3D Chromatin Structures of Mature Gametes and Structural Reprogramming during Mammalian Embryogenesis.

High-order chromatin structure plays important roles in gene expression regulation. Knowledge of the dynamics of 3D chromatin structures during mammalian embryo development remains limited. We report the 3D chromatin architecture of mouse gametes and early embryos using an optimized Hi-C method with low-cell samples. We find that mature oocytes at the metaphase II stage do not have topologically associated domains (TADs). In sperm, extra-long-range interactions (>4 Mb) and interchromosomal interactions occur frequently. The high-order structures of both the paternal and maternal genomes in zygotes and two-cell embryos are obscure but are gradually re-established through development. The establishment of the TAD structure requires DNA replication but not zygotic genome activation. Furthermore, unmethylated CpGs are enriched in A compartment, and methylation levels are decreased to a greater extent in A compartment than in B compartment in embryos. In summary, the global reprogramming of chromatin architecture occurs during early mammalian development.

Disrupted cerebellar structural connectome in spinocerebellar ataxia type 3 and its association with transcriptional profiles.

Spinocerebellar ataxia type 3 (SCA3) is primarily characterized by progressive cerebellar degeneration, including gray matter atrophy and disrupted anatomical and functional connectivity. The alterations of cerebellar white matter structural network in SCA3 and the underlying neurobiological mechanism remain unknown. Using a cohort of 20 patients with SCA3 and 20 healthy controls, we constructed cerebellar structural networks from diffusion MRI and investigated alterations of topological organization. Then, we mapped the alterations with transcriptome data from the Allen Human Brain Atlas to identify possible biological mechanisms for regional selective vulnerability to white matter damage. Compared with healthy controls, SCA3 patients exhibited reduced global and nodal efficiency, along with a widespread decrease in edge strength, particularly affecting edges connected to hub regions. The strength of inter-module connections was lower in SCA3 group and negatively correlated with the Scale for the Assessment and Rating of Ataxia score, International Cooperative Ataxia Rating Scale score, and cytosine-adenine-guanine repeat number. Moreover, the transcriptome-connectome association study identified the expression of genes involved in synapse-related and metabolic biological processes. These findings suggest a mechanism of white matter vulnerability and a potential image biomarker for the disease severity, providing insights into neurodegeneration and pathogenesis in this disease.

Associations of quantitative susceptibility mapping with cortical atrophy and brain connectome in Alzheimer's disease: A multi-parametric study.

Aberrant susceptibility due to iron level abnormality and brain network disconnections are observed in Alzheimer's disease (AD), with disrupted iron homeostasis hypothesized to be linked to AD pathology and neuronal loss. However, whether associations exist between abnormal quantitative susceptibility mapping (QSM), brain atrophy, and altered brain connectome in AD remains unclear. Based on multi-parametric brain imaging data from 30 AD patients and 26 healthy controls enrolled at the China-Japan Friendship Hospital, we investigated the abnormality of the QSM signal and volumetric measure across 246 brain regions in AD patients. The structural and functional connectomes were constructed based on diffusion MRI tractography and functional connectivity, respectively. The network topology was quantified using graph theory analyses. We identified seven brain regions with both reduced cortical thickness and abnormal QSM (p < 0.05) in AD, including the right superior frontal gyrus, left superior temporal gyrus, right fusiform gyrus, left superior parietal lobule, right superior parietal lobule, left inferior parietal lobule, and left precuneus. Correlations between cortical thickness and network topology computed across patients in the AD group resulted in statistically significant correlations in five of these regions, with higher correlations in functional compared to structural topology. We computed the correlation between network topological metrics, QSM value and cortical thickness across regions at both individual and group-averaged levels, resulting in a measure we call spatial correlations. We found a decrease in the spatial correlation of QSM and the global efficiency of the structural network in AD patients at the individual level. These findings may provide insights into the complex relationships among QSM, brain atrophy, and brain connectome in AD.

Relationship between topological efficiency of white matter structural connectome and plasma biomarkers across the Alzheimer's disease continuum.

Both plasma biomarkers and brain network topology have shown great potential in the early diagnosis of Alzheimer's disease (AD). However, the specific associations between plasma AD biomarkers, structural network topology, and cognition across the AD continuum have yet to be fully elucidated. This retrospective study evaluated participants from the Sino Longitudinal Study of Cognitive Decline cohort between September 2009 and October 2022 with available blood samples or 3.0-T MRI brain scans. Plasma biomarker levels were measured using the Single Molecule Array platform, including ß-amyloid (Aß), phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The topological structure of brain white matter was assessed using network efficiency. Trend analyses were carried out to evaluate the alterations of the plasma markers and network efficiency with AD progression. Correlation and mediation analyses were conducted to further explore the relationships among plasma markers, network efficiency, and cognitive performance across the AD continuum. Among the plasma markers, GFAP emerged as the most sensitive marker (linear trend: t = 11.164, p = 3.59 × 10-24 ; quadratic trend: t = 7.708, p = 2.25 × 10-13 ; adjusted R2 = 0.475), followed by NfL (linear trend: t = 6.542, p = 2.9 × 10-10 ; quadratic trend: t = 3.896, p = 1.22 × 10-4 ; adjusted R2 = 0.330), p-tau181 (linear trend: t = 8.452, p = 1.61 × 10-15 ; quadratic trend: t = 6.316, p = 1.05 × 10-9 ; adjusted R2 = 0.346) and Aß42/Aß40 (linear trend: t = -3.257, p = 1.27 × 10-3 ; quadratic trend: t = -1.662, p = 9.76 × 10-2 ; adjusted R2 = 0.101). Local efficiency decreased in brain regions across the frontal and temporal cortex and striatum. The principal component of local efficiency within these regions was correlated with GFAP (Pearson's R = -0.61, p = 6.3 × 10-7 ), NfL (R = -0.57, p = 6.4 × 10-6 ), and p-tau181 (R = -0.48, p = 2.0 × 10-4 ). Moreover, network efficiency mediated the relationship between general cognition and GFAP (ab = -0.224, 95% confidence interval [CI] = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA) or NfL (ab = -0.224, 95% CI = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA). Our findings suggest that network efficiency mediates the association between plasma biomarkers, specifically GFAP and NfL, and cognitive performance in the context of AD progression, thus highlighting the potential utility of network-plasma approaches for early detection, monitoring, and intervention strategies in the management of AD.

MAnorm2 for quantitatively comparing groups of ChIP-seq samples.

Eukaryotic gene transcription is regulated by a large cohort of chromatin-associated proteins, and inferring their differential binding sites between cellular contexts requires a rigorous comparison of the corresponding ChIP-seq data. We present MAnorm2, a new computational tool for quantitatively comparing groups of ChIP-seq samples. MAnorm2 uses a hierarchical strategy for normalization of ChIP-seq data and assesses within-group variability of ChIP-seq signals based on an empirical Bayes framework. In this framework, MAnorm2 allows for abundant differential ChIP-seq signals between groups of samples as well as very different global within-group variability between groups. Using a number of real ChIP-seq data sets, we observed that MAnorm2 clearly outperformed existing tools for differential ChIP-seq analysis, especially when the groups of samples being compared had distinct global within-group variability.

Utility of MRI-based vertebral bone quality scores and CT-based Hounsfield unit values in vertebral bone mineral density assessment for patients with diffuse idiopathic skeletal hyperostosis.

This study investigated bone mineral density assessment for patients with DISH. DXA-based T-scores overestimated bone quality, while MRI-based VBQ scores and CT-based HU values provided accurate assessments, particularly for advanced degenerative cases. This enhances accurate evaluation of BMD, crucial for clinical decision-making. PURPOSE: To investigate the diagnostic effectiveness of DXA, MRI, and CT in assessing bone mineral density (BMD) for diffuse idiopathic skeletal hyperostosis (DISH) patients. METHODS: Retrospective analysis of 105 DISH patients and 116 age-matched controls with lumbar spinal stenosis was conducted. BMD was evaluated using DXA-based T-scores, MRI-based vertebral bone quality (VBQ) scores, and CT-based Hounsfield unit (HU) values. Patients were categorized into three BMD subgroups. Lumbar osteophyte categories were determined by Mata score. Demographics, clinical data, T-scores, VBQ scores, and HU values were collected. Receiver operating characteristic (ROC) analysis identified VBQ and HU thresholds for diagnosing normal BMD using DXA in controls. Correlations between VBQ, HU, and lumbar T-score were analyzed. RESULTS: Age, gender, and BMI showed no significant differences between DISH and control groups. DISH patients had higher T-score (L1-4), the lowest T-score, and Mata scores. VBQ and HU did not significantly differ between groups. In controls, VBQ and HU effectively diagnosed normal BMD (AUC = 0.857 and 0.910, respectively) with cutoffs of 3.0 for VBQ and 104.3 for HU. DISH had higher normal BMD prevalence using T-scores (69.5% vs. 58.6%, P < 0.05), but no significant differences using VBQ (57.1% vs. 56.2%, P > 0.05) and HU (58.1% vs. 57.8%, P > 0.05). Correlations revealed moderate correlations between HU and T-scores (L1-4) in DISH (r = 0.642, P < 0.001) and strong in controls (r = 0.846, P < 0.001). Moderate negative correlations were observed between VBQ and T-scores (L1-4) in DISH (r = - 0.450, P < 0.001) and strong in controls (r = - 0.813, P < 0.001). CONCLUSION: DXA-based T-scores may overestimate BMD in DISH. VBQ scores and HU values could effectively complement BMD assessment, particularly in DISH patients or those with advanced lumbar degeneration.

Integrating online deliberation into ecosystem service valuation.

Stated preference valuation of ecosystem services involves participants answering hypothetical questions to express preferences. Participants tend to respond to the hypothetical questions separately, without any deliberation (the process of considering and discussing within a group). However, a relatively recent development in deliberation research involves asking participants to state preferences via deliberation. Deliberation is historically conducted in-person but can now also be done online. This paper covers the strengths and limitations of integrating online deliberation into stated preference valuation, including: (1) comparison between stated preference valuation with and without deliberation, (2) comparison between in-person and online deliberation, and (3) comparison between online deliberation media, such as typing, video meetings, and voice calls. Conducting deliberation can broaden participants' understanding of the target ecosystem services and others' preferences. However, this requires participants' willingness to deliberate and increases time investment. Online deliberation has lower costs and travel restrictions and higher time efficiency and confidentiality of personal information than in-person deliberation. However, people with low abilities or willingness to use online media are disadvantaged. Differences in the online deliberation media may reduce or improve the inclusiveness, engagement, and openness of deliberations in ways that affect valuation results. We also provide suggestions for selecting deliberation media and mitigating deliberation bias derived from the choice of deliberation media. Further research should explore how to improve time efficiency and affordability of online deliberation, how to promote inclusiveness, engagement, and openness of online deliberation, and how different deliberation media affect deliberation quality and valuation results.

Boundary of ecosystem services: Differentiating between ecosystem services and geosystem services is needed.

Geosystem services (GSs) and ecosystem services (ESs) are interconnected, both representing nature's contributions to people. Whether GSs are a subset of ESs depends on the definition of ESs. The answer would be "not necessarily" (i.e., some GSs are, while other GSs are not), if ESs are the benefits humans derive from ecological functions, processes, or characteristics. The boundary proposed by Chen et al. (2023) to differentiate ESs from other ecosystem-related benefits adopted this definition, and suggested that ESs are renewable and affected by biotic elements to occur. Gray et al. (2024) criticized this boundary for separating out bits of nature and ignoring the contributions of GSs and abiotic elements to ESs and human wellbeing. In fact, highlighting that ESs are affected by biotic elements to occur does not deny that ESs' occurrence is also affected by abiotic elements. However, ESs' dependence on abiotic elements cannot be a criterion to differentiate ESs from other benefits because abiotic elements are integral to geosystems, ecosystems, and many other natural and artificial systems, as well as to these systems' services. Conversely, while geosystems might persist without biotic elements, ecosystems cannot. Chen et al. (2023) only excluded those (not the whole) abiotic benefits, such as wind energy, that may occur independently of biotic elements, while allowing for integrating certain GSs into ESs. For example, geological structures can offer flood protection and water storage as GSs, which can also be classified as ESs when their qualities or quantities are affected by biotic elements. Differentiation between GSs and ESs should not be misinterpreted as splitting their interconnections or undervaluing or dividing nature. Instead, such differentiation and classification of nature's benefits serve to facilitate communication, management, education, research, and policy-making associated with nature's benefits, while also highlighting the richness and diversity of nature's benefits.

Transport and retention of ciprofloxacin with presence of multi-walled carbon nanotubes in the saturated porous media: impacts of ionic strength and cation types.

The environmental fate and risks of ciprofloxacin (CIP) in the subsurface have raised intensive concerns. Herein, the transport behaviors of CIP in both saturated quartz sand and sand/multi-walled carbon nanotubes (MWCNTs) mixtures under different solution ionic strength of the solution and coexisting cation types were investigated. Batch adsorption experiments highlighted growing adsorptive capacity for CIP with the increasing content of MWCNTs in the MWCNTs-quartz sand mixtures (from 0.5% to 1.5%, w/w). Breakthrough curves (BTCs) of CIP in the MWCNTs-quartz sand mixtures were well fitted by the two-site chemical nonequilibrium model (R2 > 0.833). The estimated retardation factors for CIP increased from 9.68 to 282 with growing content of MWCNTs in the sand column, suggesting the presence of MWCNTs significantly inhibited the transport of CIP in saturated porous media. Moreover, the values of retardation factors are negatively correlated with the ionic strength and higher ionic strength could facilitate the transport of CIP in the saturated porous media. Compared with monovalent cations (Na+), the presence of divalent cations (Ca2+) significantly facilitated the transport of CIP in the columns due to the complexation between CIP and Ca2+ as well as deposition of MWCNTs aggregates on the sand surface. Results regarding CIP retention in columns indicated that MWCNTs could enhance the accumulation of CIP in the layers close to the influent of sand columns, while they could hinder upward transport of CIP to the effluent. This study improves our understanding for transport behaviors and environmental risk assessments of CIP in the saturated porous media with MWCNTs.

Inhibition of endogenous hydrogen sulfide production suppresses the growth of nasopharyngeal carcinoma cells.

Hydrogen sulfide (H2 S) has been widely recognized as one of gasotransmitters. Endogenous H2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-ß-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H2 S-producing enzymes could be designed and developed for NPC treatment.

Boundary of ecosystem services: Guiding future development and application of the ecosystem service concepts.

Ecosystem Services (ESs) are either material or non-material benefits humans receive from ecosystems. Definitions, classifications, and typologies of ESs can vary to address different research and policy purposes. However, a boundary that distinguishes ESs from other ecosystem-related benefits (e.g., industrial products that consume raw materials, fossil fuels that used to be a part of ecosystems) is needed to avoid the risk of using ESs as an all-encompassing metaphor that captures any benefit. The boundary also maintains a common ground for communication and comparison of ESs across studies. To guide future development and application of the ES concepts, we suggest five criteria. ESs are (1) primary contributions of ecosystems, (2) flows assessed during a period or per time unit (not stock existing at a time point), (3) renewable (having the potential to be reproduced with a conceivable timeframe relevant to human use), (4) affected by biotic parts of ecosystems to occur. ESs include both biotic and some abiotic flows (e.g., water provisioning) but exclude abiotic flows (e.g., wind and solar energy) whose occurrence is unaffected by ecosystem functions, processes, or characteristics; and (5) inclusive to the benefits humans actually and potentially receive from ecosystems. These criteria link ESs with conservation of life-supporting and culturally important ecosystems, recognize use, option, and non-use values of ESs, and highlight ESs' sustainability.

Plasma IL-6 and TNF-α levels correlate significantly with grading changes in localized prostate cancer.

PURPOSE: To study the effect of inflammatory markers in blood such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) on the Gleason score (GS) changes in patients with prostate cancer (PCa) after radical prostatectomy (RP), we conducted this study. PATIENTS AND METHODS: From November 2012 to September 2021, a total of 237 patients underwent RP at our institution. Blood samples from all patients were collected within 1 week before surgery. Preoperative clinical characteristics include age, serum IL-6 and TNF-α, neutrophil-to-lymphocyte ratio, C-reactive protein, the platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, the prostate imaging reporting and data system (PI-RADS) score, prostate-specific antigen, and biopsy GS were assessed. Univariate and multivariate logistic regression analyzes were used to determine the risk factors of GS changes after RP. The efficiency of this prediction model was identified with the area under the curve of the receiver operating characteristic curve. RESULTS: Seventy-three patients (30.8%) had GS upgraded in the overall cohort, and 55 patients (23.2%) had GS downgraded. In comparing PCa patients with and without GS upgraded, multivariate logistic regression analysis showed that serum TNF-α (odds ratio [OR]: 2.518, p = 0.019) and IL-6 (OR: 0.478, p = 0.023) were independent factors predicting the occurrence of GS upgrade. We also compared the characteristics of patients with GS upgraded and GS downgraded; multivariate logistic regression analysis also demonstrated significant differences in serum IL-6 and TNF-α between these two groups (all p < 0.05). In addition, we found that low prostate volume and biopsy GS ≥ 7 were significantly associated with higher PI-RADS sores in multivariate analysis. CONCLUSION: The high expression of serum TNF-α level is positively correlated with GS upgraded in PCa patients. High expression of serum IL-6 level is negatively correlated with GS upgraded in PCa patients and positively related with GS downgraded.

Methodological evaluation of individual cognitive prediction based on the brain white matter structural connectome.

An emerging trend is to use regression-based machine learning approaches to predict cognitive functions at the individual level from neuroimaging data. However, individual prediction models are inherently influenced by the vast options for network construction and model selection in machine learning pipelines. In particular, the brain white matter (WM) structural connectome lacks a systematic evaluation of the effects of different options in the pipeline on predictive performance. Here, we focused on the methodological evaluation of brain structural connectome-based predictions. For network construction, we considered two parcellation schemes for defining nodes and seven strategies for defining edges. For the regression algorithms, we used eight regression models. Four cognitive domains and brain age were targeted as predictive tasks based on two independent datasets (Beijing Aging Brain Rejuvenation Initiative [BABRI]: 633 healthy older adults; Human Connectome Projects in Aging [HCP-A]: 560 healthy older adults). Based on the results, the WM structural connectome provided a satisfying predictive ability for individual age and cognitive functions, especially for executive function and attention. Second, different parcellation schemes induce a significant difference in predictive performance. Third, prediction results from different data sets showed that dMRI with distinct acquisition parameters may plausibly result in a preference for proper fiber reconstruction algorithms and different weighting options. Finally, deep learning and Elastic-Net models are more accurate and robust in connectome-based predictions. Together, significant effects of different options in WM network construction and regression algorithms on the predictive performances are identified in this study, which may provide important references and guidelines to select suitable options for future studies in this field.

Genome-wide CRISPR/Cas9 knockout screening uncovers ZNF319 as a novel tumor suppressor critical for breast cancer metastasis.

Breast cancer is prone to relapse and metastasize to many vital organs, contributing to most of the breast cancer-related death and accentuating the importance of systematic identification of key factors regulating the metastasis of breast cancer. In this study, we performed a genome-wide CRISPR/Cas9 knock out screen in an orthotopic murine model of breast cancer for essential genes monitoring the progression and metastasis of breast cancer. We found one member of the zinc finger protein (ZNF) family, i.e., ZNF319, was among the top candidate genes. We further confirmed the lower expression of ZNF319 in the tumor tissue of breast cancer patients by analyzing tissue sections with IHC staining and TCGA database. Consistently, higher expression of ZNF319 correlates with better clinical outcome in almost all subtypes of breast cancer. Moreover, knocking down or overexpressing ZNF319 in breast cancer cells dramatically affects the breast cancer growth and metastasis capacity both in vitro and in vivo, suggesting ZNF319 functions as a strong suppressor of breast cancer progression. Lastly, the transcriptome analysis on ZNF319-silenced breast cancer cells shows that ZNF319 is involved in multiple crucial signaling pathways and biological processes, especially in cell cycle and proliferation. GO and KEGG analyses of our RNA-seq results reveal the up-regulation of E2F and G2/M related genes in ZNF319-silenced cells, suggesting that ZNF319 monitors the cell cycle during the breast cancer progression through the regulation of the E2F target genes and G2/M checkpoint. In summary, our study identifies ZNF319 as a novel metastasis suppressor gene arresting tumor cell cycle in breast cancer and thus presents a novel potential therapeutic target for breast cancer treatment.

Ecosystem health, ecosystem services, and the well-being of humans and the rest of nature.

An ecosystem is healthy if it is active, maintains its organization and autonomy over time, and is resilient to stress. Healthy ecosystems provide human well-being via ecosystem services, which are produced in interaction with human, social, and built capital. These services are affected by different ecosystem stewardship schemes. Therefore, society should be aiming for ecosystem health stewardship at all levels to maintain and improve ecosystem services. We review the relationship between ecosystem health and ecosystem services, based on a logic chain framework starting with (1) a development or conservation policy, (2) a management decision or origin of the driver of change, (3) the driver of change itself, (4) the change in ecosystem health, (5) the change in the provision of ecosystem services, and (6) the change in their value to humans. We review two case studies to demonstrate the application of this framework. We analyzed 6,131 records from the Ecosystem Services Valuation Database (ESVD) and found that in approximately 58% of the records data on ecosystem health were lacking. Finally, we describe how the United Nations' System of Environmental-Economic Accounting (SEEA) incorporates ecosystem health as part of efforts to account for natural capital appreciation or depreciation at the national level. We also provide recommendations for improving this system.

Land use trade-offs in China's protected areas from the perspective of accounting values of ecosystem services.

"Accounting values" (quantity * unit value), assessed with an assumption of a constant unit value, are often used in creating macroeconomic aggregates like Gross Domestic Product (GDP). This approach has also been used to estimate the total value of ecosystem services (ES) - the benefits humans receive from functioning ecosystems. In China, this has been referred to as Gross Ecosystem Product (GEP). While the concepts of value and ES may be understood from multiple perspectives, ESs' accounting values contribute important information to the discussion of land use trade-offs in China's protected areas (PAs). These trade-offs include (1) whether additional conserved lands should be opened to tourism development, since tourism brings both positive and negative impacts; (2) whether PAs should be reduced, maintained, or expanded, since PAs safeguard sustainable wellbeing but also require maintenance; and (3) how to undertake conservation on lands traditionally used for human livelihood development, since conservation and livelihood may conflict. Previous studies have suggested (1) joint evaluation based on both GDP and ESs' values may lead to more sustainable decision-making than solely GDP-oriented evaluation; (2) the benefits of maintaining terrestrial PAs in China is $2.64 trillion/yr, over 14 times greater than the costs; (3) integrating ES valuation into environmental impact assessment helps link environmental impacts with human wellbeing and financial costs (e.g., land encroachment of a tourism highway in the Wulingyaun Scenic Area was estimated to cause permanent loss of ES values at $0.5 million/yr); and (4) integrating non-marketable cultural ESs into payment for ESs schemes can further balance conservation with livelihood development. Future research should consider (1) option and non-use values to present a more comprehensive picture of PAs' contributions to sustainable wellbeing and human interdependence with the rest of nature (2) both PAs' quantity (e.g., optimal coverage of PAs); and quality (e.g., management effectiveness, connectivity); (3) more sophisticated and feasible valuation methods (e.g., more cost-effective and engaged deliberation) to improve the credibility of aggregate values over large spatial scales; and (4) interaction between environmental components and ESs.

Cytotoxic Polyhydroxylated Oleanane Triterpenoids from Cissampelos pareira var. hirsuta.

Three new polyhydroxylated oleanane triterpenoids, cissatriterpenoid A-C (1-3), along with one known analogue (4), were isolated from the whole plant of Cissampelos pareira var. hirsuta. Their chemical structures were elucidated by extensive spectroscopic data (IR, HR-ESI-MS, 1H-NMR, 13C-NMR, DEPT, 1H-1H COSY, HSQC, HMBC, NOESY) and the microhydrolysis method. The isolation of compounds 1-4 represents the first report of polyhydroxylated oleanane triterpenoids from the family Menispermaceae. All isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines, and the inhibitory activity against NO release in LPS-induced RAW 264.7 cells. Compound 3 showed the most potent cytotoxic activities against the A549, SMMC-7721, MCF-7, and SW480 cell lines, with IC50 values of 17.55, 34.74, 19.77, and 30.39 µM, respectively, whereas three remaining ones were found to be inactive. The preliminary structure-activity relationship analysis indicated that the γ-lactone ring at C-22 and C-29, and the olefinic bond at C-12 and C-13 were structurally required for the cytotoxicity of polyhydroxylated oleanane triterpenoids against these four cell lines. Based on lipid-water partition coefficients, compound 3 is less lipophilic than 1 and 4, which agrees with their cytotoxic activities. This confirms the potential of C. pareira var. hirsuta in the tumor treatment.

Hydrogen Sulfide Biology and Its Role in Cancer.

Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.

Five novel copy number variations detected in patients with familial exudative vitreoretinopathy.

Purpose: Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disease genetically heterogeneous with multiple causative genes. The aim of this study is to report five novel copy number variation (CNV) regions in FEVR patients and to investigate the possible contributions of novel CNVs to FEVR. Methods: In this study, 824 FEVR families were collected. All cases were performed using the targeted next generation sequencing (NGS) assay, and families with no definite pathogenic mutations in FEVR genes were screened for CNVs according to the NGS results. Droplet digital polymerase chain reaction (ddPCR) testing was introduced to validate the screened CNV regions. We also reviewed the clinical presentations of the probands and affected family members associated with the novel CNVs and conducted segregation analysis. Results: Five CNVs in five patients were detected in this study: heterozygous deletions of kinesin family member 11 (KIF11) exons 2-4, KIF11 exon 11, KIF11 exons 1-10, tetraspanin-12 (TSPAN12) exons 1-3, and low-density lipoprotein receptor-related protein 5 (LRP5) exons 19-21. Among the five affected families, TSPAN12 exons 1-3 heterozygous deletion and LRP5 exons 19-21 heterozygous deletion originate from the mother and the father of the proband, respectively. No other family members manifested as FEVR except for the probands. The correlation between disease severity and CNV loci seems uncertain. Conclusions: Five novel CNV loci in FEVR patients were uncovered in this study, including one maternally-inherited and one paternally-inherited CNV region. Though there is no evidence of co-segregation between these CNVs and FEVR, our findings suggest novel genetic risk factors for FEVR.

Six New Coumarin Glycosides from the Aerial Parts of Gendarussa vulgaris.

Six new coumarin glycosides, genglycoside A-F (1-6), were isolated from the aerial parts of Gendarussa vulgaris, along with ten known analogues (7-16). Their structures were unambiguously established on the basis of extensive spectroscopic data and HPLC analysis. The cytotoxic activities of all isolated compounds were evaluated by MTT assay. Compound 12 showed the most potent cytotoxicity in Eca-109, MCF-7, and HepG2 cell lines. By the preliminary structure-activity relationships, it was firstly discovered that the glycosylation or esterification at 7,8-dihydroxy or 7-hydroxy drastically reduced the cytotoxic activity of the parent coumarin.