Orientation selectivity mapping in the visual cortex.

The orientation map is one of the most well-studied functional maps of the visual cortex. However, results from the literature are of different qualities. Clear boundaries among different orientation domains and blurred uncertain distinctions were shown in different studies. These unclear imaging results will lead to an inaccuracy in depicting cortical structures, and the lack of consideration in experimental design will also lead to biased depictions of the cortical features. How we accurately define orientation domains will impact the entire field of research. In this study, we test how spatial frequency (SF), stimulus size, location, chromatic, and data processing methods affect the orientation functional maps (including a large area of dorsal V4, and parts of dorsal V1) acquired by intrinsic signal optical imaging. Our results indicate that, for large imaging fields, large grating stimuli with mixed SF components should be considered to acquire the orientation map. A diffusion model image enhancement based on the difference map could further improve the map quality. In addition, the similar outcomes of achromatic and chromatic gratings indicate two alternative types of afferents from LGN, pooling in V1 to generate cue-invariant orientation selectivity.

Microbial metabolite sodium butyrate enhances the anti-tumor efficacy of 5-fluorouracil against colorectal cancer by modulating PINK1/Parkin signaling and intestinal flora.

Colorectal cancer (CRC) is a prevalent global health issue, with 5-fluorouracil (5-FU) being a commonly used chemotherapeutic agent for its treatment. However, the efficacy of 5-FU is often hindered by drug tolerance. Sodium butyrate (NaB), a derivative of intestinal flora, has demonstrated anti-cancer properties both in vitro and in vivo through pro-apoptotic effects and has shown promise in improving outcomes when used in conjunction with traditional chemotherapy agents. This study seeks to evaluate the impact and potential mechanisms of NaB in combination with 5-FU on CRC. We employed a comprehensive set of assays, including CCK-8, EdU staining, Hoechst 33258 staining, flow cytometry, ROS assay, MMP assay, immunofluorescence, and mitophagy assay, to detect the effect of NaB on the biological function of CRC cells in vitro. Western blotting and immunohistochemistry were used to verify the above experimental results. The xenograft tumor model was established to evaluate the in vivo anti-CRC activity of NaB. Subsequently, 16S rRNA gene sequencing was used to analyze the intestinal flora. The findings of our study demonstrate that sodium butyrate (NaB) exerts inhibitory effects on tumor cell proliferation and promotes tumor cell apoptosis in vitro, while also impeding tumor progression in vivo through the enhancement of the mitophagy pathway. Furthermore, the combined treatment of NaB and 5-fluorouracil (5-FU) yielded superior therapeutic outcomes compared to monotherapy with either agent. Moreover, this combination therapy resulted in the specific enrichment of Bacteroides, LigiLactobacillus, butyric acid-producing bacteria, and acetic acid-producing bacteria in the intestinal microbiota. The improvement in the intestinal microbiota contributed to enhanced therapeutic outcomes and reduced the adverse effects of 5-FU. Taken together, these findings indicate that NaB, a histone acetylation inhibitor synthesized through intestinal flora fermentation, has the potential to significantly enhance the therapeutic efficacy of 5-FU in CRC treatment and improve the prognosis of CRC patients.

Camelus knoblochi genome reveals the complex evolutionary history of Old World camels.

Extant Old World camels (genus Camelus) contributed to the economic and cultural exchanges between the East and West for thousands of years.1,2 Although many remains have been unearthed,3,4,5 we know neither whether the prevalent hybridization observed between extant Camelus species2,6,7 also occurred between extinct lineages and the ancestors of extant Camelus species nor why some populations became extinct while others survived. To investigate these questions, we generated paleogenomic and stable isotope data from an extinct two-humped camel species, Camelus knoblochi. We find that in the mitochondrial phylogeny, all C. knoblochi form a paraphyletic group that nests within the diversity of modern, wild two-humped camels (Camelus ferus). In contrast, they are clearly distinguished from both wild and domesticated (Camelus bactrianus) two-humped camels on the nuclear level. Moreover, the divergence pattern of the three camel species approximates a trifurcation, because the most common topology is only slightly more frequent than the two other possible topologies. This mito-nuclear phylogenetic discordance likely arose due to interspecific gene flow between all three species, suggesting that interspecific hybridization is not exclusive to modern camels but a recurrent phenomenon throughout the evolutionary history of the genus Camelus. These results suggest that the genomic complexity of Old World camels' evolutionary history is underestimated when considering data from only modern species. Finally, we find that C. knoblochi populations began declining prior to the last glacial maximum and, by integrating palaeoecological evidence and stable isotope data, suggest that this was likely due to failure to adapt to a changing environment.

Association between ascites Gustave Roussy immune score and the intratumoural microbiome in malignant ascites secondary to hepatocellular carcinoma.

BACKGROUNDS: The Gustave Roussy Immune (GRIm) score predicts survival outcomes in several cancers. However, the prognostic significance of the GRIm score in patients with malignant ascites has not yet been investigated. METHODS: Clinical samples were collected from a cohort of patients with malignant ascites secondary to hepatocellular carcinoma (HCC). We calculated serum GRIm (sGRIm) and ascites GRIm (aGRIm) scores and divided the samples into low and high GRIm score groups. Survival analysis was used to compare the prognostic significance of the sGRIm and aGRIm scores. 16S rRNA sequencing was performed to determine the profiles of the intratumoral microbiota in the groups. A fluorescent multiplex immunohistochemistry (mIHC) assay was used to detect the expression of different immune cells by labeling seven markers of malignant ascites. RESULTS: 155 patients with HCC and malignant ascites were enrolled in this study. Survival analysis revealed that the aGRIm score showed a superior prognostic significance compared to the sGRIm score. Microbial analysis demonstrated that the bacterial richness and diversity were higher in the low aGRIm score group than in the high aGRIm score group. LefSe analysis revealed that certain bacteria were correlated with high aGRIm scores. Fluorescent mIHC displayed the tumor microenvironment of malignant ascites and found that the density of CD8 + T cells was significantly higher in the low aGRIm score group than in the high aGRIm score group. CONCLUSIONS: Our present study identified a novel scoring system (aGRIm score) that can predict the survival outcome of patients with malignant ascites secondary to HCC.

Ascitic microbiota alteration is associated with portal vein tumor thrombosis occurrence and prognosis in hepatocellular carcinoma.

Portal vein tumor thrombosis (PVTT) frequently leads to malignant ascites (MA) in individuals with hepatocellular carcinoma (HCC), remaining a bottleneck in the treatment. This study aimed to explore the differences in microbes in paired groups and provide novel insights into PVTT and MA-related treatments. Formalin-fixed paraffin embedding ascite samples were collected from MA secondary to HCC and benign ascites (BA) secondary to liver cirrhosis (LC). Ascitic microbiota profiles were determined in the HCC and LC groups by 16S rRNA sequencing. Prognostic risk factors were screened using survival analysis. The correlation between the significantly different microbial signatures in the groups with PVTT (WVT) and non-PVTT (NVT) and clinical characteristics was explored. The expression of different immune cells was determined by labeling four markers in the MA tissue chips using multiplex immunohistochemistry. A total of 240 patients (196 with HCC with MA and 44 with LC with BA) were included in this study. Microbial profiles differed between the HCC and LC groups. PVTT and Barcelona Clinic Liver Cancer stage were shown to be prognostic risk factors. Significant differences in the alpha and beta diversities were observed between the WVT and NVT groups. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC MA. Differences in microbial signatures between the WVT and NVT groups were correlated with the level of C-reactive protein and apolipoprotein A1. This study revealed the microbial differences in the tumor microenvironment of MA secondary to HCC and BA secondary to LC.IMPORTANCEFirst, we explored the alteration of the ascites ecosystem through the microbiota in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Second, this is the first clinical study to investigate the differences between patients with HCC with and without portal vein tumor thrombosis via 16S rRNA sequencing. These results revealed a decreased microbial diversity and metabolic dysregulation in individuals with HCC and portal vein tumor thrombosis. Gammaproteobacteria and Acinetobacter were the most abundant in the HCC malignant ascitic fluid. Our study provides a new perspective on treating malignant ascites secondary to HCC.

The CRISPR-Cas13a Gemini System for noncontiguous target RNA activation.

Simultaneous multi-target detection and multi-site gene editing are two key factors restricting the development of disease diagnostic and treatment technologies. Despite numerous explorations on the source, classification, functional features, crystal structure, applications and engineering of CRISPR-Cas13a, all reports use the contiguous target RNA activation paradigm that only enables single-target detection in vitro and one-site gene editing in vivo. Here we propose a noncontiguous target RNA activation paradigm of Cas13a and establish a CRISPR-Cas13a Gemini System composed of two Cas13a:crRNA binary complexes, which can provide rapid, simultaneous, highly specific and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown. CRISPR-Cas13a Gemini System are demonstrated in the detection of two miRNAs (miR-155 and miR-375) for breast cancer diagnosis and two small RNAs (EBER-1 and EBER-2) for Epstein-Barr virus diagnosis using multiple diagnostic platforms, including fluorescence and colorimetric-based lateral flow systems. We also show that CRISPR-Cas13a Gemini System can knockdown two foreign genes (EGFP and mCherry transcripts) in mammalian cells simultaneously. These findings suggest the potential of highly effective and simultaneous detection of multiple biomarkers and gene editing of multiple sites.

Pterostilbene suppresses gastric cancer proliferation and metastasis by inhibiting oncogenic JAK2/STAT3 signaling: In vitro and in vivo therapeutic intervention.

BACKGROUND: Gastric cancer (GC) represents a significant health burden with dire prognostic implications upon metastasis and recurrence. Pterostilbene (PTE) has been proven to have a strong ability to inhibit proliferation and metastasis in other cancers, while whether PTE exhibits anti-GC activity and its potential mechanism remain unclear. PURPOSE: To explore the efficacy and potential mechanism of PTE in treating GC. METHODS: We employed a comprehensive set of assays, including CCK-8, EdU staining, colony formation, flow cytometry, cell migration, and invasion assays, to detect the effect of PTE on the biological function of GC cells in vitro. The xenograft tumor model was established to evaluate the in vivo anti-GC activity of PTE. Network pharmacology was employed to predict PTE's potential targets and pathways within GC. Subsequently, Western blotting, immunofluorescence, and immunohistochemistry were utilized to analyze protein levels related to the cell cycle, EMT, and the JAK2/STAT3 pathway. RESULTS: Our study demonstrated strong inhibitory effects of PTE on GC cells both in vitro and in vivo. In vitro, PTE significantly induced cell cycle arrest at G0/G1 and S phases and suppressed proliferation, migration, and invasion of GC cells. In vivo, PTE led to a dose-dependent reduction in tumor volume and weight. Importantly, PTE exhibited notable safety, leaving mouse weight, liver function, and kidney function unaffected. The involvement of the JAK2/STAT3 pathway in PTE's anti-GC effect was predicted utilizing network pharmacology. PTE suppressed JAK2 kinase activity by binding to the JH1 kinase structural domain and inhibited the downstream STAT3 signaling pathway. Western blotting confirmed PTE's inhibition of the JAK2/STAT3 pathway and EMT-associated protein levels. The anti-GC effect was partially reversed upon STAT3 activation, validating the pivotal role of the JAK2/STAT3 signaling pathway in PTE's activity. CONCLUSION: Our investigation validates the potent inhibitory effects of PTE on the proliferation and metastasis of GC cells. Importantly, we present novel evidence implicating the JAK2/STAT3 pathway as the key mechanism through which PTE exerts its anti-GC activity. These findings not only establish the basis for considering PTE as a promising lead compound for GC therapeutics but also contribute significantly to our comprehension of the intricate molecular mechanisms underlying its exceptional anti-cancer properties.

Kinome-Wide Virtual Screening by Multi-Task Deep Learning.

Deep learning is a machine learning technique to model high-level abstractions in data by utilizing a graph composed of multiple processing layers that experience various linear and non-linear transformations. This technique has been shown to perform well for applications in drug discovery, utilizing structural features of small molecules to predict activity. Here, we report a large-scale study to predict the activity of small molecules across the human kinome-a major family of drug targets, particularly in anti-cancer agents. While small-molecule kinase inhibitors exhibit impressive clinical efficacy in several different diseases, resistance often arises through adaptive kinome reprogramming or subpopulation diversity. Polypharmacology and combination therapies offer potential therapeutic strategies for patients with resistant diseases. Their development would benefit from a more comprehensive and dense knowledge of small-molecule inhibition across the human kinome. Leveraging over 650,000 bioactivity annotations for more than 300,000 small molecules, we evaluated multiple machine learning methods to predict the small-molecule inhibition of 342 kinases across the human kinome. Our results demonstrated that multi-task deep neural networks outperformed classical single-task methods, offering the potential for conducting large-scale virtual screening, predicting activity profiles, and bridging the gaps in the available data.

Function of mast cell and bile-cholangiocarcinoma interplay in cholangiocarcinoma microenvironment.

OBJECTIVE: The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites. DESIGN: Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9. RESULTS: Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation. CONCLUSION: Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.

Development and validation of nomograms to predict clinical outcomes of preeclampsia.

Background: Preeclampsia (PE) is one of the most severe pregnancy-related diseases; however, there is still a lack of reliable biomarkers. In this study, we aimed to develop models for predicting early-onset PE, severe PE, and the gestation duration of patients with PE. Methods: Eligible patients with PE were enrolled and divided into a training (n = 253) and a validation (n = 108) cohort. Multivariate logistic and Cox models were used to identify factors associated with early-onset PE, severe PE, and the gestation duration of patients with PE. Based on significant factors, nomograms were developed and evaluated using the area under the curve (AUC) and a calibration curve. Results: In the training cohort, multiple gravidity experience (p = 0.005), lower albumin (ALB; p < 0.001), and higher lactate dehydrogenase (LDH; p < 0.001) were significantly associated with early-onset PE. Abortion history (p = 0.017), prolonged thrombin time (TT; p < 0.001), and higher aspartate aminotransferase (p = 0.002) and LDH (p = 0.003) were significantly associated with severe PE. Abortion history (p < 0.001), gemellary pregnancy (p < 0.001), prolonged TT (p < 0.001), higher mean platelet volume (p = 0.014) and LDH (p < 0.001), and lower ALB (p < 0.001) were significantly associated with shorter gestation duration. Three nomograms were developed and validated to predict the probability of early-onset PE, severe PE, and delivery time for each patient with PE. The AUC showed good predictive performance, and the calibration curve and decision curve analysis demonstrated clinical practicability. Conclusion: Based on the clinical features and peripheral blood laboratory indicators, we identified significant factors and developed models to predict early-onset PE, severe PE, and the gestation duration of pregnant women with PE, which could help clinicians assess the clinical outcomes early and design appropriate strategies for patients.

Polydopamine-assisted aptamer-carrying tetrahedral DNA microelectrode sensor for ultrasensitive electrochemical detection of exosomes.

BACKGROUND: Exosomes are nanoscale extracellular vesicles (30-160 nm) with endosome origin secreted by almost all types of cells, which are considered to be messengers of intercellular communication. Cancerous exosomes serve as a rich source of biomarkers for monitoring changes in cancer-related physiological status, because they carry a large number of biological macromolecules derived from parental tumors. The ultrasensitive quantification of trace amounts of cancerous exosomes is highly valuable for non-invasive early cancer diagnosis, yet it remains challenging. Herein, we developed an aptamer-carrying tetrahedral DNA (Apt-TDNA) microelectrode sensor, assisted by a polydopamine (PDA) coating with semiconducting properties, for the ultrasensitive electrochemical detection of cancer-derived exosomes. RESULTS: The stable rigid structure and orientation of Apt-TDNA ensured efficient capture of suspended exosomes. Without PDA coating signal amplification strategy, the sensor has a linear working range of 102-107 particles mL-1, with LOD of ~ 69 exosomes and ~ 42 exosomes for EIS and DPV, respectively. With PDA coating, the electrochemical signal of the microelectrode is further amplified, achieving single particle level sensitivity (~ 14 exosomes by EIS and ~ 6 exosomes by DPV). CONCLUSIONS: The proposed PDA-assisted Apt-TDNA microelectrode sensor, which integrates efficient exosome capture, sensitive electrochemical signal feedback with PDA coating signal amplification, provides a new avenue for the development of simple and sensitive electrochemical sensing techniques in non-invasive cancer diagnosis and monitoring treatment response.

Targeted degrader technologies as prospective SARS-CoV-2 therapies.

COVID-19 remains a severe public health threat despite the WHO declaring an end to the public health emergency in May 2023. Continual development of SARS-CoV-2 variants with resistance to vaccine-induced or natural immunity necessitates constant vigilance as well as new vaccines and therapeutics. Targeted protein degradation (TPD) remains relatively untapped in antiviral drug discovery and holds the promise of attenuating viral resistance development. From a unique structural design perspective, this review covers antiviral degrader merits and challenges by highlighting key coronavirus protein targets and their co-crystal structures, specifically illustrating how TPD strategies can refine existing SARS-CoV-2 3CL protease inhibitors to potentially produce superior protease-degrading agents.

Relationships of Late Pleistocene giant deer as revealed by Sinomegaceros mitogenomes from East Asia.

The giant deer, widespread in northern Eurasia during the Late Pleistocene, have been classified as western Megaloceros and eastern Sinomegaceros through morphological studies. While Megaloceros's evolutionary history has been unveiled through mitogenomes, Sinomegaceros remains molecularly unexplored. Herein, we generated mitogenomes of giant deer from East Asia. We find that, in contrast to the morphological differences between Megaloceros and Sinomegaceros, they are mixed in the mitochondrial phylogeny, and Siberian specimens suggest a range contact or overlap between these two groups. Meanwhile, one deep divergent clade and another surviving until 20.1 thousand years ago (ka) were detected in northeastern China, the latter implying this area as a potential refugium during the Last Glacial Maximum (LGM). Moreover, stable isotope analyses indicate correlations between climate-introduced vegetation changes and giant deer extinction. Our study demonstrates the genetic relationship between eastern and western giant deer and explores the promoters of their extirpation in northern East Asia.

A dual amplification-based CRISPR/Cas12a biosensor for sensitive detection of miRNA in prostate cancer.

MicroRNA (miRNA) has gained significant attention as a potential biomarker for cancer clinics, and there is an urgent need for developing sensing strategies with high selectivity, sensitivity, and low background. In vitro diagnosis based on Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-Associated protein (CRISPR/Cas) technology could simplify the detection procedure, improve sensitivity and selectivity, and has broad application prospects as the next-generation molecular diagnosis technology. We propose a novel dual signal amplification strategy, called CENTER, which integrates the CRISPR/Cas12a system, an entropy-driven DNA signaling network, and strand displacement amplification to achieve ultrasensitive detection of miR-141, a potential marker for prostate cancer. The experimental results demonstrate that CENTER can distinguish single nucleotide mutations, and the strategy exhibits a good linear calibration curve ranging from 100 aM to 1 pM. Due to dual signal amplification, the detection limit is as low as 34 aM. We proposed a method for identifying miR-141 expressed in human serum and successfully distinguished between prostate cancer patients (n = 20) and healthy individuals (n = 15) with an impressive accuracy of 94%. Overall, CENTER shows great promise for the detection of miRNA.

Interphasial Pre-lithiation and Reinforcement of Micro-Si Anode through Fluorine-free Electrolytes.

Micro-sized silicon (mSi) anodes offer advantages in cost and tap density over nanosized counterparts. However, its practical application still suffers from poor cyclability and low initial and later-cycle coulombic efficiency (CE), caused by the unstable solid electrolyte interphase (SEI) and irreversible lithiation of the surface oxide layer. Herein, a bifunctional fluorine (F)-free electrolyte was designed for the mSi anode to stabilize the interphase and improve the CE. A combined analysis revealed that this electrolyte can chemically pre-lithiate the native oxide layer by the reductive LiBH4 , and relieve SEI formation and accumulation to preserve the internal conductive network. The significance of this F-free electrolyte brings unprecedented F-free interphase that also enables the high-performance mSi electrode (80 wt % mSi), including high specific capacity of 2900 mAh/g, high initial CE of 94.7 % and excellent cyclability capacity retention of 94.3 % after 100 cycles at 0.2 C. This work confirms the feasibility of F-free interphase, thus opening up a new avenue toward cost-advantaged and environmentally friendly electrolytes for more emerging battery systems.

Ancient mitogenomes reveal a high maternal genetic diversity of Pleistocene woolly rhinoceros in Northern China.

BACKGROUND: Woolly rhinoceros (Coelodonta antiquitatis) is a typical indicator of cold-stage climate that was widely distributed in Northern Hemisphere during the Middle-Late Pleistocene. Although a plethora of fossils have been excavated from Northern China, their phylogenetic status, intraspecific diversity and phylogeographical structure are still vague. RESULTS: In the present study, we generated four mitogenomes from Late Pleistocene woolly rhinoceros in Northern China and compared them with published data. Bayesian and network analyses indicate that the analyzed individuals contain at least four maternal haplogroups, and Chinese samples fall in three of them. One of our samples belongs to a previously unidentified early diverging clade (haplogroup D), which separated from other woolly rhinoceros around 0.57 Ma (95% CI: 0.76-0.41 Ma). The timing of this clade's origin coincides with the first occurrence of woolly rhinoceros, which are thought to have evolved in Europe. Our other three samples cluster in haplogroup C, previously only identified from one specimen from Wrangel Island (ND030) and initially considered to be an isolated clade. Herein, our findings suggest that ND030 is likely descended from a northward dispersal of the individuals carrying haplogroup C from Northern China. Additionally, Chinese woolly rhinoceros specimens exhibit higher nucleotide diversity than those from Siberia. CONCLUSION: Our findings highlight Northern China as a possible refugium and a key evolution center of the Pleistocene woolly rhinoceros.

A Novel Deoxyribonuclease Low-Molecular-Weight Bacteriocin, Carocin S4, from Pectobacterium carotovorum subsp. carotovorum.

Pectobacterium carotovorum subsp. carotovorum (Pcc) is known to produce different types of bacteriocins, active protein substances that inhibit or kill related strains and are known to be induced by several factors. In this paper, we report the discovery, isolation, characterization, and functional analysis of Carocin S4, a novel low-molecular-weight bacteriocin (LMWB) from Pcc. A 2750 bp gene fragment was isolated from the chromosomal DNA of Pcc mutant strain rif-TO6, a rifampicin-resistant strain of TO6. The gene contains caroS4K and caroS4I within two open reading frames, which encode CaroS4K and CaroS4I, with molecular weights of about 90 kD and 10 kD, respectively. The unique characteristics of Carocin S4 were revealed after homology analysis with the previously discovered bacteriocins from Pcc. CaroS4K, which shares 23% and 85% homology with CaroS1K and CaroS3K, respectively, is also a deoxyribonuclease. However, unlike the two which can only hydrolyze genomic DNA, CaroS4K hydrolyzes both genomic and plasmid DNA. On the other hand, CaroS4K was found to be 90% homologous with CaroS2K but works differently in killing the target cell, as the latter is a ribonuclease. The optimal reaction temperature for CaroS4K to hydrolyze dsDNA is approximately 50 °C and requires the divalent metal ions Mg2+, Ca2+, and Zn2+ to catalyze its DNase activity. This study reveals another nuclease type of bacteriocin in Pcc, with CaroS4K and CaroS4I functioning as killer and immunity proteins, respectively.

A genetic glimpse of the Chinese straight-tusked elephants.

Straight-tusked elephants (genus: Palaeoloxodon) including their island dwarf forms are extinct enigmatic members of the Pleistocene megafauna and the most common Pleistocene elephants after the mammoths. Their taxonomic placement has been revised several times. Using palaeogenomic evidence, previous studies suggested that the European P. antiquus has a hybrid origin, but no molecular data have been retrieved from their Asian counterparts, leaving a gap in our knowledge of the global phylogeography and population dynamics of Palaeoloxodon. Here, we captured a high-quality complete mitogenome from a Pleistocene Elephantidae molar (CADG841) from Northern China, which was previously morphologically assigned to the genus Elephas (Asian elephant), and partial mitochondrial sequences (838 bp) of another Palaeoloxodon sp. specimen (CADG1074) from Northeastern China. We found that both Chinese specimens cluster with a 244 000-year-old P. antiquus (specimen name: WE) from Western Europe, suggesting that this clade may represent a population with a large spatial span across Eurasia. Based on the fossil record and the molecular dating of both the divergences of different Palaeoloxodon mitochondrial clades and previously determined hybridization events, we propose that this Eurasian-wide WE clade provides evidence for an earlier migration and/or another hybridization event that happened in the evolutionary history of straight-tusked elephants.

The value of serum HE4 and CA125 levels for monitoring the recurrence and risk stratification of endometrial endometrioid carcinoma.

To evaluate the role of serum human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125) levels for predicting and monitoring the recurrence of endometrial endometrioid carcinoma (EEC) and assessing preoperative risk stratification in EEC patients. A total of 434 EEC patients were selected for this retrospective study between May 2011 and August 2018. Serum HE4 and CA125 levels were analyzed before the initial treatment, at the first postoperative follow-up, and at recurrence or the last follow-up. Patients were risk stratified according to the European Society for Medical Oncology (ESMO), European Society for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) guideline. We compared the ability of these biomarkers for prediction and monitoring by performing receiver operating characteristic curve analysis and identified optimal cut-off values by determining the Youden index. Kaplan-Meier analyses were also performed to determine prognostic value. Preoperative serum HE4 was identified as a significant predictor for the recurrence of EEC (p = 0.014). Preoperative serum HE4 and CA125 levels were related to depth of myometrial invasion, lymph node status and FIGO stage. Serum HE4 and CA125 levels were both statistically significant markers for monitoring the recurrence of EEC (P = 0.000 for each biomarker). When combined, the two markers showed higher levels of sensitivity and specificity. The two biomarkers were also significant biomarkers for evaluating the risk stratification of patients undergoing lymphadenectomy (P = 0.000 for each biomarker). For premenopausal stage I patients, preoperative serum HE4 and CA125 levels were significant predictors of the need for ovarian preservation (P = 0.000 and P = 0.002, respectively). For premenopausal patients with stage I intramucosal differentiation, preoperative serum levels of HE4 were significant predictors for fertility preservation (P = 0.024). Preoperative serum HE4 level can be used to predict the recurrence of EEC. Postoperative serum HE4 and CA125 levels can be used to monitor the recurrence of EEC and are more sensitive when combined. Preoperative serum levels of CA125 and HE4 levels are of significant value for risk stratification in EEC patients.