Mapping Geological Events and Nitrogen Fixation Evolution Onto the Timetree of the Evolution of Nitrogen-Fixation Genes.

Nitrogen is essential for all organisms, but biological nitrogen fixation (BNF) occurs only in a small fraction of prokaryotes. Previous studies divided nitrogenase-gene-carrying prokaryotes into Groups I to IV and provided evidence that BNF first evolved in bacteria. This study constructed a timetree of the evolution of nitrogen-fixation genes and estimated that archaea evolved BNF much later than bacteria and that nitrogen-fixing cyanobacteria evolved later than 1,900 MYA, considerably younger than the previous estimate of 2,200 MYA. Moreover, Groups III and II/I diverged ∼2,280 MYA, after the Kenorland supercontinent breakup (∼2,500-2,100 MYA) and the Great Oxidation Event (∼2,400-2,100 MYA); Groups III and Vnf/Anf diverged ∼2,086 MYA, after the Yarrabubba impact (∼2,229 MYA); and Groups II and I diverged ∼1,920 MYA, after the Vredefort impact (∼2,023 MYA). In summary, this study provided a timescale of BNF events and discussed the possible effects of geological events on BNF evolution.

Construction and evaluation of a cloud follow-up platform for gynecological patients receiving chemotherapy.

BACKGROUND: Patient follow-up is an essential component of hospital management. In the current information era, the patient follow-up scheme is expected to be replaced by Internet technology. This study constructed a cloud follow-up platform for gynecological chemotherapy patients and assessed its cost-effectiveness and patients' feedback. METHODS: A total of 2,538 patients were followed up using a cloud follow-up system between January and October 2021. Prior to this, 690 patients were followed manually via telephone calls. Patients' characteristics, follow-up rate, satisfaction, and session duration were compared between the cloud follow-up and manual follow-up groups. In addition, the read rate of health education materials in the cloud follow-up group was analyzed. RESULTS: General information, including age, education attainment, cancer stage, and disease category, and follow-up rate (cloud: 6,957/7,614, 91.4%; manual: 1,869/2,070, 90.3%; P = 0.13) did not significantly differ between the two groups. The follow-up satisfaction of the cloud follow-up patients was significantly better than that of the manual follow-up group (cloud: 7,192/7,614, 94.5%; manual: 1,532/2,070, 74.0%; P<0.001). The time spent on the follow-up was approximately 1.2 h for 100 patients in the cloud follow-up group and 10.5 h in the manual follow-up group. Multivariate analysis indicated that the cloud follow-up group had significantly greater follow-up satisfaction (odds ratio: 2.239, 95% CI: 1.237 ~ 5.219). Additionally, the average follow-up duration of the cloud follow-up group decreased by 9.287 h (coefficient: -9.287, 95% CI: -1.439~-0.165). The read rate of health education materials was 72.9% in the cloud follow-up group. CONCLUSIONS: The follow-up effect of the cloud follow-up group was not inferior to that of the manual follow-up group. The cloud follow-up was more effective for prevention and control requirements in the post-epidemic era. Cloud follow-up can save medical resources, improve cost-effectiveness, provide sufficient health education resources for patients, and improve their satisfaction.

Associations between long-term ambient PM2.5 exposure and the incidence of cardiopulmonary diseases and diabetes, attributable years lived with disability, and policy implication.

Long-term exposure to ambient PM2.5 is known associated with cardiovascular and respiratory health effects. However, the heterogeneous concentrationresponse function (CRF) between PM2.5 exposure across different concentration range and cardiopulmonary disease and diabetes mellitus (DM) incidence, and their implications on attributable years lived with disability (YLD) and regulation policy has not been well-studied. In this retrospective longitudinal cohort study, disease-free participants (approximately 170,000 individuals, aged ≥ 30 years) from the MJ Health Database were followed up (2007-2017) regarding incidents of coronary heart disease (CHD), ischemic stroke, chronic obstructive pulmonary disease (COPD), lower respiratory tract infections (LRIs), and DM. We used a time-dependent nonlinear weight-transformation Cox regression model for the CRF with an address-matched 3-year mean PM2.5 exposure estimate. Town/district-specific PM2.5-attributable YLD were calculated by multiplying the disease incidence rate, population attributable fraction, disability weight, and sex-age group specific subpopulation for each disease separately. The estimated CRFs for cardiopulmonary diseases were heterogeneously with the hazard ratios (HRs) increased rapidly for CHD and ischemic stroke at PM2.5 concentration lower than 10 µg/m3, whereas the HRs for DM (LRIs) increased with PM2.5 higher than 15 (20) µg/m3. Women had higher HRs for ischemic stroke and DM but not CHD. Relative to the lowest observed PM2.5 concentration of 6 µg/m3 of the study population, the PM2.5 level with an extra risk of 0.1 % (comparable to the disease incidence) for CHD, ischemic stroke, DM, and LRIs were 8.59, 11.85, 22.09, and 24.23 µg/m3, respectively. The associated attributable YLD decreased by 51.4 % with LRIs reduced most (83.6 %), followed by DM (63.7 %) as a result of PM2.5 concentration reduction from 26.10 to 16.82 µg/m3 during 2011-2019 in Taiwan. The proportion of YLD due to CHD and ischemic stroke remained dominant (56.4 %-69.9 %). The cost-benefit analysis for the tradeoff between avoidable YLD and mitigation cost suggested an optimal PM2.5 exposure level at 12 µg/m3. CRFs for cardiopulmonary diseases, attributable YLD, and regulation level, may vary depending on the national/regional background and spatial distribution of PM2.5 concentrations, as well as demographic characteristics.

Origin and Evolution of Nitrogen Fixation in Prokaryotes.

The origin of nitrogen fixation is an important issue in evolutionary biology. While nitrogen is required by all living organisms, only a small fraction of bacteria and archaea can fix nitrogen. The prevailing view is that nitrogen fixation first evolved in archaea and was later transferred to bacteria. However, nitrogen-fixing (Nif) bacteria are far larger in number and far more diverse in ecological niches than Nif archaea. We, therefore, propose the bacteria-first hypothesis, which postulates that nitrogen fixation first evolved in bacteria and was later transferred to archaea. As >30,000 prokaryotic genomes have been sequenced, we conduct an in-depth comparison of the two hypotheses. We first identify the six genes involved in nitrogen fixation in all sequenced prokaryotic genomes and then reconstruct phylogenetic trees using the six Nif proteins individually or in combination. In each of these trees, the earliest lineages are bacterial Nif protein sequences and in the oldest clade (group) the archaeal sequences are all nested inside bacterial sequences, suggesting that the Nif proteins first evolved in bacteria. The bacteria-first hypothesis is further supported by the observation that the majority of Nif archaea carry the major bacterial Mo (molybdenum) transporter (ModABC) rather than the archaeal Mo transporter (WtpABC). Moreover, in our phylogeny of all available ModA and WtpA protein sequences, the earliest lineages are bacterial sequences while archaeal sequences are nested inside bacterial sequences. Furthermore, the bacteria-first hypothesis is supported by available isotopic data. In conclusion, our study strongly supports the bacteria-first hypothesis.

Retroconversion of estrogens into androgens by bacteria via a cobalamin-mediated methylation.

Steroid estrogens modulate physiology and development of vertebrates. Conversion of C19 androgens into C18 estrogens is thought to be an irreversible reaction. Here, we report a denitrifying Denitratisoma sp. strain DHT3 capable of catabolizing estrogens or androgens anaerobically. Strain DHT3 genome contains a polycistronic gene cluster, emtABCD, differentially transcribed under estrogen-fed conditions and predicted to encode a cobalamin-dependent methyltransferase system conserved among estrogen-utilizing anaerobes; an emtA-disrupted DHT3 derivative could catabolize androgens but not estrogens. These data, along with the observed androgen production in estrogen-fed strain DHT3 cultures, suggested the occurrence of a cobalamin-dependent estrogen methylation to form androgens. Consistently, the estrogen conversion into androgens in strain DHT3 cell extracts requires methylcobalamin and is inhibited by propyl iodide, a specific inhibitor of cobalamin-dependent enzymes. The identification of the cobalamin-dependent estrogen methylation thus represents an unprecedented metabolic link between cobalamin and steroid metabolism and suggests that retroconversion of estrogens into androgens occurs in the biosphere.

Melatonin Ameliorates Neuropsychiatric Behaviors, Gut Microbiome, and Microbiota-Derived Metabolites in Rats with Chronic Sleep Deprivation.

With the increasing prevalence of sleep deprivation (SD)-related disorders, the effective treatment of sleep disorders has become a critical health research topic. Thus, we hypothesized and investigated the effectiveness of a 3-week melatonin intervention on neuropsychiatric behavioral responses mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD. Eighteen 6-week-old Wistar rats were used and divided into the control grup (C, n = 6), SD group (n = 6), and melatonin-supplemented group (SDM, n = 6). During weeks 0 to 6, animals were provided with the AIN-93M diet and free access to water. Four-week chronic SD was conducted from weeks 7 to 10. Exogenous melatonin administration (10 mg/kg BW) was injected intraperitoneally 1 h before the daily administration of SD for 3 weeks in the SDM group. SD rats exhibited anxiety-like behavior, depression-like behavior, and cognitive impairment. Exogenous melatonin administration ameliorated neuropsychiatric behaviors induced by chronic SD. Analysis of fecal metabolites indicated that melatonin may influence brain messaging through the microbiota-gut-brain axis by increasing the production of short-chain fatty acids (SCFA) and decreasing the production of secondary bile acids (SBA). Four-week SD reduced the cerebral cortex expression of MT1, but not in the colon. Chronic SD led to anxiety and depression-like behaviors and cognitive decline, as well as the reduced intestinal level of SCFAs and the enhanced intestinal level of SBAs in rats. In this work, we confirmed our hypothesis that a 3-week melatonin intervention on neuropsychiatric behavioral response mediated throughout melatonin receptors, gut microbiota, and lipid metabolites in rats with chronic SD.

Myocardial microvascular function assessed by CMR first-pass perfusion in patients treated with chemotherapy for gynecologic malignancies.

OBJECTIVES: Cancer chemotherapy potentially increases the risk of myocardial ischemia. This study assessed myocardial microvascular function by cardiac magnetic resonance (CMR) first-pass perfusion in patients treated with chemotherapy for gynecologic malignancies. METHODS: A total of 81 patients treated with chemotherapy for gynecologic malignancies and 39 healthy volunteers were prospectively enrolled and underwent CMR imaging. Among the patients, 32 completed CMR follow-up, with a median interval of 6 months. The CMR sequences comprised cardiac cine, rest first-pass perfusion, and late gadolinium enhancement. RESULTS: There were no significant differences in the baseline characteristics between the patients and normal controls (all p > 0.05). Compared with the normal controls, the patients had a lower myocardial perfusion index (PI) (13.62 ± 2.01% vs. 12% (11 to 14%), p = 0.001) but demonstrated no significant variation with an increase in the number of chemotherapy cycles at follow-up (11.79 ± 2.36% vs. 11.19 ± 2.19%, p = 0.234). In multivariate analysis with adjustments for clinical confounders, a decrease in the PI was independently associated with chemotherapy treatment (ß = - 0.362, p = 0.002) but had no correlation with the number of chemotherapy cycles (r = - 0.177, p = 0.053). CONCLUSION: Myocardial microvascular dysfunction was associated with chemotherapy treatment in patients with gynecologic malignancies, and can be assessed and monitored by rest CMR first-pass perfusion. KEY POINTS: • Chemotherapy was associated with but did not aggravate myocardial microvascular dysfunction in patients with gynecologic malignancies. • Rest CMR first-pass perfusion is an ideal modality for assessing and monitoring alterations in myocardial microcirculation during chemotherapy treatment.

Biotransformation of bisphenol F by white-rot fungus Phanerochaete sordida YK-624 under non-ligninolytic condition.

Environmental bisphenol F (BPF) has a cyclic endocrine disruption effect, seriously threatening animal and human health. It is frequently detected in environmental samples worldwide. For BPF remediation, biological methods are more environmentally friendly than physicochemical methods. White-rot fungi have been increasingly studied due to their potential capability to degrade environmental pollutants. Phanerochaete sordida YK-624 has been shown to degrade BPF by ligninolytic enzymes under ligninolytic conditions. In the present study, degradation of BPF under non-ligninolytic conditions (no production of ligninolytic enzymes) was investigated. Our results showed that BPF could be completely removed after 7-d incubation. A metabolite of BPF, 4,4'-dihydroxybenzophenone (DHBP) was identified by mass spectrometry and nuclear magnetic resonance, and DHBP was further degraded by this fungus to form 4-hydroxyphenyl 4-hydroxybenzoate (HPHB). DHBP and HPHB were the intermediate metabolites of BPF and would be further degraded by P. sordida YK-624. We also found that cytochrome P450s played an important role in BPF degradation. Additionally, transcriptomic analysis further supported the involvement of these enzymes in the action of BPF degradation. Therefore, BPF is transformed to DHBP and then to HPHB likely oxidized by cytochrome P450s in P. sordida YK-624. Furthermore, the toxicological studies demonstrated that the order of endocrine-disrupting activity for BPF and its metabolites was HPHB > BPF > DHBP. KEY POINTS: • White-rot fungus Phanerochaete sordida YK-624 could degrade BPF. • Cytochrome P450s were involved in the BPF degradation. • The order of endocrine disrupting activity was: HPHB > BPF > DHBP.

Vibrio salinus sp. nov., a marine nitrogen-fixing bacterium isolated from the lagoon sediment of an islet inside an atoll in the western Pacific Ocean.

A marine, facultatively anaerobic, nitrogen-fixing bacterium, designated strain DNF-1T, was isolated from the lagoon sediment of Dongsha Island, Taiwan. Cells grown in broth cultures were Gram-negative rods that were motile by means of monotrichous flagella. Cells grown on plate medium produced prosthecae and vesicle-like structures. NaCl was required and optimal growth occurred at about 2-3% NaCl, 25-30 °C and pH 7-8. The strain grew aerobically and was capable of anaerobic growth by fermenting D-glucose or other carbohydrates as substrate. Both the aerobic and anaerobic growth could be achieved with NH4Cl as a sole nitrogen source. When N2 served as the sole nitrogen source only anaerobic growth was observed. Major cellular fatty acids were C14:0, C16:0 and C16:1 ω7c, while major polar lipids were phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content was 42.2 mol% based on the genomic DNA data. Phylogenetic analyses based on 16S rRNA genes and the housekeeping genes, gapA, pyrH, recA and gyrB, revealed that the strain formed a distinct lineage at species level in the genus Vibrio of the family Vibrionaceae. These results and those from genomic, chemotaxonomic and physiological studies strongly support the assignment of a novel Vibrio species. The name Vibrio salinus sp. nov. is proposed for the novel species, with DNF-1T (= BCRC 81209T = JCM 33626T) as the type strain. This newly proposed species represents the second example of the genus Vibrio that has been demonstrated to be capable of anaerobic growth by fixing N2 as the sole nitrogen source.

WITHDRAWN: Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization.

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of ß-tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in time and dose-dependent manners. All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study.

Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization.

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in a time and dose-dependent manner. All the results suggest that the indoline derivatives may be a class of novel tubulin inhibitors with potential anticancer activity, and which is worthy of further study.

Progress in the development of small molecular inhibitors of the Bruton's tyrosine kinase (BTK) as a promising cancer therapy.

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.

Vibrio nitrifigilis sp. nov., a marine nitrogen-fixing bacterium isolated from the lagoon sediment of an islet inside an atoll.

A nitrogen-fixing isolate of facultatively anaerobic, marine bacterium, designated strain NFV-1T, was recovered from the lagoon sediment of Dongsha Island, Taiwan. It was a Gram-negative rod which exhibited motility with monotrichous flagellation in broth cultures. The strain required NaCl for growth and grew optimally at about 25-35 °C, 3% NaCl and pH 7-8. It grew aerobically and could achieve anaerobic growth by fermenting D-glucose or other carbohydrates as substrates. NH4Cl could serve as a sole nitrogen source for growth aerobically and anaerobically, whereas growth with N2 as the sole nitrogen source was observed only under anaerobic conditions. Cellular fatty acids were predominated by C16:1 ω7c, C16:0, and C18:1 ω7c. The major polar lipids consisted of phosphatidylethanolamine and phosphatidylserine. Strain NFV-1T had a DNA G + C content of 42.5 mol%, as evaluated according to the chromosomal DNA sequencing data. Analyses of sequence similarities and phylogeny based on the 16S rRNA genes, together with the housekeeping genes, gyrB, ftsZ, mreB, topA and gapA, indicated that the strain formed a distinct species-level lineage in the genus Vibrio of the family Vibrionaceae. These phylogenetic data and those from genomic and phenotypic characterisations support the establishment of a novel Vibrio species, for which the name Vibrio nitrifigilis sp. nov. (type strain NFV-1T = BCRC 81211T = JCM 33628T) is proposed.

Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway.

Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative, compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC50 values of 0.36 µM (MGC-803 cells), 0.70 µM (HCT-116 cells), 1.04 µM (PC-3 cells), and 0.81 µM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo. Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.

Discovery of Novel Diarylamide N-Containing Heterocyclic Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity.

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 µM, 3.56 µM and 14.5 µM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of ß-tubulin.

Design, Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives.

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure-activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.

Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy.

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through "proteolysis targeting chimera" (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

Long-term warming destabilizes aquatic ecosystems through weakening biodiversity-mediated causal networks.

Understanding how ecosystems will respond to climate changes requires unravelling the network of functional responses and feedbacks among biodiversity, physicochemical environments, and productivity. These ecosystem components not only change over time but also interact with each other. Therefore, investigation of individual relationships may give limited insights into their interdependencies and limit ability to predict future ecosystem states. We address this problem by analyzing long-term (16-39 years) time series data from 10 aquatic ecosystems and using convergent cross mapping (CCM) to quantify the causal networks linking phytoplankton species richness, biomass, and physicochemical factors. We determined that individual quantities (e.g., total species richness or nutrients) were not significant predictors of ecosystem stability (quantified as long-term fluctuation of phytoplankton biomass); rather, the integrated causal pathway in the ecosystem network, composed of the interactions among species richness, nutrient cycling, and phytoplankton biomass, was the best predictor of stability. Furthermore, systems that experienced stronger warming over time had both weakened causal interactions and larger fluctuations. Thus, rather than thinking in terms of separate factors, a more holistic network view, that causally links species richness and the other ecosystem components, is required to understand and predict climate impacts on the temporal stability of aquatic ecosystems.

Comparative Genome Analysis Reveals Cyanidiococcus gen. nov., A New Extremophilic Red Algal Genus Sister to Cyanidioschyzon (Cyanidioschyzonaceae, Rhodophyta).

The taxonomic placement of strains belonging to the extremophilic red alga Galdieria maxima has been controversial due to the inconsistent phylogenetic position inferred from molecular phylogenetic analyses. Galdieria maxima nom. inval. was classified in this genus based on morphology and molecular data in the early work, but some subsequent molecular phylogenetic analyses have inferred strains of G. maxima to be closely related to the genus Cyanidioschyzon. To address this controversy, an isolated strain identified as G. maxima using the rbcL gene sequence as the genetic barcode was examined using a comprehensive analysis across morphological, physiological, and genomic traits. Herein are reported the chloroplast-, mitochondrion-, and chromosome-level nuclear genome assemblies. Comparative analysis of orthologous gene clusters and genome arrangements suggested that the genome structure of this strain was more similar to that of the generitype of Cyanidioschyzon, C. merolae than to the generitype of Galdieria, G. sulphuraria. While the ability to uptake various forms of organic carbon for growth is an important physiological trait of Galdieria, this strain was identified as an ecologically obligate photoautotroph (i.e., the inability to utilize the natural concentrations of organic carbons) and lacked various gene models predicted as sugar transporters. Based on the genomic, morphological, and physiological traits, we propose this strain to be a new genus and species, Cyanidiococcus yangmingshanensis. Re-evaluation of the 18S rRNA and rbcL gene sequences of the authentic strain of G. maxima, IPPAS-P507, with those of C. yangmingshanensis suggests that the rbcL sequences of "G. maxima" deposited in GenBank correspond to misidentified isolates.

Highly Oxygenated Constituents from a Marine Alga-Derived Fungus Aspergillus giganteus NTU967.

Agar-based disc diffusion antimicrobial assay has shown that the ethyl acetate extract of the fermented broth of Aspergillus giganteus NTU967 isolated from Ulva lactuca exhibited significant antimicrobial activity in our preliminary screening of bioactive fungal strains. Therefore, column chromatography of the active principles from liquid- and solid-state fermented products of the fungal strain was carried out, and which had led to isolation of eleven compounds. Their structures were determined by spectral analysis to be seven new highly oxygenated polyketides, namely aspergilsmins A-G (1-7), along with previously reported patulin, deoxytryptoquivaline, tryptoquivaline and quinadoline B. Among these, aspergilsmin C (3) and patulin displayed promising anticancer activities against human hepatocellular carcinoma SK-Hep-1 cells and prostate cancer PC-3 cells with IC50 values between 2.7-7.3 µM. Furthermore, aspergilsmin C (3) and patulin exhibited significant anti-angiogenic functions by impeding cell growth and tube formation of human endothelial progenitor cells without any cytotoxicity.