We report the case of a Chinese male with schizoaffective disorder, an active smoker and a nonresponder to clozapine (600 mg daily). Therapeutic clozapine monitoring was analyzed, revealing a low ...concentration‐dose ratio. A pharmacogenetic test showed that the patient had the CYP1A2*1F/*1F genotype, indicating an ultra‐rapid clozapine metabolizer. In combination with fluvoxamine, a CYP1A2 enzyme inhibitor, clozapine plasma concentrations approached the reference range and achieved clinical improvement. This case demonstrates how pharmacogenetics can help understand the value of therapeutic drug monitoring to enhance the treatment of refractory schizoaffective disorder.
In this work, a localizing gradient damage model (LGDM) based on the generalized micromorphic theory is adopted to investigate the quasi-brittle fracture behaviour of concrete at mesoscale for the ...first time. Micro Computed Tomography (CT) image-based realistic concrete models are generated including aggregates, mortar, pores, and aggregate-mortar interfacial transition zones (ITZs). In the LGDM, an additional micro-force equilibrium equation is formulated with a damage-dependent interaction function to prevent spurious energetic interactions during the softening stage. The damage driving forces are evaluated as history variables through the maximum nonlocal equivalent strains at the integration points. The stiffness matrices and residual vectors for displacement and nonlocal equivalent strain fields are formulated through the conventional shape function and strain matrices of finite elements, by using the user-defined element (UEL) subroutine implemented with the Broyden–Fletcher–Goldfarb–Shanno (BFGS) algorithm to improve numerical performance. Typical nonlinear fracture benchmarks are presented to investigate the variability of mesoscale fracture evolution, crack trajectories, and load–displacement curves as well as numerical performance. It is found that the LGDM significantly improves the computational efficiency over the conventional phase-field cohesive zone model (PFCZM) with 60% savings of CPU time, and holds great potential for multiscale fracture evaluation of quasi-brittle composite materials, through the high-fidelity representation of real materials’ microstructures, and flexible simulation of the complicated nonlinear fracture without the need for re-meshing or mesh enrichments.
•Simulate mesoscale fracture of concrete using a localizing gradient damage model (LGDM) for the first time.•Enable a robust and efficient monolithic framework by the BFGS quasi-Newton algorithm.•Successfully capture quasi-brittle fracture behaviour of mesoscale concrete using CT images with high fidelity.•Demonstrate considerable reduction (60%) in computational time over the phase-field cohesive zone model.•Widen the applicability and acceptability of the LGDM among researchers.
Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied.
Three public CRC gene ...databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo.
OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3β, we verified GSK3β was over-activated in OLA1-KO cell lines.
OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3β.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune deficiency is one of the hallmarks of HIV infection and a major cause of adverse outcomes in people living with HIV (PLWH). Long‐lived memory CD8+ T cells (LLMCs) are essential executors of ...long‐term protective immunity; however, the generation and maintenance of LLMCs during chronic HIV infection are not well understood. In the present study, we analyzed circulating LLMCs in healthy controls (HCs) and PLWH with different disease statuses, including treatment naïve patients (TNs), complete responders (CRs), and immunological nonresponders (INRs). We found that both TNs and INRs showed severely compromised LLMCs compared with HCs and CRs, respectively. The decrease of LLMCs in TNs correlated positively with the reduction of their precursors, namely memory precursor effector T cells (MPECs), which might be associated with elevated pro‐inflammatory cytokines. Strikingly, INRs showed an accumulation of MPECs, which exhibited diminished responsiveness to interleukin 7 (IL‐7), thereby indicating abrogated differentiation into LLMCs. Moreover, in vitro studies showed that treatment with dexamethasone could improve the IL7‐phosphorylated (p)‐signal transducer and activator of transcription (STAT5) response by upregulating the expression of the interleukin 7 receptor (IL‐7Rα) on MPECs in INRs. These findings provide insights that will encourage the development of novel therapeutics to improve immune function in PLWH.
The loss of LLMCs is mainly attributed to poor MPEC maintenance in TNs, but is caused by differentiation failure of MPECs in INRs. IP‐10 serves as a determinant factor for MPEC survival in TNs, while impaired IL‐7 responsiveness of MPECs accounts for the differential defects in INRs.
Background
MiR-125b functions as an oncogene in many cancers; however, its clinical significance and molecular mechanism in gastric cancers have never been sufficiently investigated. Here, we ...elucidated the functions and molecular regulated pathway
s
of MiR-125b in gastric cancer.
Methods
We investigated MiR-125b expression in fresh tissues from 50 gastric cancer patients and 6 gastric cancer cell lines using RT-PCR, and explored its prognostic value by hybridizing MiR-125b in situ for 300 clinical gastric tumor tissues with pathological diagnosis and clinical parameters. The effects of MiR-125b on gastric cancer cells and downstream target genes and proteins were analyzed by MTT, transwell assay, RT-PCR, and western blot on the basis of silencing MiR-125b in vitro. Luciferase reporter plasmid was constructed to demonstrate MiR-125b’s direct target.
Results
MiR-125b was upregulated in gastric cancer tissues and cell lines, and significantly promoted cellular proliferation, migration, and invasion by downregulating the expression of PPP1CA and upregulating Rb phosphorylation. MiR-125b expression was significantly correlated with tumor size and depth of invasion, lymph nodes, distant metastasis, and TNM stage. The high-MiR-125b-expression group had a significantly poorer prognosis than the low-expression group (
P
< 0.05) in stages I, II, and III, and the 5-year survival rate in of the high-expression group was significantly lower than that of the low-expression group.
Conclusions
MiR-125b functions as an oncogene by targeting downregulated PPP1CA and upregulated Rb phosphorylation in gastric cancer. MiR-125b not only promotes cellular proliferation, migration, and invasion in vitro, but also acts as an independent prognostic factor in gastric cancer.
The presence of estrogens residues in dairy products is a growing concern due to their potential health risk. Herein, in this study, we have developed a membrane-protected magnetic solid-phase ...extraction (MP-MSPE) method that utilized a magnetic adsorbent (Fe
O
@COF-LZU1) with in-situ growth for the efficient extraction of estrone (E1), 17β-estradiol (E2), and estriol (E3). When combined with HPLC-FLD, this method allows for the efficient detection of estrogens in dairy products. The stability of the MP-MSPE was improved by the presence of a dialysis membrane, which remained a high extraction efficiency (90 %) even after ten reuse cycles. The hydrogen bonding, π-π interactions and pore size effect contribute to the excellent adsorption of three estrogens onto Fe
O
@COF-LZU1. Under optimal conditions, the method exhibits a low detection limit (0.01-0.15 μg L
), wide linear range (0.1-800 μg L
), and favorable recoveries (77.3 %-109.4 %) at three concentration levels (10, 50 and 100 μg L
). This proposed method is characterized by its simplicity, high efficiency and eco-friendliness, making it a promising approach for extracting estrogens from dairy products.
Thermoelectric generators (TEGs) provide a unique solution for energy harvesting from waste heat, presenting a potential solution for green energy. However, traditional rigid and flexible TEGs cannot ...work on complex and dynamic surfaces. Here, we report a stretchable TEG (S-TEG) (over 50% stretchability of the entire device) that is geometrically suitable for various complex and dynamic surfaces of heat sources. The S-TEG consists of hot-pressed nanolayered p-(Sb
Te
) and n-(Bi
Te
)-type thermoelectric couple arrays and exploits the wavy serpentine interconnects to integrate all units. The internal resistance of a 10 × 10 array is 22 ohm, and the output power is ∼0.15 mW/cm
at Δ
= 19 K on both developable and nondevelopable surfaces, which are much improved compared with those of existing S-TEGs. The energy harvesting of S-TEG from the dynamic surfaces of the human skin offers a potential energy solution for the wearable devices for health monitoring.
Although numerous studies on the impacts of climate change on biodiversity have been published, only a handful are focused on the intraspecific level or consider population‐level models (separate ...models per population). We endeavored to fill this knowledge gap relative to the Qinghai‐Tibetan plateau (QTP) by combining species distribution modeling (SDMs) with population genetics (i.e., population‐level models) and phylogenetic methods (i.e., phylogenetic tree reconstruction and phylogenetic diversity analyses). We applied our models to 11 endemic and widely distributed herpetofauna species inhabiting high elevations in the QTP. We aimed to determine the influence of environmental heterogeneity on species’ responses to climate change, the magnitude of climate‐change impacts on intraspecific diversity, and the relationship between species range loss and intraspecific diversity losses under 2 shared socioeconomic pathways (SSP245 and SSP585) and 3 future periods (2050s, 2070s, and 2090s). The effects of global climatic change were more pronounced at the intraspecific level (22% of haplotypes lost and 36% of populations lost) than the morphospecies level in the SSP585 climate change scenario. Maintenance of genetic diversity was in general determined by a combination of factors including range changes, species genetic structure, and the part of the range predicted to be lost. This is owing to the fact that the loss and survival of populations were observed in species irrespective of the predicted range changes (contraction or expansion). In the southeast (mountainous regions), climate change had less of an effect on range size (>100% in 3 species) than in central and northern QTP plateau regions (range size <100% in all species). This may be attributed to environmental heterogeneity, which provided pockets of suitable climate in the southeast, whereas ecosystems in the north and central regions were homogeneous. Generally, our results imply that mountainous regions with high environmental heterogeneity and high genetic diversity may buffer the adverse impacts of climate change on species distribution and intraspecific diversity. Therefore, genetic structure and characteristics of the ecosystem may be crucial for conservation under climate change.
Impactos del cambio climático sobre la diversidad de herpetofauna en la meseta Qinghai‐Tíbet
Región
Aunque se han publicado numerosos estudios sobre los impactos del cambio climática en la biodiversidad, son muy pocos los que se enfocan en el nivel intraespecífico o que consideran modelos a nivel poblacional (modelos separados por población). Intentamos cerrar este vacío de conocimiento en relación con la meseta Qinghai‐Tíbet (MQT) con la combinación entre modelos de distribución de especies (MDE) y genética poblacional (modelos a nivel poblacional) y métodos filogenéticos (reconstrucción de árboles filogenéticos y análisis de diversidad filogenética). Aplicamos nuestros modelos a once especies endémicas de herpetofauna con distribución amplia en las elevaciones más altas de la MQT. Nos planteamos determinar la influencia de la heterogeneidad de las especies sobre la respuesta de las especies al cambio climático, la magnitud de los impactos del cambio climático sobre la diversidad intraespecífica y la relación entre la pérdida de distribución de la especie y las pérdidas de diversidad intraespecífica bajo dos vías socioeconómicas (SSP245 y SSP585) y tres periodos del futuro (2050s, 2070s y 2090s). Los efectos del cambio climático global fueron más pronunciados a nivel intraespecífico (22% de pérdida en los haplotipos y 36% en las poblaciones) que al nivel morfoespecie en el escenario de cambio climático SSP585. El mantenimiento de la diversidad genética casi siempre estuvo determinado por una combinación de factores que incluyen cambios en la distribución, estructura genética de las especies y la parte de la distribución que se pronosticó se perdería. Esto se debe a que observamos la pérdida y supervivencia de las poblaciones sin importar los cambios pronosticados en la distribución (contracción o expansión). En las regiones montañosas del sureste, el cambio climático tuvo un efecto menor sobre la distribución (>100% en tres especies) comparado con las regiones de la meseta central y del norte de la MQT (distribución <100% en todas las especies). Esto puede atribuirse a la heterogeneidad ambiental, la cual proporciona recovecos de clima adecuado en el sureste, mientras que los ecosistemas en las regiones central y norte fueron homogéneos. De manera general, nuestros resultados implican que las regiones montañosas con una elevada heterogeneidad ambiental y una gran diversidad genética podrían reducir los impactos adversos del cambio climático sobre la distribución de las especies y la diversidad intraespecífica. Por lo tanto, la estructura genética y las características del ecosistema pueden ser cruciales para conservar bajo el cambio climático.
【摘要】
尽管已有大量有关气候变化对生物多样性影响的研究发表, 但只有少数研究考虑种下或种群水平的模型。我们将物种分布模型(SDMs)与种群遗传学和系统发生学方法相结合, 填补青藏高原地区(QTP)在这一方面的研究空白。我们对11种栖息在青藏高原特有且分布广泛的两栖爬行动物进行了模型分析, 探究环境异质性对物种响应气候变化的影响、气候变化对种内多样性的影响程度、以及在SSP245和SSP585两种情景下, 未来(2050年、2070年和2090年)物种分布范围丧失与种内多样性丧失之间的关系。结果显示, 在SSP585气候变化情景中, 在种下有22%的单倍型和36%的种群将会丢失, 全球气候变化对种内多样性的影响比种间更为明显。遗传多样性是否能够维持一般由多种因素共同决定, 包括分布区的变化、物种遗传结构以及预测丢失的分布区。在青藏高原东南部山区, 气候变化对物种分布范围大小的影响(有3个物种的分布范围扩张)小于青藏高原北部和中部地区(所有物种的分布范围均缩小), 主要原因可能是东南部环境异质性更高, 物种可以选择较为合适的生境, 而北部和中部地区环境则趋于同质化。本研究结果表明, 环境异质性高、遗传多样性高的山区可以缓冲气候变化对物种分布和种内多样性的不利影响。因此, 生态系统的遗传结构和特征对于气候变化下的多样性保护至关重要。
The third-generation ground-based gravitational-wave (GW) detector, Cosmic Explorer (CE), is scheduled to start its observation in the 2030s. In this paper, we make a forecast for cosmological ...parameter estimation with gravitational-wave standard siren observation from the CE. We use the simulated GW standard siren data of CE to constrain the ΛCDM, wCDM and CPL models. We combine the simulated GW data with the current cosmological electromagnetic observations including the latest cosmic microwave background anisotropies data from Planck, the optical baryon acoustic oscillation measurements, and the type Ia supernovae observation (Pantheon compilation) to do the analysis. We find that the future standard siren observation from CE will improve the cosmological parameter estimation to a great extent, since the future GW standard siren data can well break the degeneracies generated by the optical observations between various cosmological parameters. We also find that the CE's constraining capability on the cosmological parameters is slightly better than that of the same-type GW detector, the Einstein Telescope. In addition, the synergy between the GW standard siren observation from CE and the 21 cm emission observation from SKA is also discussed.
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