Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

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.

Shenyu ningshen tablet reduced neuronal damage in the hippocampus of chronic restraint stress model rat by inhibiting A1-reactive astrocytes.

Context: Shenyu Ningshen (SYNS) tablet is the first pure Chinese medicinal small compound preparation approved for clinical trials for the treatment of depression in China. Clinical experiments confirmed that the formulation had a significant Improvement effect against depression due to the deficiency of both qi and yin. It has been shown to exhibit noticeable anti-inflammatory effect in an animal model of depression. Our previous study showed that SYNS could effectively inhibit the inflammatory response in a depression model. Aim of the study: The purpose of this study was to investigate the protective effects of SYNS on neurons and explore whether the underlying mechanism was associated with A1s. Materials and methods: The depression model of solitary raising-chronic restraint stress (CRS) rats was established; body weight examination, sugar water preference test, open field test, and histological analysis were performed to preliminarily verify the efficacy of the formulation. Subsequently, neuronal nucleus (NeuN) and synaptic-associated proteins (MAP2 and PSD95) were labeled, and the protective effect of SYNS on hippocampal neurons was observed based on the fluorescence intensity of the above indicators. Western blotting, histological examination, and immunofluorescence were used to evaluate the inhibitory effects of SYNS on neuroinflammation and activation of A1s in CRS depression model. Results: SYNS improved behavioral indicators such as weight loss, pleasure loss, and reduced exercise volume in CRS rat model. SYNS restored the CRS-induced histopathological changes in the hippocampus. SYNS showed a certain degree of protective effect on synapses. Further, SYNS inhibited the activation of A1s by inhibiting neuroinflammatory factors in the hippocampus. Conclusion: Our results showed that SYNS had a certain degree of neuroprotective effect, which might be related to its inhibition of the inflammatory response and A1s.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

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.

gjSOX9 Cloning, Expression, and Comparison with gjSOXs Family Members in Gekko japonicus.

SOX9 plays a crucial role in the male reproductive system, brain, and kidneys. In this study, we firstly analyzed the complete cDNA sequence and expression patterns for SOX9 from Gekko japonicus SOX9 (gjSOX9), carried out bioinformatic analyses of physiochemical properties, structure, and phylogenetic evolution, and compared these with other members of the gjSOX family. The results indicate that gjSOX9 cDNA comprises 1895 bp with a 1482 bp ORF encoding 494aa. gjSOX9 was not only expressed in various adult tissues but also exhibited a special spatiotemporal expression pattern in gonad tissues. gjSOX9 was predicted to be a hydrophilic nucleoprotein with a characteristic HMG-Box harboring a newly identified unique sequence, "YKYQPRRR", only present in SOXE members. Among the 20 SOX9 orthologs, gjSOX9 shares the closest genetic relationships with Eublepharis macularius SOX9, Sphacrodactylus townsendi SOX9, and Hemicordylus capensis SOX9. gjSOX9 and gjSOX10 possessed identical physicochemical properties and subcellular locations and were tightly clustered with gjSOX8 in the SOXE group. Sixteen gjSOX family members were divided into six groups: SOXB, C, D, E, F, and H with gjSOX8, 9, and 10 in SOXE among 150 SOX homologs. Collectively, the available data in this study not only facilitate a deep exploration of the functions and molecular regulation mechanisms of the gjSOX9 and gjSOX families in G. japonicus but also contribute to basic research regarding the origin and evolution of SOX9 homologs or even sex-determination mode in reptiles.

Distinct functions between ferrous and ferric iron in lung cancer cell growth.

Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe2+ ; ferrous) or oxidized (Fe3+ ; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5-IRP2 axis, a ubiquitin-dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin-dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor-bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth.

Pharmacological effects and mechanism of Kaihoujian Throat Spray (children's type) in the treatment of pediatric acute pharyngitis and tonsillitis.

Context: Kaihoujian Throat Spray children's type (KHJSC) is a Chinese medicine prescription for treating pediatric acute pharyngitis and tonsillitis (APT). However, its relevant mechanisms remain unclear. Objective: To investigate the pharmacological effects of KHJSC on APT in vitro and in vivo, and explore the possible mechanism and target proteins. Materials and methods: The antiviral and antibacterial effects in vitro were evaluated by IC50 and MICs. Thirty-six Japanese white rabbits were averagely divided into control group, model group, amoxicillin group and 3 dose groups of KHJSC (720, 540 and 360 µL/kg/d). The model rabbits were injected with ß-hemolytic Streptococcus solution into the tonsils for 2 consecutive days. KHJSC treatment started on the third day. The whole blood, serum, tonsil tissues and pharyngeal mucosa tissues were collected for routine blood tests, proteomic, ELISA and other tests on the sixth day. Results: The IC50 of KHJSC on HCoV-229E, influenza PR8 and Ad3 were 1.99, 1.99 and 4.49 mg/mL, respectively; MICs of MDR-PA, MRSA and ß-hemolytic Streptococcus were 350, 350, and 175 mg/mL. KHJSC markedly decreased the number of white blood cells, lymphocytes, neutrophils, and the level of IL-1ß, IL-5, IL-6, IL-18, TNF-α and MCP-1; increased the content of IL-2 and IFN-γ. Proteomic analysis and ELISA revealed that PI3K-Akt signaling pathway, NF-κB signaling pathway and Toll-like receptor signaling pathway were the potential mechanisms of KHJSC against APT. Discussion and conclusion: These results provided the reference and scientific basis for the application of KHJSC in clinic and further mechanisms study.

Can nesting behaviour allow reptiles to adapt to climate change?

A range of abiotic parameters within a reptile nest influence the viability and attributes (including sex, behaviour and body size) of hatchlings that emerge from that nest. As a result of that sensitivity, a reproducing female can manipulate the phenotypic attributes of her offspring by laying her eggs at times and in places that provide specific conditions. Nesting reptiles shift their behaviour in terms of timing of oviposition, nest location and depth of eggs beneath the soil surface across spatial and temporal gradients. Those maternal manipulations affect mean values and variances of both temperature and soil moisture, and may modify the vulnerability of embryos to threats such as predation and parasitism. By altering thermal and hydric conditions in reptile nests, climate change has the potential to dramatically modify the developmental trajectories and survival rates of embryos, and the phenotypes of hatchlings. Reproducing females buffer such effects by modifying the timing, location and structure of nests in ways that enhance offspring viability. Nonetheless, our understanding of nesting behaviours in response to climate change remains limited in reptiles. Priority topics for future studies include documenting climate-induced changes in the nest environment, the degree to which maternal behavioural shifts can mitigate climate-related deleterious impacts on offspring development, and ecological and evolutionary consequences of maternal nesting responses to climate change. This article is part of the theme issue 'The evolutionary ecology of nests: a cross-taxon approach'.

Sanwei DouKou Decoction ameliorate Alzheimer disease by increasing endogenous neural stem cells proliferation through the Wnt/ß-catenin signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Sanwei DouKou decoction (SDKD) is a traditional Chinese medicine (TCM) prescription derived from the Tibetan medical book "Si Bu Yi Dian" and is clinically used for the treatment of Alzheimer's disease (AD). However, the potential mechanism of SDKD treatment for AD remains elusive. AIM OF THE STUDY: This study aims to explore the potential mechanism by which SDKD alleviates AD. MATERIALS AND METHODS: Extracts of SDKD were identified with Gas chromatograph-mass spectrometer (GC-MS). 5 × FAD mice were treated with SDKD for 8 weeks. The efficacy of SDKD against AD was evaluated by in-vivo experiments. Morris water maze and contextual fear conditioning tests were used to detect the learning and memory ability of mice. Hematoxylin-eosin staining (H&E) staining was used to observe the pathological changes of brain tissue. Immunohistochemistry was used to detect the positive expression of Nestin in hippocampus. In in-vitro experiments, the Cell Counting Kit 8 (CCK-8) technique was used to detect cell viability, the proliferation of neural stem cells was detected by immunofluorescence staining, the intracellular protein expression was detected by Western Blot. RESULTS: The results of this study suggested that SDKD may ameliorate AD. SDKD significantly shortened the escape latency of mice in the Morris water maze experiment, increased the number of times the mice crossed the target quadrant, and prolonged freezing time in the contextual fear memory experiment. SDKD also improved neuronal pathology in the hippocampus, decreased neuronal loss, and increased Nestin protein levels. Furthermore, in in-vitro experiments, SDKD could significantly increase Neural stem cells (NSCs) viability, promoted NSCs proliferation, and also effectively activated the Wnt/ß-catenin signalling pathway, increased Wnt family member 3A (Wnt3a), ß-catenin and CyclinD1 protein levels, activated the NSCs proliferation pathways in AD model mouse brain tissue. CONCLUSIONS: The present study demonstrated that sanwei doukou decoction can ameliorate AD by increasing endogenous neural stem cells proliferation through the Wnt/ß-catenin signalling pathway. Our observations justify the traditional use of SDKD for a treatment of AD in nervous system.

Remediation of lindane contaminated soil by fluidization-like dielectric barrier discharge.

This study proposed the fluidization-like dielectric barrier discharge (DBD) plasma for the remediation of lindane contaminated soil and integrated physical and chemical reaction pathway. Soil particle distribution within the reactor was simulated with Euler-Euler and Gidaspow drag models, and a bipolar pulsed power supply was applied to energize the DBD reactor after full fluidized. The effect of soil particles movement on electric features was discussed in terms of voltage waveforms and Lissajous figures. Lindane degradation was found to be related to electrics parameters and soil properties. Soil samples before and after treatment were analyzed by XRD and SEM methods. A 95.98% lindane decomposition and 0.66 mgLindane/h average reaction rate were obtained with 3 wt% CaO injection by pulse power drove fluidization-like DBD after 32 min treatment. Ozone was proved to play a major role during lindane degrading by plasma. The reaction potential pathway of lindane decomposition contains 4 steps, including dehydrogen, dehydrochlorination, and dechlorination, respectively.

Past, present, and future predictions on the suitable habitat of the Slender racer (Orientocoluber spinalis) using species distribution models.

Species distribution models (SDMs) across past, present, and future timelines provide insights into the current distribution of these species and their reaction to climate change. Specifically, if a species is threatened or not well-known, the information may be critical to understand that species. In this study, we computed SDMs for Orientocoluber spinalis, a monotypic snake genus found in central and northeast Asia, across the past (last interglacial, last glacial maximum, and mid-Holocene), present, and future (2070s). The goal of the study was to understand the shifts in distribution across time, and the climatic factors primarily affecting the distribution of the species. We found the suitable habitat of O. spinalis to be persistently located in cold-dry winter and hot summer climatic areas where annual mean temperature, isothermality, and annual mean precipitation were important for suitable habitat conditions. Since the last glacial maximum, the suitable habitat of the species has consistently shifted northward. Despite the increase in suitable habitat, the rapid alterations in weather regimes because of climate change in the near future are likely to greatly threaten the southern populations of O. spinalis, especially in South Korea and China. To cope with such potential future threats, understanding the ecological requirements of the species and developing conservation plans are urgently needed.

Latitudinal Variation in the Pattern of Temperature-Dependent Sex Determination in the Japanese Gecko, Gekko japonicus.

Identifying latitudinal variation in the pattern of temperature-dependent sex determination (TSD) may provide insight into the evolution of sex determining system in vertebrates, but such studies remain limited. Here, we quantified TSD patterns of three geographically separated populations of the Japanese gecko (Gekko japonicus) along the latitudinal cline of China. We incubated gecko eggs from the three populations at constant temperatures of 24, 26, 28, 30, and 32 °C to quantify the TSD pattern. Our study demonstrated that G. japonicus exhibited a FMF pattern of TSD, with the low and high incubation temperatures yielding significantly female-biased hatchlings, and the medium temperatures producing male-biased hatchlings. More interestingly, we found latitudinal variations in the TSD pattern in terms of pivotal temperatures (Tpivs), transitional range of temperatures (TRT), and the sex ratios at the medium temperatures. The Tpivs for the low-latitude population were lower than those for the two high-latitude populations. The low-latitude population has a narrower FM TRT, but a wider MF TRT. The sex ratio is almost 50:50 for the low-latitude population when eggs were incubated from 26 to 30 °C. Conversely, the sex ratio is male-biased for the two high-latitude populations at 28 or 30 °C. Therefore, G. japonicus may provide an interesting system to explore the evolution of TSD in reptiles given the diversity of TSD patterns among populations.

Population origin, maternal effects, and hydric conditions during incubation determine embryonic and offspring survival in a desert-dwelling lizard.

While the effects of incubation environment on embryonic development and offspring traits have been extensively studied in oviparous vertebrates, studies into how genetic inheritance (population origin), maternal effects, and incubation environment interact to produce varying phenotypes, are rare. To elucidate the interactive role of those three factors during incubation in shaping offspring phenotypes through hydric conditions, we conducted a fully factorial experiment [arid and semiarid populations × maternal dry and wet treatments (MDT and MWT) × embryonic dry and wet treatments (EDT and EWT)] with a desert-dwelling lacertid lizard (Eremias argus). Female lizards in dry conditions produced larger clutch sizes but smaller eggs. The incubation period and hatching success were significantly affected by embryonic but not by maternal moisture treatments. Eggs in the EDT hatched later than those in the EWT in both arid and semiarid populations. Hatching success was lower in EDT than in EWT in the semiarid population, but not in the arid population. Hatchlings from the EDT had a slower post-hatch increase in body mass than those from the EWT. EDT would decrease the survival rates of hatchlings in the semiarid population only. In addition, structural equation models revealed that population had a stronger effect on embryonic and offspring survival than maternal and embryonic moisture. Our study demonstrates locally adaptive strategies of drought resistance at multiple life-history stages in lizard populations from diverse hydric habitats and highlights the importance of genetic factors in determining embryonic drought resistance in oviparous lizards.

Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin.

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.

The role of inflammatory cytokines in anemia and gastrointestinal mucosal injury induced by foot electric stimulation.

Foot electrical stimulation (FES) has been considered as a classic stressor that can disturb homeostasis. Acute anemia was observed in the model induced by FES. The aim of this study was to explore the role of inflammatory cytokines underlying the acute anemia and gastrointestinal (GI) mucosal injury in the FES. Twenty-four male Kunming mice (20 ± 2 g) were randomly divided into control group and experimental group. The mice were placed in a footshock chamber that can generate 0.5 mA electrical impulse periodically for 0.5 h. After the process, red blood cell count, hemoglobin concentration and hematocrit, the levels of corticotropin releasing hormone (CRH) in serum and hypothalamus, and adrenocorticotropic hormone (ACTH) in serum and pituitary were detected separately. In addition, we investigated the expressions of inflammatory cytokines (IL-1, IL-6, TNF-α, iNOS, and IL-10) in the hypothalamus and duodenum by Polymerase Chain Reaction (PCR). Results showed that this FES model induced anemia, increased CRH and ACTH activity in the serum after the FES. Moreover, the expressions of IL-1ß, IL-6, TNF-α, and iNOS were significantly increased following the process, while IL-10 was not activated. These findings suggest that anemia, the inflammatory cytokines in the hypothalamus and duodenum of the mice in the model induced by FES is closely related to GI mucosal injury/bleeding. Taken together, these results underscore the importance of anemia, GI mucosal injury/bleeding and stress, future studies would be needed to translate these findings into the benefit of affected patients.

Phenotypic consequences of maternally selected nests: a cross-fostering experiment in a desert lizard.

Despite the importance of maternally selected nests in shaping offspring phenotypes, our understanding of how the nest environment affects embryonic development and offspring traits of most non-avian reptiles is rather limited largely due to the logistical difficulty in locating their nests. To identify the relative contributions of environmental (temporal [seasonal] and spatial [nest-site]) and intrinsic (clutch) factors on embryonic development and offspring traits, we conducted a cross-fostering experiment by swapping eggs between maternally-selected nests of the toad-headed agama (Phrynocephalus przewalskii) in the field. We found that nest environment explained a large proportion of variation in incubation duration, hatching success, and offspring size and growth. In contrast, clutch only explained a small proportion of variation in these embryonic and offspring traits. More significantly, compared with spatial effects, seasonal effects explained more phenotypic variation in both embryonic development and offspring traits. Eggs laid early in the nesting season had longer incubation durations and produced smaller hatchlings with higher post-hatching growth rates than did later-laid eggs. Consequently, hatchlings from early-laid eggs reached larger body sizes prior to winter. In addition, we found that female toad-headed agama did not select nests specific to reaction norms of their own offspring because hatchlings from original or translocated nests had similar phenotypic traits. Overall, our study demonstrates the importance of seasonal variation in nest environments in determining embryonic development and offspring phenotypes, which has not been widely appreciated at least in non-avian reptiles.

The complete mitochondrial genome of Pseudoxenodon stejnegeri (Squamata: Colubridae: Pseudoxenodontinae) and its phylogeny.

The mitochondrial genome sequence of Pseudoxenodon stejnegeri (Squamata: Colubridae: Pseudoxenodontinae) from Taishun County, Zhejiang Province, China, which is 18,475 bp in length and contains 25 tRNAs (including extra two tRNA-Tyr genes and extra one tRNA-Met gene), two rRNAs, 13 protein-coding genes and two identical control regions. The overall AT content of the mitogenome is 59.6% (A = 32.6%, T = 27%, C = 27%, G = 13.4%). In BI and ML phylogenetic analyses, the monophyly of the family Colubridae was well supported and P. stejnegeri was a basal clade of Colubridae.

Behavioural thermoregulation by the endangered crocodile lizard (Shinisaurus crocodilurus) in captivity.

Understanding the factors that may affect behavioural thermoregulation of endangered reptiles is important for their conservation because thermoregulation determines body temperatures and in turn physiological functions of these ectotherms. Here we measured seasonal variation in operative environmental temperature (Te), body temperature (Tb), and microhabitat use of endangered crocodile lizards (Shinisaurus crocodilurus) from a captive population, within open and shaded enclosures, to understand how they respond to thermally challenging environments. Te was higher in open enclosures than in shaded enclosures. The Tb of lizards differed between the open and shaded enclosures in summer and autumn, but not in spring. In summer, crocodile lizards stayed in the water to avoid overheating, whereas in autumn, crocodile lizards perched on branches seeking optimal thermal environments. Crocodile lizards showed higher thermoregulatory effectiveness in open enclosures (with low thermal quality) than in shaded enclosures. Our study suggests that the crocodile lizard is capable of behavioural thermoregulation via microhabitat selection, although overall, it is not an effective thermoregulator. Therefore, maintaining diverse thermal environments in natural habitats for behavioural thermoregulation is an essential measure to conserve this endangered species both in the field and captivity.

Wax composition and concentration in jujube (Ziziphus jujuba Mill.) cultivars with differential resistance to fruit cracking.

Fruit cracking is a key problem restricting the development of the jujube (Ziziphus jujuba) industry, and is closely related to the distribution of the wax layer on the surface of the fruit. Three jujube cultivars with different levels of cracking resistance, namely 'Popozao', 'Banzao', and 'Hupingzao', were selected for comparison. Cracks on the cuticular membrane (CM) of 'Hupingzao' widened and deepened during the coloring period. The wax level of highly cracking-resistant 'Popozao' was significantly higher than that of 'Hupingzao' during the fruit coloring period. The fruit wax composition of the three jujube cultivars were quite similar, consisting mainly of alkanes, triterpenoids, aldehydes, amines, phenols, esters, ketones, fatty acids, primary alcohols, and other, unclassified compounds. Fatty acids, primary alcohols, and alkanes were the predominant fruit wax compounds of the three cultivars. We further analyzed the carbon chain length of aliphatic compounds and found that the concentration of fatty acids in 'Popozao' was significantly lower than that in 'Banzao' and 'Hupingzao' during the coloring period. Moreover, C28-30 were the most abundant primary alcohols during fruit development. Highly cracking-resistant cultivar 'Popozao' contains more very-long-chain alkanes and aldehydes (carbon atom >20) than 'Banzao' and 'Hupingzao' during the coloring period. In addition, we assessed the expression levels of 11 genes involved in fatty acid biosynthesis, elongation, and degradation, and in wax biosynthesis. Gene expression analysis indicated that KCS1, CER1, CYP86B1, and CYP86A play crucial roles in wax formation on jujube fruit. In conclusion, fruit cracking was correlated with whether wax synthesis is coordinated with fruit enlargement and'Popozao' has a stronger ability to synthesize very-long-chain alkanes and aldehydes. Understanding the diff ;erences in the cuticular wax and the activities of the corresponding genes in jujube cultivars with different sensitivities to cracking will provide a specific way to prevent fruit cracking.

The association between frailty and incidence of dementia in Beijing: findings from 10/66 dementia research group population-based cohort study.

BACKGROUND: The relationship between frailty and dementia is unclear and there are very few population-based studies regarding this issue in China. The purpose of this study is to estimate the association between frailty and incident dementia in China, and to explore different effects of frailty established by three definitions of frailty on dementia incidence. METHODS: A five-year prospective cohort study was carried out in 2022 participants aged 65 years and over in urban and rural sites in Beijing, China. The participants were interviewed by trained community primary health care workers from 2004 to 2009. Frailty was defined using modified Fried frailty phenotype, physical frailty definition, and multidimensional frailty definition. Dementia was diagnosed using the 10/66 dementia criterion for calculating cumulative incidence. Both competing risk regression models and Cox proportional hazards models were applied to examine the associations between frailty at baseline and five-year cumulative incidence of dementia. RESULTS: At the end of follow-up the five-year cumulative incidence rates of dementia with frailty and without frailty defined by the modified Fried frailty were 21.0% and 9.6%, those defined by the physical frailty were 19.9% and 9.0%, and those defined by the multidimensional frailty were 22.8% and 8.9%, respectively. Compared with non-frail participants, frail people had a higher risk of incident dementia using multidimensional frailty definition after adjusting covariates based on competing risk regression model (HR = 1.47, 95% CI 1.01~2.17) and Cox proportional hazards model (HR = 1.56, 95% CI 1.07~2.26). The association between frailty and incident dementia was statistically significant in participants in the upper three quartiles of age (aged 68 years and over) using the multidimensional frailty definition based on the competing risk regression model (HR = 1.61, 95% CI 1.06~2.43) and Cox proportional hazard model (HR = 1.76, 95% CI 1.19~2.61). CONCLUSIONS: Multidimensional frailty may play an inherent role in incident dementia, especially in the people aged over 68, which is significant for distinguishing high risk people and determining secondary prevention strategies for dementia patients.

Embryonic and post-embryonic responses to high-elevation hypoxia in a low-elevation lizard.

Low-elevation species can migrate toward higher elevations to survive in a warming world. However, animals' responses to hypoxia when migrating to high elevations have rarely been addressed. To identify the response of low-elevation lizards to high-elevation hypoxia, we collected field body temperatures (Tfb ) and operative temperatures (Te ) of lizards (Eremias argus) from a low-elevation population (1036 m) and a high-elevation population (2036 m), and then determined adult thermal physiology, embryonic development, and hatchling phenotypes after acclimating low-elevation lizards and incubating their eggs in conditions mimicking the low-elevation oxygen condition (18.5% O2 ) and high-elevation oxygen (hypoxic) condition (16.5% O2 ). Our study revealed that Tfb and Te were higher for the low-elevation population compared to the high-elevation population. We also found adults from low elevation acclimated to hypoxia preferred lower body temperatures, but did not show changes in locomotor performance or growth. In addition, hypoxia did not affect embryonic development (hatching time and success) or hatchling phenotypes (body size and locomotor performance). These results suggest that adult lizards from low elevations can respond to hypoxia-induced stress when migrating to high elevations by behaviorally thermoregulating to lower body temperatures in order to sustain normal functions. Similarly, low-elevation embryos can develop normally (with unchanged hatching success and offspring phenotypes) under the high-elevation hypoxic condition. This study highlights that low-elevation populations of a species that inhabits a range of elevations can buffer the impact of high-elevation hypoxic conditions to some degree and thus attain similar fitness to the source population.