show that the use of new finned heat sinks can improve the COP of the thermoelectric refrigeration system. Within the scope of the study, the thermal resistance of the new fins can be reduced by 42.6%, and the system COP value can be increased by 22.8%. In addition, increasing the cooling wind speed can further reduce the cold side temperature. Within the research range, the lowest temperature can reach −8.25 °C, but the power consumed by the fan is 166% of that of the conventional fin heat sink refrigeration device.
We use the numerical simulation to investigate an optimized metallized barrier layer for enhancing the performance of the Bi2Te3-based thermoelectric cooler (TEC). The maximal cooling capacity of ...15.627 W and 5.646 W has been obtained under perfect and rough contact TEC. For the actual rough contact TEC, the Ag layer has the best cooling performance among conventional materials such as Ag, Ni, Ti, Co and Pd. The maximal cooling capacity (Qc max) for the rough contact TEC with Ag layer is 84.5% of the perfect contact TEC, which is 2.33 times of the rough contact TEC without any barrier layers. Subsequently, the roughness slope of the TEC and the pressure applied on the TEC have been researched. The Qc max can achieve 90% of the perfect contact TEC when the slope of the roughness is higher than 0.8. Under pressure over 3000 kPa, the Qc max can reach 91% of the perfect contact TEC. For practical production of Bi2Te3-based TEC can introduce Ag as the metallized layer to reduce the contact resistance and improve the cooling performance.
Dear Editor,
Receptor-like kinases （RLKs） constitute the major family of cell surface-associated receptors in plants and play essential roles in perceiving extracellular signals 1. Over two hundred ...members of the largest subfam- ily of RLKs that contain leucine-rich repeat extracellular domains （LRR-RLK） are found in Arabidopsis, among which BRIl-associated kinase 1 （BAK1） is one of the best studied. BAK1 was initially identified based on its association with the LRR-RLK BRI1, which perceives brassinosteroid, an important hormone that regulates a wide range of developmental and physiological processes in plants 2. BAK1 also serves as a co-receptor for sev- eral other LRR-RLKs that perceive pathogen-associated molecular patterns （PAMPs）, including flagellin-sensing 2 （FLS2） and elongation factor EF-Tu receptor 3, 4, and is therefore required for the innate immunity of plants. The reciprocal phosphorylation on the cytoplas- mic domains of BAK1 and the ligand-binding RLKs in the complex is a prerequisite for the full activation of the receptor kinase 5. The crystal structure of BAK1 com- plexed with AvrPtoB, which is an effector secreted by Pseudomonas syringae pv. Tomato to suppress PAMP- triggered immunity, recently revealed the mechanism by which BAK1 activity is inhibited 6. However, the mechanism for BAK1 activation, particularly the impact of phosphorylation of key residues on BAK1 activation, remains unclear.
Purpose
This phase 1, open-label, single-arm clinical trial evaluated pharmacokinetics, safety, and biomarker activity of palbociclib-letrozole as first-line treatment for estrogen ...receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC) in postmenopausal Chinese women to support palbociclib approval in China.
Methods
Patients received palbociclib 125 mg once daily (3/1 schedule) plus letrozole 2.5 mg once daily. Blood samples were collected predose and ≤ 120 h after single and multiple doses of palbociclib. The incidence and severity of adverse events were reported. Skin biopsy tissues and blood samples were collected for biomarker assessments.
Results
By 31 July 2018, 26 patients were enrolled. After single and multiple dosing, palbociclib maximum plasma concentration was 82.14 and 139.7 ng/mL, apparent clearance was 52.40 and 49.97 L/h, AUC
τ
was 1217 and 2501 ng∙h/mL, and
t
½
was 23.46 and 27.26 h, respectively. Levels of Ki67, retinoblastoma protein, and thymidine kinase decreased after palbociclib treatment. A similar safety profile as previously reported was observed.
Conclusions
Pharmacokinetic and pharmacodynamic effects of palbociclib were well characterized in Chinese patients with ABC. Despite higher exposure, pharmacokinetic parameters were similar to those of a previously studied non-Asian population. No palbociclib dose adjustment based on Chinese ethnicity is needed. Palbociclib-letrozole had a manageable safety profile.
Clinical trial registration
NCT02499146
Background Adverse reactions are prone to occur in the early stage of chemotherapy and can negatively affect the dietary intake and nutritional status of breast cancer (BC) patients. Consequently, ...they need to participate in health self-management and lifestyle promotion programs. Early multidisciplinary interventions aim to enhance dietary management behavior and quality of life in chemotherapy-treated BC patients. Methods This single-blinded, single-center, randomized controlled trial will include 88 females who have not yet started the early or middle stage of the chemotherapy cycle. A random number table will be used randomly assign females to the intervention group or usual group at a 1:1 ratio. The intervention elements are based on the theoretical guidance of the Integrated Theory of Health Behavior Change (ITHBC). A multidisciplinary team (MDT) comprising oncologists, dietitians, nurses, traditional Chinese medicine (TCM) practitioners, and psychologists will provide the intervention. Intervention sessions will be conducted once a week for 8 weeks, beginning in the early or middle stage of the chemotherapy cycle and continuing through admission and a home-based interval chemotherapy period. The intervention includes face-to-face discussions, online meetings, WeChat messaging, and telephone calls. The themes target adverse reactions, dietary information and habits, self-care self-efficacy, treatment self-regulation, dietary supplement and TCM use, social support, weight management, and outcome expectations. The primary outcome is dietary management behavior measured by the Dietary Management Behavior Questionnaire (DMBQ). Secondary outcomes are self-care self-efficacy assessed by the Strategies Used by People to Promote Health (SUPPH); quality of life measured by the Functional Assessment of Cancer Therapy-Breast (FACT-B); and body mass index (BMI) measured by an electronic meter. All participants will be assessed at baseline and immediately, 1 month, 3 months, 6 months, and 12 months after the intervention. Discussion Early dietary intervention is needed, as diet is one of the most common health self-management behaviors influenced by chemotherapy. Early multidisciplinary interventions may provide a foundation for dietary self-management and improve nutritional status in the survival period. Trial registration This intervention protocol was registered with the Chinese Clinical Trials Registry (ChiCTR2300076503, October 10, 2023). Keywords: Breast cancer, Chemotherapy, Diet, Health management behavior, Nutrition, Quality of life
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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