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Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor‐associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement‐dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next‐generation GD2‐specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3‐16 IgG1m4 antibody from ch14.18 IgG1. H3‐16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2‐positive cell lines as revealed by ELISA, and its cross‐binding activity to other gangliosides was not altered. The CDC activity of H3‐16 IgG1m4 was decreased, and the antibody‐dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3‐16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague–Dawley (SD) rats. In summary, H3‐16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusions The penetrance of the RNF213 p.R4810K, a founder mutation of moyamoya disease (MMD), is estimated to be only 1/150–1/300. However, the factors affecting its penetrance remain unclear. Therefore, our study aims to identify modifier genes associated with the incomplete penetrance of this founder mutation.Whole‐exome sequencing (WES) was performed on 36 participants, including 22 MMD patients and 14 non‐MMD controls with RNF213 p.R4810K mutation. Fisher's exact test was used to assess the presence of genetic variants that differed significantly between MMD patients and non‐MMD controls. In order to exclude false‐positive results, another 55 carriers were included to perform Fisher's exact test for the selected sites in the WES discovery stage. Subsequently, human brain microvascular endothelial cells were transfected with wild‐type and mutant HAPLN3 for tube formation assays and western blotting to explore the impact of candidate genes on angiogenesis.Analysis of variants from WES data revealed a total of 12 non‐synonymous variants. Through bioinformatics analysis, the focus was on the HAPLN3 p.T34A variant with a significant p value of 0.00731 in Fisher's exact test. Validation through Sanger sequencing confirmed the presence of this variant in the WES data. In vitro experiments revealed that silencing HAPLN3 and transfecting HAPLN3 p.T34A significantly enhanced tube formation and increased the relative protein expression of vascular endothelial growth factor in endothelial cells.These results suggest that HAPLN3 may function as a modifier gene of RNF213 p.R4810K, promoting the development of MMD and contributing to the incomplete penetrance of MMD founder mutations. [ABSTRACT FROM AUTHOR]

Degenerative disc disease (DDD) represents a significant global health challenge, yet its underlying molecular mechanisms remain elusive. This study aimed to investigate the role of type 1 phosphatidylinositol 4‐phosphate 5‐kinase (Pip5k1) in intervertebral disc (IVD) homeostasis and disease. All three Pip5k1 isoforms, namely Pip5k1α, Pip5k1β, and Pip5k1γ, were detectable in mouse and human IVD tissues, with Pip5k1γ displaying a highest expression in nucleus pulposus (NP) cells. The expression of Pip5k1γ was significantly down‐regulated in the NP cells of aged mice and patients with severe DDD. To determine whether Pip5k1γ expression is required for disc homeostasis, we generated a Pip5k1γfl/fl; AggrecanCreERT2 mouse model for the conditional knockout of the Pip5k1γ gene in aggrecan‐expressing IVD cells. Our findings revealed that the conditional deletion of Pip5k1γ did not affect the disc structure or cellular composition in 5‐month‐old adult mice. However, in aged (15‐month‐old) mice, this deletion led to several severe degenerative disc defects, including decreased NP cellularity, spontaneous fibrosis and cleft formation, and a loss of the boundary between NP and annulus fibrosus. At the molecular level, the absence of Pip5k1γ reduced the anabolism of NP cells without markedly affecting their catabolic or anti‐catabolic activities. Moreover, the loss of Pip5k1γ significantly dampened the activation of the protective Ampk pathway in NP cells, thereby accelerating NP cell senescence. Notably, Pip5k1γ deficiency blunted the effectiveness of metformin, a potent Ampk activator, in activating the Ampk pathway and mitigating lumbar spine instability (LSI)‐induced disc lesions in mice. Overall, our study unveils a novel role for Pip5k1γ in promoting anabolism and maintaining disc homeostasis, suggesting it as a potential therapeutic target for DDD. [ABSTRACT FROM AUTHOR]

Background: Fear of cancer recurrence (FCR) and psychological distress are common psychological problems in breast cancer (BC) patients and ultimately affecting their health‐related quality of life (HRQoL). Heart rate variability (HRV) can reflect the activity of the parasympathetic nervous system. However, the pathways through which HRV influences between FCR and HRQoL are unclear. This study preliminarily explored the intermediary role of HRV in FCR and HRQoL in BC patients. Methods: A total of 101 BC patients participated in this study. HRV parameters were measured by a 5‐min dynamic electrocardiogram. FCR, psychological distress and HRQoL were evaluated by the Fear of disease progression simplified scale (FOP‐Q‐SF), Distress thermometer and SF‐36 concise health survey. The intermediary effect model was established to test the intermediary effect of high frequency‐HRV (HF‐HRV) on FCR and HRQoL. Results: FCR and psychological distress were negatively correlated with HRV in the time domain, negatively correlated with HF‐HRV in the frequency domain, and positively correlated with low frequency/high frequency (LF/HF). HF‐HRV had a partial mediating effect on the FCR and physical health and mental health, with effects of 30.23% and 9.53%, respectively. Conclusion: FCR and psychological distress are correlated with HRV parameters in the time domain and the frequency domain, and we preliminarily believe that parasympathetic nerves play an important intermediary role between FCR and subjective physical and mental health. This may provide intervention information for improving the HRQoL of BC patients. [ABSTRACT FROM AUTHOR]

A Mesoproterozoic granite covering about 5 km2 is firstly recognized in the Zhusileng area, which is located between the northern Alxa Block and the South Gobi microcontinent. New geochronological data from this area provide new insight for understanding the Precambrian crustal evolution of the middle segment of the southern Central Asian Orogenic Belt (CAOB). Based on the crystal shapes, internal textures, and high Th/U ratios, the zircons from this Mesoproterozoic granite are interpreted as magmatic origin. Meanwhile, LA‐ICP‐MS zircon U–Pb dating shows that it was emplaced at 1458 ± 7.5 Ma. Published geochronological data and Sr–Nd isotopic compositions of igneous rocks from the Zhusileng area and its vicinity are also compiled in this study. The Late Palaeozoic granitoids from the Zhusileng area have strongly negative εNd(t) values (−0.1 to −10.8), high (87Sr/86Sr)i (0.69657–0.73423) and old Nd model ages (0.9–1.8 Ga), suggesting the existence of Precambrian microcontinent in the Zhusileng area. Furthermore, the statistical analysis (or isotopic mapping) of Sr–Nd isotopic compositions of Palaeozoic granitoids from the middle segment of the southern CAOB also displays similar εNd(t) values and relatively old Nd model ages along the Hanshan Block, Zhusileng, Tsaggan Uul terrane, and Hutag Uul terrane. Therefore, we propose that those units may share a common basement during Mesoproterozoic to Early Neoproterozoic. [ABSTRACT FROM AUTHOR]

The Fushan Depression is one of the prolific hydrocarbon‐bearing depressions in the Beibuwan Basin, South China Sea. In this study, a total of 133 mudstone samples, 18 well‐logging curves, and 12 seismic sections were analysed to investigate the geochemical features and spatial distribution of effective source rocks of the Palaeogene Liushagang Formation within a sequence stratigraphic geochemical framework. The results suggest that depositional centres of mudstones northward migrated from the central Huangtong Sag during the Liushagang period. Good hydrocarbon generation potential source rocks containing Type II kerogen occur in the transgressive systems tract (TST)–highstand systems tract (HST) of lower Liushagang sequence (SQls3), the middle Liushagang sequence (SQls2), and the lowstand systems tract (LST)–TST of upper Liushagang sequence (SQls1). The occurrence of effective source rock kitchens, which are mainly controlled by the thermal maturity is distributed in the strip‐shaped area of SQls3 sequence, the whole Huangtong Sag of SQls2 sequence, and the central and northern part of Huangtong Sag of SQls1 sequence, respectively. Fewer hydrocarbon accumulations were found in the southern slope due to the relatively deeper hydrocarbon generation threshold depth and to the limited occurrence of effective source rock kitchens. [ABSTRACT FROM AUTHOR]

Background: Aberrant TAK1 (transforming growth factor β‐activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab‐like GTPase activator and myotubularin domain containing 4) is a newly discovered p53‐independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma). Results: In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen‐activated protein kinase) and NF‐κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients. Conclusions: GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF‐κB signalling pathways. [ABSTRACT FROM AUTHOR]

The interactions between crops and the atmosphere significantly impact surface energy and hydrology budgets, climate, crop yield, and agricultural management. In this study, a multipass land data assimilation scheme (MLDAS) is proposed based on the Noah‐MP‐Crop model. The ensemble Kalman filter (EnKF) method is used to jointly assimilate the leaf area index (LAI), soil moisture (SM), and solar‐induced chlorophyll fluorescence (SIF) observations to predict sensible (H) and latent (LE) heat fluxes, gross primary productivity (GPP), etc. Such joint assimilation is demonstrated to be effective in constraining the model state variables (i.e., leaf biomass and SM) and optimizing key crop‐model parameters (i.e., specific leaf area [SLA], and maximum rate of carboxylation, Vcmax). The performance of the MLDAS is evaluated against observations at two AmeriFlux cropland sites, revealing good an agreement with the observed H, LE, and GPP. When using optimized model parameters (SLA and Vcmax) and jointly assimilating LAI, SM, and SIF observations, the MLDAS produces 34.28%, 26.90%, and 51.82% lower root mean square deviations for daily H, LE, and GPP estimates compared with the Noah‐MP‐Crop open loop simulation. Our findings also indicate that the H and LE predictions are more sensitive to SM measurements, while the GPP simulations are more affected by LAI and SIF observations. The results indicate that performances of physical models can be greatly improved by assimilating multi‐source observations within MLDAS. Plain Language Summary: Accurate estimations of water and carbon fluxes in croplands are required for monitoring crop yield, hydrology, and irrigation scheduling. Thus, many crop models are aimed at modeling crop dynamics to establish more accurate water, carbon, and energy processes. The data assimilation (DA) method can combine land surface and vegetation phenological information with a process‐based model to reduce the uncertainty in model variables and optimize model parameters. In this study, multi‐source observations of the land surface and vegetation phenology are assimilated into a land‐surface‐crop model to improve the water, carbon, and energy fluxes over croplands. This research involved the construction of a DA framework with multipass ensemble Kalman filter method. The results show that the assimilation of soil moisture observations significantly improves the surface heat fluxes estimates, while the assimilation of vegetation phenological observations significantly improves the vegetation dynamics and crop yield estimates. Key Points: The Multipass Land Data Assimilation Scheme (MLDAS) is proposed based on the Noah‐MP‐Crop modelLeaf area index (LAI), soil moisture (SM), and solar‐induced chlorophyll fluorescence (SIF) measurements are assimilated into the MLDAS to predict sensible heat flux (H), latent heat flux (LE), and gross primary productivity (GPP)H and LE estimates are more sensitive to SM measurements, while the GPP retrievals are more affected by LAI and SIF observations [ABSTRACT FROM AUTHOR]

In order to study the subsidence characteristics, temporal–spatial variation, and their controlling factors of the Pearl River Mouth Basin, we have calculated and mapped 34 wells' subsidence via 1‐D backstripping method, from which 12 typical wells have been selected as a sample to compare. Three typical profiles also have been chosen to compile subsidence evolution profiles by 2‐D backstripping method. All wells were synthesized as the holistic subsidence of the whole basin. The results indicate that the holistic subsidence of the basin can be divided into three episodes: The first one was Eocene with the mean total subsidence rate of 85 m/Ma; the second episode was from Oligocene to Middle Miocene with the mean total subsidence rate of 146 m/Ma; and the third episode was from Late Miocene up to present, and its mean total subsidence rate was 104 m/Ma. It is a common phenomenon that variation of subsidence and evolution existing in different units during the same period as well as different periods in the same unit. According to the distribution of subsidence rate in the plane, the basin can be divided into three zones from east to west and several belts in the same zone from north to south for each period. The variant change of subsidence evolution is related to the phase of basin evolution and structural characteristics. The holistic subsidence of the whole basin is controlled by basin dynamics, and the temporal–spatial variation of subsidence is affected by both basin dynamics and structural framework. [ABSTRACT FROM AUTHOR]

The known mode of action of isoniazid (INH) is to inhibit bacterial cell wall synthesis following activation by the bacterial catalase-peroxidase enzyme KatG in Mycobacterium tuberculosis (Mtb). This simplistic model fails to explain (a) how isoniazid penetrates waxy granulomas with its very low lipophilicity, (b) how isoniazid kills latent Mtb lacking a typical cell wall, and (c) why isoniazid treatment time is remarkably long in contrast to most other antibiotics. To address these questions, a novel comprehensive mode of action of isoniazid has been proposed here. Briefly, isoniazid eradicates latent tuberculosis (TB) by prompting slow differentiation of pro-inflammatory monocytes and providing protection against reactive species-induced "self-necrosis" of phagocytes. In the case of active TB, different immune cells form INH-NAD+ adducts to inhibit Mtb's cell wall biosynthesis. This additionally suggests that the antibacterial properties of INH do not rely on KatG of Mtb. As such, isoniazid-resistant TB needs to be re-evaluated. [ABSTRACT FROM AUTHOR]

A‐kinase‐interacting protein 1 (AKIP1) has previously been reported to act as a potential oncogenic protein in various cancers. The clinical significance and biological role of AKIP1 in gastric cancer (GC) is, however, still elusive. Herein, this study aimed to investigate the functional and molecular mechanism by which AKIP1 influences GC. AKIP1 mRNA and protein expressions in GC tissues were examined by quantitative real‐time PCR (qRT‐PCR), Western blot and immunohistochemistry. Other methods including stably transfected against AKIP1 into gastric cancer cells, wound healing, transwell assays, CCK‐8, colony formation, qRT‐PCR and Western blot in vitro and tumorigenesis in vivo were also performed. The up‐regulated expression of AKIP1 in GC specimens significantly correlated with clinical metastasis and poor prognosis in patients with GC. AKIP1 knockdown markedly suppressed GC cells proliferation, invasion and metastasis both in vitro and in vivo. In contrast, AKIP1 overexpression resulted in the opposite effects. Moreover, mechanistic analyses indicated that Slug‐induced epithelial‐mesenchymal transition (EMT) might be responsible for AKIP1‐influenced GC cells behaviour. Our findings demonstrated that high AKIP1 expression significantly correlated with clinical metastasis and unfavourable prognosis in patients with GC. Additionally, AKIP1 promoted GC cells proliferation, migration and invasion by activating Slug‐induced EMT. [ABSTRACT FROM AUTHOR]

Changes in global fire activity are influenced by a multitude of factors including land‐cover change, policies, and climatic conditions. This study uses 17 climate models to evaluate when changes in fire weather, as realized through the Fire Weather Index, emerge from the expected range of internal variability due to anthropogenic climate change using the time of emergence framework. Anthropogenic increases in extreme Fire Weather Index days emerge for 22% of burnable land area globally by 2019, including much of the Mediterranean and the Amazon. By the midtwenty‐first century, emergence among the different Fire Weather Index metrics occurs for 33–62% of burnable lands. Emergence of heightened fire weather becomes more widespread as a function of global temperature change. At 2 °C above preindustrial levels, the area of emergence is half that for 3 °C. These results highlight increases in fire weather conditions with human‐caused climate change and incentivize local adaptation efforts to limit detrimental fire impacts. Plain Language Summary: Observed increases in the frequency and severity of fire weather have been observed across portions of the globe over the past half century. We used climate models to identify where and when anthropogenic climate change causes fire weather conditions to exceed that of natural variability. Modeling results show that emergence for some fire weather indices is already under way for a sizable portion of the globe, including much of southern Europe and the Amazon, and with an expansion of this area with continued warming over the twenty‐first century. These findings suggest substantial increases in fire potential in regions where vegetation abundance and ignitions are not limiting, highlighting the urgency to adapt to changes in fire disturbances and hazards. Key Points: Anthropogenic climate change is projected to enhance fire weather across most burnable global land surfaces during the twenty‐first centuryEmergence of fire weather conditions from natural variability is modeled to occur in the first half of the twenty‐first century in many regionsExtent of fire‐weather emergence is twice as large when global temperature surpasses 3 °C, compared to 2 °C, above preindustrial levels [ABSTRACT FROM AUTHOR]

Abstract: Alpha B‐crystallin (CRYAB) is overexpressed in a variety of cancers. However, little is known about its specific function and regulatory mechanism in gastric cancer. Here, we first explore the role of CRYAB in gastric cancer progression and metastasis. The expression of CRYAB was determined by western blot and immunohistochemistry in gastric cancer tissues. Besides, methods including stably transfected against CRYAB into gastric cancer cells, western blot, migration and invasion assays in vitro and metastasis assay in vivo were also conducted. The expression of CRYAB is up‐regulated in gastric cancer tissues compared with matched normal tissues. High expression level of CRYAB is closely correlated with cancer metastasis and shorter survival time in patients with gastric cancer. Additionally, CRYAB silencing significantly suppresses epithelial‐mesenchymal transition (EMT), migration and invasion of gastric cancer cells in vitro and in vivo, whereas CRYAB overexpression dramatically reverses these events. Mechanically, CRYAB facilitates gastric cancer cells invasion and metastasis via nuclear factor‐κ‐gene binding (NF‐κB)‐regulated EMT. These findings suggest that CRYAB expression predicts a poor prognosis in patients with gastric cancer. Besides, CRYAB contributes to gastric cancer cells migration and invasion via EMT, mediated by the NF‐κB signalling pathway, thus possibly providing a novel therapeutic target for gastric cancer. [ABSTRACT FROM AUTHOR]

Abstract: Long‐term ecological data can be an effective tool to help ecologists integrate future projections with historical contexts and provide unique insights into the long‐term dynamics of endangered species. However, hampered by data limitations, including incomplete and spatially biased data, relatively few studies have used multidecadal datasets or have examined changes in biogeography from a historical perspective. The black‐billed capercaillie (Tetrao urogalloides) is a large capercaillie (classified as Least Concern [LC] on the IUCN red list) that has undergone a dramatic decline in population during the late 20th century and is considered endangered. Its conservation status is pessimistic, and the species requires immediate protection. Therefore, we supplemented a historical dataset to identify changes in this bird's range and population in northeast China over the long term. The study area spanned Heilongjiang Province, Jilin Province, and the northeast corner of Inner Mongolia in northeast China. We integrated an ecological niche model (BIOMOD2) with long‐term ecological data on this species to estimate the magnitude of change in distribution over time. Our results revealed a 35.25% reduction in the current distribution of this species compared to their potential distribution in the 1970s. This decline is expected to continue under climate change. For example, the future range loss was estimated to be 38.79 ± 0.22% (8.64–90.19%), and the actual state could be worse, because the baseline range of the model was greater than the real range in the 2000s, showing a 12.39% overestimation. To overcome this poor outlook, a conservation strategy should be established in sensitive areas, including the southwestern Greater Khingan Mountains and northern Lesser Khingan Mountains. Actions that should be considered include field investigations, establishing a monitor network, designing ecological corridors, and cooperating with local inhabitants, governments, and conservation biologists to improve the conservation of the black‐billed capercaillie. [ABSTRACT FROM AUTHOR]

A new genus of Compositae, Shangwua, is described to accomodate all species formerly placed in Saussurea sect. Jacea. This genus is distinct from the other genera of tribe Cardueae in its unique combination of states of characters including involucral bracts, receptacle, paleae, anther, style, achene and pappus. Phylogenetic analyses based on molecular data suggest that this new genus belongs to the Xeranthemum group, a lineage of the Carduinae that diversified early, with only distant relationships to Saussurea and related genera. The genus Shangwua consists of three species occurring in the Qinghai-Tibetan Plateau and Himalayas. [ABSTRACT FROM AUTHOR]

ZnO quantum dots were synthesized via a low-temperature solvothermal process without using surfactants. Heat treatment of ZnCl2 and NaOH solutions in tetra-ethylene glycol at 140°C led to the formation of spherical ZnO nanoparticles consisting of the aggregates of uniform-sized quantum dots. The particle size and morphology were characterized using transmission electron microscopy, dynamic light scattering, X-ray diffraction, and Brunauer–Emmett–Teller gas absorption measurements. It was found that the quantum dots in the particles were single crystals of ZnO of ∼5 nm in diameter having the wurtzite structure. The quantum dots showed quantum size effects even in the agglomerated form. The growth mechanism of this new type of ZnO nanoparticles is proposed. [ABSTRACT FROM AUTHOR]