Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models.

Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis.

Genetic adaptation of skin pigmentation in highland Tibetans.

Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have darker baseline skin color compared with lowland Han Chinese, as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production. A genome-wide search for the responsible genes identifies GNPAT showing strong signals of positive selection in Tibetans. An enhancer mutation (rs75356281) located in GNPAT intron 2 is enriched in Tibetans (58%) but rare in other world populations (0 to 18%). The adaptive allele of rs75356281 is associated with darker skin in Tibetans and, under UVB treatment, it displays higher enhancer activities compared with the wild-type allele in in vitro luciferase assays. Transcriptome analyses of gene-edited cells clearly show that with UVB treatment, the adaptive variant of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisomes with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection.

The totipotent 2C-like state safeguards genomic stability of mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) sporadically transition to a transient totipotent state that resembles blastomeres of the two-cell (2C) embryo stage, which has been proposed to contribute to exceptional genomic stability, one of the key features of mESCs. However, the biological significance of the rare population of 2C-like cells (2CLCs) in ESC cultures remains to be tested. Here we generated an inducible reporter cell system for specific elimination of 2CLCs from the ESC cultures to disrupt the equilibrium between ESCs and 2CLCs. We show that removing 2CLCs from the ESC cultures leads to dramatic accumulation of DNA damage, genomic mutations, and rearrangements, indicating impaired genomic instability. Furthermore, 2CLCs removal results in increased apoptosis and reduced proliferation of mESCs in both serum/LIF and 2i/LIF culture conditions. Unexpectedly, p53 deficiency results in defective response to DNA damage, leading to early accumulation of DNA damage, micronuclei, indicative of genomic instability, cell apoptosis, and reduced self-renewal capacity of ESCs when devoid of 2CLCs in cultures. Together, our data reveal that transition to the privileged 2C-like state is a major component of the intrinsic mechanisms that maintain the exceptional genomic stability of mESCs for long-term self-renewal.

A complete oral regimen for induction therapy of patients with high-risk APL: An oral etoposide instead of intravenous infusion for cytoreductive chemotherapy.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.

Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Serum IgA as a Prognostic Beacon: Anticipating Systemic Therapy Efficacy in Metastatic Clear Cell Renal Cell Carcinoma.

OBJECTIVE: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) therapy has revolutionized the treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC); however, the absence of effective biomarkers poses a challenge in predicting the efficacy of these regimens. This study aims to explore the predictive and prognostic value of serum immunoglobulin A (IgA) in mccRCC patients undergoing IO-TKI therapy. METHODS: Ninety-six mccRCC patients treated with IO-TKI therapy from 2019 to 2023 were enrolled and serum IgA levels were assessed at the pretreatment baseline and after 3 months of treatment. RESULTS: Notably, baseline levels of IgA showed no correlation with the objective response rate. However, patients achieving complete or partial responses exhibited a remarkable decrease in IgA levels, while those with stable or progressive disease displayed an increase in IgA levels after 3 months of treatment. Furthermore, the dynamic alteration in IgA levels after 3 months of treatment demonstrated predictive value for both progression-free survival (PFS) and overall survival (OS). The time-dependent receiver operating characteristic curves exhibited outstanding performance in predicting PFS (AUC 0.793) and OS (AUC 0.738). CONCLUSION: Taken together, this study demonstrates that dynamic alteration of serum IgA after 3 months of treatment was significantly correlated with prognosis and therapeutic efficacy in mccRCC patients.

A nigroincertal projection mediates aversion and enhances coping responses to potential threat.

Recent studies have shown that the non-DA neurons in the ventral tegmental area (VTA) and substantia nigra (SN) not only modulate motivational behaviors but also regulate defensive behaviors. While zona incerta (ZI) is a threat-responsive substrate and receives innervations from the ventral midbrain, the function of the ventral midbrain-to-ZI connection remains poorly defined. Here, we demonstrate that the ZI receives heterogenous innervations from the ventral midbrain. By utilizing a retrograde AAV preferentially labeling non-DA neurons in the ventral midbrain, we found that ZI-projecting non-DA cells in the ventral midbrain are activated by restraint stress. We focused on the SN and found that SN-to-ZI GABAergic input is engaged by a predatory odor. Sustained pan-neuronal SN-to-ZI activation results in aversion and enhances defensive behaviors, likely through a disinhibition mechanism to recruit downstream brain regions that regulate defensive behaviors. Collectively, our results reveal a novel role of nigroincertal projection in mediating negative valence and regulating defensive behaviors.

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

A new tau dephosphorylation-targeting chimera for the treatment of tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

Combined effects of vitamin D deficiency and systemic inflammation on all-cause mortality and cause-specific mortality in older adults.

BACKGROUND: Vitamin D deficiency and systemic inflammation share common pathological mechanisms in muscle loss, cardio-pulmonary function decline, and abnormal metabolism, which are linked to chronic conditions, senescence, and early mortality. However, their combined effect on mortality in older adults has not been well established. This study longitudinal aimed to explore the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] and high sensitivity C-reactive protein (hs-CRP) with mortality risk in Chinese community-based older people. METHODS: 3072 older adults (86.07 ± 11.87 years, 54.52% female) from the Chinese Longitudinal Healthy Longevity Survey (2012-2018) were enrolled. Baseline 25(OH)D and hs-CRP levels were collected, and survival information was recorded in the 2014 and 2018 follow-up waves. Cox proportional hazard regressions were conducted to explore the associations between 25(OH)D, hs-CRP, and mortality. Demographic characteristics, health behaviors, and chronic disease biomarkers were adjusted. RESULTS: During 10,622.3 person-years of follow-up (median: 3.51 years), 1321 older adults died, including 448 deaths due to cardiovascular disease (CVD). Increased mortality risk was associated with lower 25(OH)D and higher hs-CRP quantiles, even after adjusting for each other and multiple covariates (all P-trend < 0.05). In combined analyses, the highest all-cause mortality (HR: 2.18, 95% CI: 1.73 ~ 2.56), CVD mortality (HR: 2.30, 95% CI: 1.64 ~ 3.21), and non-CVD mortality (HR: 2.19, 95% CI: 1.79 ~ 2.49) were obtained in participants with both 25(OH)D deficiency (< 50 nmol/L) and high hs-CRP (≥ 3.0 mg/L), respectively. We observed significant additive interactions of 25(OH)D and hs-CRP on all-cause mortality and non-CVD mortality (RERIS>0). CONCLUSIONS: Low 25(OH)D and high hs-CRP, both independently and jointly, increase mortality risk in Chinese community-dwelling older adults. Thus, priority should be given to early detection and appropriate intervention in older individuals with combined vitamin D deficiency and systemic inflammation. Molecular mechanisms of related adverse health effect are worthy of further investigation.

Targeted metabolomic profiles of serum amino acids are independently correlated with malnutrition in older adults.

BACKGROUND: Malnutrition is a common geriatric syndrome that is closely associated with adverse clinical outcomes and poses significant harm to older adults. Early assessment of nutritional status plays a crucial role in preventing and intervening in cases of malnutrition. However, there is currently a lack of measurable methods and biomarkers to evaluate malnutrition in older adults accurately. The aim of this study is to investigate the independent correlation between serum levels of amino acids and malnutrition in older adults, and to identify effective metabolomics biomarkers that can aid in the early detection of geriatric malnutrition. METHODS: A total of 254 geriatric medical examination participants from Beijing Hospital were included in the study, consisting of 182 individuals with normal nutritional status (Normal group) and 72 patients at risk of malnutrition or already malnourished (MN group). Malnutrition was assessed using the Mini-Nutritional Assessment Short-Form (MNA-SF). Demographic data were collected, and muscle-related and lipid indexes were determined. Serum amino acid concentrations were measured using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation between serum amino acid levels and malnutrition was analyzed using non-parametric tests, partial correlation analysis, linear regression, and logistic regression. RESULTS: The geriatric MN group exhibited significantly lower serum aromatic amino acid levels (P < 0.05) compared to the normal group. A positive correlation was observed between serum aromatic amino acid levels and the MNA-SF score (P = 0.002), as well as with known biomarkers of malnutrition such as body mass index (BMI) (P < 0.001) and hemoglobin (HGB) (P = 0.005). Multivariable logistic or linear regression analyses showed that aromatic amino acid levels were negatively correlated with MN and positively correlated with the MNA-SF score, after adjusting for some confounding factors, such as age, gender, BMI, smoking status, history of dyslipidemia, diabetes mellitus and frailty. Stratified analyses revealed that these trends were more pronounced in individuals without a history of frailty compared to those with a history of frailty, and there was an interaction between aromatic amino acid levels and frailty history (P = 0.004). CONCLUSION: Our study suggests that serum aromatic amino acids are independently associated with malnutrition in older adults. These results have important implications for identifying potential biomarkers to predict geriatric malnutrition or monitor its progression and severity, as malnutrition can result in poor clinical outcomes.

Bridging and Bonding Social Capital by Analyzing the Demographics, User Activities, and Social Network Dynamics of Sexual Assault Centers on Twitter: Mixed Methods Study.

BACKGROUND: Social media platforms have gained popularity as communication tools for organizations to engage with clients and the public, disseminate information, and raise awareness about social issues. From a social capital perspective, relationship building is seen as an investment, involving a complex interplay of tangible and intangible resources. Social media-based social capital signifies the diverse social networks that organizations can foster through their engagement on social media platforms. Literature underscores the great significance of further investigation into the scope and nature of social media use, particularly within sectors dedicated to service delivery, such as sexual assault organizations. OBJECTIVE: This study aims to fill a research gap by investigating the use of Twitter by sexual assault support agencies in Canada. It seeks to understand the demographics, user activities, and social network structure within these organizations on Twitter, focusing on building social capital. The research questions explore the demographic profile, geographic distribution, and Twitter activity of these organizations as well as the social network dynamics of bridging and bonding social capital. METHODS: This study used purposive sampling to investigate sexual assault centers in Canada with active Twitter accounts, resulting in the identification of 124 centers. The Twitter handles were collected, yielding 113 unique handles, and their corresponding Twitter IDs were obtained and validated. A total of 294,350 tweets were collected from these centers, covering >93.54% of their Twitter activity. Preprocessing was conducted to prepare the data, and descriptive analysis was used to determine the center demographics and age. Furthermore, geolocation mapping was performed to visualize the center locations. Social network analysis was used to explore the intricate relationships within the network of sexual assault center Twitter accounts, using various metrics to assess the network structure and connectivity dynamics. RESULTS: The results highlight the substantial presence of sexual assault organizations on Twitter, particularly in provinces such as Ontario, British Columbia, and Quebec, underscoring the importance of tailored engagement strategies considering regional disparities. The analysis of Twitter account creation years shows a peak in 2012, followed by a decline in new account creations in subsequent years. The monthly tweet activity shows November as the most active month, whereas July had the lowest activity. The study also reveals variations in Twitter activity, account creation patterns, and social network dynamics, identifying influential social queens and marginalized entities within the network. CONCLUSIONS: This study presents a comprehensive landscape of the demographics and activities of sexual assault centers in Canada on Twitter. This study suggests that future research should explore the long-term consequences of social media use and examine stakeholder perceptions, providing valuable insights to improve communication practices within the nonprofit human services sector and further the missions of these organizations.

Genetic and cultural adaptations underlie the establishment of dairy pastoralism in the Tibetan Plateau.

BACKGROUND: Domestication and introduction of dairy animals facilitated the permanent human occupation of the Tibetan Plateau. Yet the history of dairy pastoralism in the Tibetan Plateau remains poorly understood. Little is known how Tibetans adapted to milk and dairy products. RESULTS: We integrated archeological evidence and genetic analysis to show the picture that the dairy ruminants, together with dogs, were introduced from West Eurasia into the Tibetan Plateau since ~ 3600 years ago. The genetic admixture between the exotic and indigenous dogs enriched the candidate lactase persistence (LP) allele 10974A > G of West Eurasian origin in Tibetan dogs. In vitro experiments demonstrate that - 13838G > A functions as a LP allele in Tibetans. Unlike multiple LP alleles presenting selective signatures in West Eurasians and South Asians, the de novo origin of Tibetan-specific LP allele - 13838G > A with low frequency (~ 6-7%) and absence of selection corresponds - 13910C > T in pastoralists across eastern Eurasia steppe. CONCLUSIONS: Results depict a novel scenario of genetic and cultural adaptations to diet and expand current understanding of the establishment of dairy pastoralism in the Tibetan Plateau.

Construction of an instrument to enable the assessment of the risk of falls in older outpatients: A quantitative methodological study.

OBJECTIVES: To develop an instrument to facilitate the risk assessment of falls in older outpatients. DESIGN: A quantitative methodological study using the cross-sectional data. METHODS: This study enrolled 1988 older participants who underwent comprehensive geriatric assessment (CGA) in an outpatient clinic from May 2020 to November 2022. The history of any falls (≥1 falls in a year) and recurrent falls (≥2 falls in a year) were investigated. Potential risk factors of falls were selected by stepwise logistic regression, and a screening tool was constructed based on nomogram. The tool performance was compared with two reference tools (Fried Frailty Phenotype; CGA with 10 items, CGA-10) by using receiver operating curves, sensitivity (Sen), specificity (Spe), and area under the curve (AUC). RESULTS: Age, unintentional weight loss, depression measured by the Patient Health Questionnaire-2, muscle strength measured by the five times sit-to-stand test, and stand balance measured by semi- and full-tandem standing were the most important risk factors for falls. A fall risk screening tool was constructed with the six measurements (FRST-6). FRST-6 showed the best AUC (Sen, Spe) of 0.75 (Sen = 0.72, Spe = 0.69) for recurrent falls and 0.65 (Sen = 0.74, Spe = 0.48) for any falls. FRST-6 was comparable to CGA-10 and outperformed FFP in performance. CONCLUSIONS: Age, depression, weight loss, gait, and balance were important risk factors of falls. The FRST-6 tool based on these factors showed acceptable performance in risk stratification. IMPACT: Performing a multifactorial assessment in primary care clinics is urgent for falls prevention. The FRST-6 provides a simple and practical way for falls risk screening. With this tool, healthcare professionals can efficiently identify patients at risk of falling and make appropriate recommendations in resource-limited settings. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution was received, due to our study design.

Development of natural perfume as potential fungicide candidates: construction and biological evaluation of vanillin analogs bearing the 1,3,4-oxadiazole/1,3-thiazolidin-4-one fragments.

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 µg/ml) and 7a (38.15 µg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 µg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 µg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.

New triterpenoids from the aerial parts of the Uygur medicine Salvia deserta.

Phytochemical investigation on the aerial parts of Salvia deserta led to the isolation of eight new pentacyclic triterpenoids including three oleanane- (1 - 3) and five ursane-type (4 - 8) triterpenoids, whose structures were elucidated based on extensive spectroscopic analysis and quantum chemical calculation. Weak immunosuppressive potency was observed for compounds 1, 2, and 4 - 8 via inhibiting the secretion of cytokines TNF-α and IL-6 in LPS-induced macrophages RAW264.7 at 20 µM. In addition, compounds 1, 2, and 4 - 6 exhibited moderate protective activity on t-BHP-induced oxidative injury in HepG2 cells.

High-Strength Carbon Nanotube Fibers from Purity Control by Atomized Catalytic Pyrolysis and Alignment Improvement by Continuous Large Prestraining.

Transferring the high strength of individual carbon nanotubes (CNTs) to macroscopic fibers is still a major technical challenge. In this study, CNT fibers are wound from a hollow cylindrical assembly. In particular, atomized catalytic pyrolysis is utilized to produce the fiber and control its purity. The pristine fiber is then continuously prestrained to have a highly aligned structure for subsequent full densification. Experimental measurements show that the final fiber possesses a high tensile strength (8.0 GPa), specific strength (5.54 N tex-1 (tex: the weight (g) of a fiber of 1 km long)), Young's modulus (350 GPa), and elongation at break (4%). Such an excellent combination is superior to that of any other existing fiber and attributed to the efficient stress transfer among the highly aligned and packed CNTs. Our study provides a new strategy involving atomized catalysis for developing superstrong CNT assemblies such as fibers and films for practical applications.

Sulfur, sterol and trehalose metabolism in the deep-sea hydrocarbon seep tubeworm Lamellibrachia luymesi.

BACKGROUND: Lamellibrachia luymesi dominates cold sulfide-hydrocarbon seeps and is known for its ability to consume bacteria for energy. The symbiotic relationship between tubeworms and bacteria with particular adaptations to chemosynthetic environments has received attention. However, metabolic studies have primarily focused on the mechanisms and pathways of the bacterial symbionts, while studies on the animal hosts are limited. RESULTS: Here, we sequenced the transcriptome of L. luymesi and generated a transcriptomic database containing 79,464 transcript sequences. Based on GO and KEGG annotations, we identified transcripts related to sulfur metabolism, sterol biosynthesis, trehalose synthesis, and hydrolysis. Our in-depth analysis identified sulfation pathways in L. luymesi, and sulfate activation might be an important detoxification pathway for promoting sulfur cycling, reducing byproducts of sulfide metabolism, and converting sulfur compounds to sulfur-containing organics, which are essential for symbiotic survival. Moreover, sulfide can serve directly as a sulfur source for cysteine synthesis in L. luymesi. The existence of two pathways for cysteine synthesis might ensure its participation in the formation of proteins, heavy metal detoxification, and the sulfide-binding function of haemoglobin. Furthermore, our data suggested that cold-seep tubeworm is capable of de novo sterol biosynthesis, as well as incorporation and transformation of cycloartenol and lanosterol into unconventional sterols, and the critical enzyme involved in this process might have properties similar to those in the enzymes from plants or fungi. Finally, trehalose synthesis in L. luymesi occurs via the trehalose-6-phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP) pathways. The TPP gene has not been identified, whereas the TPS gene encodes a protein harbouring conserved TPS/OtsA and TPP/OtsB domains. The presence of multiple trehalases that catalyse trehalose hydrolysis could indicate the different roles of trehalase in cold-seep tubeworms. CONCLUSIONS: We elucidated several molecular pathways of sulfate activation, cysteine and cholesterol synthesis, and trehalose metabolism. Contrary to the previous analysis, two pathways for cysteine synthesis and the cycloartenol-C-24-methyltransferase gene were identified in animals for the first time. The present study provides new insights into particular adaptations to chemosynthetic environments in L. luymesi and can serve as the basis for future molecular studies on host-symbiont interactions and biological evolution.

The genome of a vestimentiferan tubeworm (Ridgeia piscesae) provides insights into its adaptation to a deep-sea environment.

BACKGROUND: Vestimentifera (Polychaeta, Siboglinidae) is a taxon of deep-sea worm-like animals living in deep-sea hydrothermal vents, cold seeps, and organic falls. The morphology and lifespan of Ridgeia piscesae, which is the only vestimentiferan tubeworm species found in the hydrothermal vents on the Juan de Fuca Ridge, vary greatly according to endemic environment. Recent analyses have revealed the genomic basis of adaptation in three vent- and seep-dwelling vestimentiferan tubeworms. However, the evolutionary history and mechanism of adaptation in R. piscesae, a unique species in the family Siboglinidae, remain to be investigated. RESULT: We assembled a draft genome of R. piscesae collected at the Cathedral vent of the Juan de Fuca Ridge. Comparative genomic analysis showed that vent-dwelling tubeworms with a higher growth rate had smaller genome sizes than seep-dwelling tubeworms that grew much slower. A strong positive correlation between repeat content and genome size but not intron size and the number of protein-coding genes was identified in these deep-sea tubeworm species. Evolutionary analysis revealed that Ridgeia pachyptila and R. piscesae, the two tubeworm species that are endemic to hydrothermal vents of the eastern Pacific, started to diverge between 28.5 and 35 million years ago. Four genes involved in cell proliferation were found to be subject to positive selection in the genome of R. piscesae. CONCLUSION: Ridgeia pachyptila and R. piscesae started to diverge after the formation of the Gorda/Juan de Fuca/Explorer ridge systems and the East Pacific Rise. The high growth rates of vent-dwelling tubeworms might be derived from their small genome sizes. Cell proliferation is important for regulating the growth rate in R. piscesae.