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The transparency and refractive properties of the lens are maintained by the cellular physiology provided by an internal microcirculation system that utilizes spatial differences in ion channels, transporters and gap junctions to establish standing electrochemical and hydrostatic pressure gradients that drive the transport of ions, water and nutrients through this avascular tissue. Aging has negative effects on lens transport, degrading ion and water homeostasis, and producing changes in lens water content. This alters the properties of the lens, causing changes in optical quality and accommodative amplitude that initially result in presbyopia in middle age and ultimately manifest as cataract in the elderly. Recent advances have highlighted that the lens hydrostatic pressure gradient responds to tension transmitted to the lens through the Zonules of Zinn through a mechanism utilizing mechanosensitive channels, multiple sodium transporters respond to changes in hydrostatic pressure to restore equilibrium, and that connexin hemichannels and diverse intracellular signaling cascades play a critical role in these responses. The mechanistic insight gained from these studies has advanced our understanding of lens transport and how it responds and adapts to different inputs both from within the lens, and from surrounding ocular structures.

Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial GC receptor (GR), but not whole intestinal tissue GR, promoted chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In patients with colorectal cancer, GR was enriched in intestinal epithelial cells and high epithelial cell GR levels were associated with poor prognosis. Consistently, intestinal epithelium–specific deletion of GR (GR iKO) in mice increased macrophage infiltration, improved tissue recovery, and enhanced antitumor response in a chronic inflammation–associated colorectal cancer model. Consequently, GR iKO mice developed fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early phase of tissue injury delayed recovery and accelerated the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling repressed acute colitis but promoted chronic inflammation–associated colorectal cancer. Our study suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that, although synthetic GC treatment for IBD should be used with caution, there is a therapeutic window for GC therapy during colorectal cancer development in immunocompetent patients.

The composition of interplanetary coronal mass ejections (ICMEs), including the ionic charge states and elemental abundances of heavy elements, is tightly correlated with their source regions and eruption processes. This can help in analyzing the eruption mechanisms and plasma origins of CMEs, and deepen our understanding of energetic solar activities. The active regions and quiet-Sun regions have different physical properties; thus, from a statistical point of view, ICMEs originating from the two types of regions should exhibit different compositional characteristics. To demonstrate the differences comprehensively, we conduct survey studies on the ionic charge states of five elements (Mg, Fe, Si, C, and O) and the relative abundances of six elements (Mg/O, Fe/O, Si/O, C/O, Ne/O, and He/O) within ICMEs from 1998 February to 2011 August using data from the Advanced Composition Explorer. The results show that ICMEs from active regions have higher ionic charge states and relative abundances than those from quiet-Sun regions. For the active-region ICMEs, we further analyze the relations between their composition and flare class, and find a positive relationship between them, i.e., the higher the classes of the associated flares, the larger the means of the ionic charge states and relative abundances (except the C/O) within ICMEs. As more (less) fractions of ICMEs originate from active regions around the solar maximum (minimum), and active-region ICMEs usually are associated with higher-class flares, our studies might answer why the composition of ICMEs measured near 1 au exhibits a solar cycle dependence.

How structures, e.g., magnetic loops, in the upper atmosphere, i.e., the transition region and corona, are heated and sustained is one of the major unresolved issues in solar and stellar physics. Various theoretical and observational studies on the heating of coronal loops have been undertaken. The heating of quiescent loops caused by eruptions, however, is rarely observed. In this study, employing data from the Solar Dynamics Observatory (SDO) and Solar Upper Transition Region Imager (SUTRI), we report the heating of quiescent loops associated with nearby eruptions. In active regions (ARs) 13092 and 13093, a long filament and a short filament, and their overlying loops, were observed on 2022 September 4. In AR 13093, a warm channel erupted toward the northeast, whose material moved along its axis toward the northwest under the long filament, turned to the west above the long filament, and divided into two branches falling to the solar surface. Subsequently, the short filament erupted toward the southeast. Associated with these two eruptions, the quiescent loops overlying the long filament appeared in SDO/Atmospheric Imaging Assembly (AIA) high-temperature images, indicating the heating of loops. During the heating, the signature of magnetic reconnection between loops is identified, including the inflowing motions of loops, and the formation of X-type structures and newly reconnected loops. The heated loops then cooled down. They appeared sequentially in AIA and SUTRI lower-temperature images. All the results suggest that the quiescent loops are heated by reconnection between loops caused by the nearby warm channel and filament eruptions.

The eruption of magnetic flux ropes (MFRs), often taking filaments together, leads to coronal mass ejections (CMEs). Theoretical studies propose that both the resistive magnetic reconnection and the ideal instability of an MFR system can release magnetic-free energy and accelerate CMEs (i.e., MFRs or filaments) during eruptions. Observations find that the full kinematic evolution of CMEs usually undergoes three phases: the initiation phase, impulsive acceleration phase, and propagation phase. The impulsive acceleration phase often starts and ceases simultaneously with the flare onset time and peak time, respectively. This synchronization can be explained by the positive feedback relationship between the acceleration of CMEs and flare magnetic reconnection, and suggests that the reconnection has the dominant contribution to the acceleration of CMEs. It is rare to see strong evidence that supports the dominant contribution of ideal instability to the acceleration. In this paper, we report an intriguing filament eruption that occurred on 2011 May 11. Its complete acceleration is well recorded by the Atmospheric Imaging Assembly on board the Solar Dynamics Observatory. The kinematic analysis shows that the impulsive acceleration phase starts and ceases obviously earlier than the flare onset time and peak time, respectively, which means a complete asynchronization between the impulsive acceleration phase and flare rise phase, and strongly supports that the ideal instability plays a dominant role in this impulsive acceleration. Furthermore, the accompanied flare is a B-class one, also implying that the contribution of reconnection is negligible in the energy release process.

Partial eruptions of solar filaments are the typical representatives of solar eruptive behavior diversity. Here we investigate a typical filament partial eruption event and present integrated evidence for the configuration of the pre-eruption filament and its formation. The Chinese H α Solar Explorer H α observations reveal a structured Doppler velocity distribution within the pre-eruption filament, where distinct redshift only appeared in the eastern narrow part of the southern filament region and then disappeared after the partial eruption, while the northern part dominated by blueshift remained. Combining the Solar Dynamics Observatory and Advanced Space-based Solar Observatory observations, together with nonlinear-force-free-field modeling results, we verify that there were two independent material flow systems within the preflare filament, whose magnetic topology is a special double-decker configuration consisting of two magnetic flux ropes (MFRs) with opposite magnetic twist. During the formation of this filament system, continuous magnetic flux cancellation and footpoint motion were observed around its northern end. Therefore, we propose a new double-decker formation scenario: that the two MFRs composing such a double-decker configuration originated from two magnetic systems with different initial connections and opposite magnetic twist. Subsequent magnetic reconnection with the surrounding newly emerging fields resulted in the motion of the footpoint of the upper MFR to the region around the footpoint of the lower MFR, thus leading to the eventual formation of the double-decker configuration consisting of two MFRs with similar footpoints but opposite signs of magnetic twist. These results provide a potential way to determine unambiguously the progenitor configuration of a partially eruptive filament and reveal a special type of double-decker MFR configuration and a new double-decker formation scenario.

Objective: To evaluate the influence of the abdominal incision length on the gastrointestinal function recovery post-operatively.Background: Gut motility recovers more quickly after the minimally invasive laparoscopic surgery compared than after the traditional open surgery; however, whether the minimal abdominal incision contributes to the faster gut motility recovery is controversial and lacks solid clinical evidence.Methods: A registry-based secondary cohort analysis was conducted to evaluate the association between the abdominal incision length and gut motility recovery post-operatively based on a multicenter, prospective, and observational study of the prolonged post-operative ileus (PPOI) incidence and the risk factors in the patients with the major abdominal surgery. The incision length, in the centimeters, was the exposure. The primary outcome measures were the PPOI incidence and its association with the incision length. The secondary outcome included the days to the first passage of flatus and the days to the first passage of stool.Results: Overall, 1,840 patients, including 287 (15.7%) patients with the PPOI, were recruited. The PPOI incidence was 17.6% and 13.3% in the long-incision (>18 cm) and short-incision patients ( ≤ 18 cm), respectively. The incidence of the PPOI increased by 1.1% (1.0–1.1) by each centimeter increment of the incision length after adjusting for the confounding factors. In comparison to the short-incision patients, the long-incision patients had prolonged passage of stool (4.46 vs. 4.95 days, p < 0.001). Each centimeter increment of the incision length contributed to a 2% increased risk of delay in the first bowel movement [hazard ratio (HR) 0.980 (0.967, 0.994)].Conclusion: A long abdominal incision length independently contributed to the prolonged gut function recovery post-operatively mainly by delaying the time to the first bowel movement, but not influencing the time to first passage of flatus.

BackgroundThe management of 2-5 cm gastric gastrointestinal stromal tumours (GISTs) is still debated between surgeons and endoscopists. We aimed to investigate short-term and long-term outcomes between surgical resection (SR) and endoscopic resection (ER).MethodsThis study included 67 and 215 patients between 2010 and 2020 who underwent ER and SR, respectively. After propensity score matching, the clinical outcomes were compared. Individual patient information that requires special instructions is also summarized.ResultsAfter matching, the operation time (P=0.005) and postoperative hospital stay (P=0.005) were significantly longer in the SR group than in the ER group. However, there were no significant differences in blood loss (P=0.741), resection margin (P=1.000) or time to liquid diet (P=0.055). Statistical differences were also seen in en bloc resection (P

Abstract Background NF1(Neurofibromatosis type 1) is an autosomal dominant genetic disorder. Patients with NF1 have an increased risk of developing benign or malignant tumours, such as gastrointestinal stromal tumours (GISTs). However, the coexistence of NF1, GIST and colon cancer is very rare, and few cases have been reported in the literature. Case presentation We admitted a case of a 64-year-old man with type 1 neurofibromatosis, GISTs, and ascending colon cancer. This case was characterized by café-au-lait macules, discrete cutaneous neurofibromas, nodular neurofibromas, multiple jejunal tumours, and ascending colon cancer. Laparoscopic exploration revealed ascending colon cancer and multiple jejunal tumours. Laparoscopic right hemicolectomy and local excision of the jejunal tumours were performed successfully. The pathological results confirmed moderate differentiated adenocarcinoma of the ascending colon with multiple jejunal GISTs (low risk, very low risk). Moreover, the immunohistochemistry results of multiple jejunal GISTs suggest that NF1 is positive. Whole-exome sequencing (WES) of colon cancer revealed mutations in more than 20 genes, including KRAS, PIK3CA, APC, SMAD4, etc. The results of whole-exome sequencing (WES) of jejunal GISTs revealed an NF1 mutation and no KIT or PDGFR gene mutation. Conclusion We report a rare case of simultaneous NF1, GIST and colon adenocarcinoma. For patients with NF1, benign and/or malignant tumours are often combined. Therefore, these patients should undergo regular physical examinations so that early detection and early treatment can be achieved.

Abstract Background Tumor purity is the percent of cancer cells present in a sample of tumor tissue. The non-cancerous cells (immune cells, fibroblasts, etc.) have an important role in tumor biology. The ability to determine tumor purity is important to understand the roles of cancerous and non-cancerous cells in a tumor. Methods We applied a supervised machine learning method, XGBoost, to data from 33 TCGA tumor types to predict tumor purity using RNA-seq gene expression data. Results Across the 33 tumor types, the median correlation between observed and predicted tumor-purity ranged from 0.75 to 0.87 with small root mean square errors, suggesting that tumor purity can be accurately predicted υσινγ expression data. We further confirmed that expression levels of a ten-gene set (CSF2RB, RHOH, C1S, CCDC69, CCL22, CYTIP, POU2AF1, FGR, CCL21, and IL7R) were predictive of tumor purity regardless of tumor type. We tested whether our set of ten genes could accurately predict tumor purity of a TCGA-independent data set. We showed that expression levels from our set of ten genes were highly correlated (ρ = 0.88) with the actual observed tumor purity. Conclusions Our analyses suggested that the ten-gene set may serve as a biomarker for tumor purity prediction using gene expression data.

A complete knowledge of tibiofemoral joint kinematics is essential for understanding the function of the healthy and pathological joint. The objective of the present study was to establish a dual fluoroscopic measurement protocol and a data processing approach for the creep response of the knee joint in order to further evaluate the mechanical properties of articular cartilage and meniscus in vivo. A computational approach was developed for the determination of 3D translations and rotations of the joints of young participants with no history of injury using dual fluoroscopic images of loaded joints and joint geometry reconstructed from magnetic resonance imaging of the unloaded joints. High-resolution X-ray images were obtained for the distal femur and proximal tibia during 10-min standing when approximately ¾ body weight was slowly applied to the right leg and then kept constant for the rest duration of the test. Anatomic coordinate systems were established for the 3D models of distal femur and proximal tibia. Translations and rotations of the joint as functions of time were then evaluated using the X-ray images and these coordinate systems with the JointTrack software. The displacements in the proximal-distal direction obtained from two participants were consistent, showing a substantial increase in the initial phase when joint loading increased from nil to ¾ body weight and a continued small increase over time while the joint loading remained constant. The maximum anterior-posterior translations during 10-min standing were approximately 4 mm for both participants, although one showed better stability than the other. In conclusion, a creep loading protocol of the knee joint can be reasonably established for in vivo conditions and evaluated with the image-based computational approach. Keywords: Creep, In vivo study, Knee joint kinematics, Dual fluoroscopy, Magnetic resonance imaging, Image-based computer model

Coronal mass ejections (CMEs) are one of the most energetic explosions in the solar system. It is generally accepted that CMEs result from eruptions of magnetic flux ropes, which are dubbed as magnetic clouds (MCs) in interplanetary space. The composition (including the ionic charge states and elemental abundances) is determined prior to and/or during CME eruptions in the solar atmosphere and does not alter during MC propagation to 1 AU and beyond. It has been known that the composition is not uniform within a cross section perpendicular to the MC axis, and the distribution of ionic charge states within a cross section provides us an important clue to investigate the formation and eruption processes of flux ropes due to the freeze-in effect. The flux rope is a three-dimensional magnetic structure intrinsically, and it remains unclear whether the composition is uniform along the flux rope axis as most MCs are only detected by one spacecraft. In this study, we report an MC that was observed by Advanced Composition Explorer at ∼1 AU during March 4–6, 1998, and Ulysses at ∼5.4 AU during March 24–28, 1998, sequentially. At these times, both spacecraft were located around the ecliptic plane, and the latitudinal and longitudinal separations between them were ∼2.2° and ∼5.5°, respectively. It provides us an excellent opportunity to explore the axial inhomogeneity of flux rope composition, as both spacecraft almost intersected the cloud center at different sites along its axis. Our study shows that the average values of ionic charge states exhibit significant difference along the axis for carbon, and the differences are relatively slight but still obvious for charge states of oxygen and iron as well as the elemental abundances of iron and helium. Besides the means, the composition profiles within the cloud measured by both spacecraft also exhibit some discrepancies. We conclude that the inhomogeneity of composition exists along the cloud axis.

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.

We have previously shown that the conditional deletion of either the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), or its opposing phosphatase, phosphatase and tensin homolog (PTEN), had distinct effects on lens growth and homeostasis. The deletion of p110α reduced the levels of phosphorylated Akt and equatorial epithelial cell proliferation, and resulted in smaller transparent lenses in adult mice. The deletion of PTEN increased levels of phosphorylated Akt, altered lens sodium transport, and caused lens rupture and cataract. Here, we have generated conditional p110α/PTEN double-knockout mice, and evaluated epithelial cell proliferation and lens homeostasis. The double deletion of p110α and PTEN rescued the defect in lens size seen after the single knockout of p110α, but accelerated the lens rupture phenotype seen in PTEN single-knockout mice. Levels of phosphorylated Akt in double-knockout lenses were significantly higher than in wild-type lenses, but not as elevated as those reported for PTEN single-knockout lenses. These results showed that the double deletion of the p110α catalytic subunit of PI3K and its opposing phosphatase, PTEN, exacerbated the rupture defect seen in the single PTEN knockout and alleviated the growth defect observed in the single p110α knockout. Thus, the integrity of the PI3K signaling pathway was absolutely essential for proper lens homeostasis, but not for lens growth.

Abstract The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts’ clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

Coronal mass ejections (CMEs) result from eruptions of magnetic flux ropes (MFRs) and can possess a three-part structure in white-light coronagraphs, including a bright front, dark cavity, and bright core. In traditional opinion, the bright front forms due to the plasma pileup along the MFR border, the cavity represents the cross section of the MFR, and the bright core corresponds to the erupted prominence. However, this explanation on the nature of the three-part structure is being challenged. In this paper, we report an intriguing event that occurred on 2014 June 14 that was recorded by multiple space- and ground-based instruments seamlessly, clearly showing that the CME front originates from the plasma pileup along the magnetic arcades overlying the MFR, and the core corresponds to a hot-channel MFR. Thus the dark cavity is not an MFR; instead it is a low-density zone between the CME front and a trailing MFR. These observations are consistent with a new explanation on the CME structure. If the new explanation is correct, most (if not all) CMEs should exhibit the three-part appearance in their early eruption stage. To examine this prediction, we make a survey of all CMEs in 2011 and find that all limb events have the three-part feature in the low corona, regardless of their appearances in the high corona. Our studies suggest that the three-part structure is the intrinsic structure of CMEs, which has fundamental importance for understanding CMEs.

Abstract Background The knee joint performs mechanical functions with various loading and unloading processes. Past studies have focused on the kinematics and elastic response of the joint with less understanding of the rate-dependent load response associated with viscoelastic and poromechanical behaviors. Methods Forty-five fresh porcine knee joints were used in the present study to determine the loading-rate-dependent force-compression relationship, creep and relaxation of normal, dehydrated and meniscectomized joints. Results The mechanical tests of all normal intact joints showed similar strong compression-rate-dependent behavior: for a given compression-magnitude up to 1.2 mm, the reaction force varied 6 times over compression rates. While the static response was essentially linear, the nonlinear behavior was boosted with the increased compression rate to approach the asymptote or limit at approximately 2 mm/s. On the other hand, the joint stiffness varied approximately 3 times over different joints, when accounting for the maturity and breed of the animals. Both a loss of joint hydration and a total meniscectomy greatly compromised the load support in the joint, resulting in a reduction of load support as much as 60% from the corresponding intact joint. However, the former only weakened the transient load support, but the latter also greatly weakened the equilibrium load support. A total meniscectomy did not diminish the compression-rate-dependence of the joint though. Conclusions These findings are consistent with the fluid-pressurization loading mechanism, which may have a significant implication in the joint mechanical function and cartilage mechanobiology.

Abstract Background The clinicopathological characteristics of small intestinal neuroendocrine neoplasms (SI-NENs) and the prognostic validity of WHO grading classification for SI-NENs are still unknown in Asian patients. Methods 277 patients and 8315 patients with SI-NENs were retrieved respectively from eleven Chinese hospitals and Surveillance, Epidemiology, and End Results (SEER) cancer registry. Overall survival was used as the major study outcome. Survival analysis using Kaplan-Meier analysis with log-rank test and cox regression analysis were applied. Results Clinicopathological characteristics of SI-NENs were quite different among different races. Duodenum was the predominant tumor site in Chinese patients and Asian/Pacific Islander patients but not in white patients from SEER database. Patients with duodenal NENs tended to have more localized disease than patients with jejunal/ileal NENs which were confirmed by patients from SEER database. Grade 3 or poorly differentiated/undifferentiated tumor were more common and tumor size was significantly larger in ampullary NENs compared with that in non-ampullary duodenal NENs. As for the prognostic validity of WHO grading classification, survival between patients with grade 1 and grade 2 disease was not significantly different. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 than Ki-67 index of 2% in SI-NENs. Conclusions Our study revealed that the clinicopathological characteristics of SI-NENs among different races were quite different. This might because duodenal NENs was much more common in Chinese patients and Asian/Pacific Islander patients. Duodenal NENs and jejunal/ileal NENs, ampullary and non-ampullary duodenal NENs shared different characteristics. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 in SI-NENs.

Abstract Background The Cancer Genome Atlas (TCGA) has generated comprehensive molecular profiles. We aim to identify a set of genes whose expression patterns can distinguish diverse tumor types. Those features may serve as biomarkers for tumor diagnosis and drug development. Methods Using RNA-seq expression data, we undertook a pan-cancer classification of 9,096 TCGA tumor samples representing 31 tumor types. We randomly assigned 75% of samples into training and 25% into testing, proportionally allocating samples from each tumor type. Results We could correctly classify more than 90% of the test set samples. Accuracies were high for all but three of the 31 tumor types, in particular, for READ (rectum adenocarcinoma) which was largely indistinguishable from COAD (colon adenocarcinoma). We also carried out pan-cancer classification, separately for males and females, on 23 sex non-specific tumor types (those unrelated to reproductive organs). Results from these gender-specific analyses largely recapitulated results when gender was ignored. Remarkably, more than 80% of the 100 most discriminative genes selected from each gender separately overlapped. Genes that were differentially expressed between genders included BNC1, FAT2, FOXA1, and HOXA11. FOXA1 has been shown to play a role for sexual dimorphism in liver cancer. The differentially discriminative genes we identified might be important for the gender differences in tumor incidence and survival. Conclusions We were able to identify many sets of 20 genes that could correctly classify more than 90% of the samples from 31 different tumor types using TCGA RNA-seq data. This accuracy is remarkable given the number of the tumor types and the total number of samples involved. We achieved similar results when we analyzed 23 non-sex-specific tumor types separately for males and females. We regard the frequency with which a gene appeared in those sets as measuring its importance for tumor classification. One third of the 50 most frequently appearing genes were pseudogenes; the degree of enrichment may be indicative of their importance in tumor classification. Lastly, we identified a few genes that might play a role in sexual dimorphism in certain cancers.

Quantifying cell-type proportions and their corresponding gene expression profiles in tissue samples would enhance understanding of the contributions of individual cell types to the physiological states of the tissue. Current approaches that address tissue heterogeneity have drawbacks. Experimental techniques, such as fluorescence-activated cell sorting, and single cell RNA sequencing are expensive. Computational approaches that use expression data from heterogeneous samples are promising, but most of the current methods estimate either cell-type proportions or cell-type-specific expression profiles by requiring the other as input. Although such partial deconvolution methods have been successfully applied to tumor samples, the additional input required may be unavailable. We introduce a novel complete deconvolution method, CDSeq, that uses only RNA-Seq data from bulk tissue samples to simultaneously estimate both cell-type proportions and cell-type-specific expression profiles. Using several synthetic and real experimental datasets with known cell-type composition and cell-type-specific expression profiles, we compared CDSeq's complete deconvolution performance with seven other established deconvolution methods. Complete deconvolution using CDSeq represents a substantial technical advance over partial deconvolution approaches and will be useful for studying cell mixtures in tissue samples. CDSeq is available at GitHub repository (MATLAB and Octave code): https://github.com/kkang7/CDSeq.

Due to the poor prognosis of advanced metastatic melanoma, it is crucial to find early biomarkers that help identify which melanomas will metastasize. By comparing the gene expression data from primary and cutaneous melanoma samples from The Cancer Genome Atlas (TCGA), we identified GPC6 among a set of genes whose expression levels can distinguish between primary melanoma and regional cutaneous/subcutaneous metastases. Glypicans are thought to play a role in tumor growth by regulating the signaling pathways of Wnt, Hedgehogs, fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs). We showed that GPC6 expression was up-regulated in a melanoma cell line compared to normal melanocytes and in metastatic melanoma compared to primary melanoma. Furthermore, GPC6 expression was positively correlated with genes largely involved in cell adhesion and migration in both melanoma samples and in RNA-seq samples from other TCGA tumors. Our results suggest that GPC6 may play a role in tumor metastatic progression. In TCGA melanoma samples, we also showed that GPC6 expression was negatively correlated with miR-509-3p, which has previously been shown to function as a tumor suppressor in various cancer cell lines. We overexpressed miR-509-3p in A375 melanoma cells and showed that GPC6 expression was significantly suppressed. This result suggested that GPC6 was a putative target of miR-509-3p in melanoma. Together, our findings identified GPC6 as an early biomarker for melanoma metastatic progression, one that can be regulated by miR-509-3p.

Mir-22-3p is associated with many important biological processes, including neuroprotection, tumorigenesis, and various other tumor progressions. Our study aimed to investigate the roles of Mir-22-3p in chemosensitivity of gastrointestinal stromal tumor (GIST-T1) cells to cisplatin and explore its underlying mechanisms. Mir-22-3p high-expressing cell line was established by transfecting GIST-T1 cell line cells with Mir-22-3p mimic. After treatment with cisplatin (10 μM), Cell counting kits-8 (CCK-8) method was used to detect the cell viability. Flow cytometry was applied to measure the degree of cell apoptosis. Scratch wound healing test was used to detect the migration ability of cells. The protein and mRNA levels of the phosphatase and tensin homolog deleted on chromosome ten (PTEN)/phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway-related factors were analyzed by Western blot and qRT-PCR. The mRNA level of Mir-22-3p was increased in transfected GIST-T1 cells compared with that in control cells. The survival rate and Bcl-2/Bax ratio of GIST-T1 cells treated with both Mir-22-3p analogue and cisplatin were significantly decreased, while the apoptosis rate and protein level of caspase-3 were significantly increased (p

A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αβ T cells and suppress the expansion of innate-like αβ T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional αβ T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional αβ T cells.

The SWI/SNF complex plays an important role in mouse embryonic stem cells (mESCs), but it remains to be determined whether this complex is required for the pluripotency of human ESCs (hESCs). Using RNAi, we demonstrated that depletion of BRG1, the catalytic subunit of the SWI/SNF complex, led to impaired self-renewing ability and dysregulated lineage specification of hESCs. A unique composition of the BRG1-SWI/SNF complex in hESCs was further defined by the presence of BRG1, BAF250A, BAF170, BAF155, BAF53A, and BAF47. Genome-wide expression analyses revealed that BRG1 participated in a broad range of biological processes in hESCs through pathways different from those in mESCs. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that BRG1 played a repressive role in transcriptional regulation by modulating the acetylation levels of H3K27 at the enhancers of lineage-specific genes. Our data thus provide valuable insights into molecular mechanisms by which transcriptional repression affects the self-renewal and differentiation of hESCs.

Patients with Down syndrome (DS) are at risk for both obstructive sleep apnea (OSA) and central sleep apnea (CSA); however, it is unclear how these components evolve as patients age and whether patients are also at risk for hypoventilation. A retrospective review of 144 diagnostic polysomnograms (PSG) in a tertiary care facility over 10 years was conducted. Descriptive data and exploratory correlation analyses were performed. Sleep disordered breathing was common (seen in 78% of patients) with an average apnea-hypopnea index (AHI) = 10. The relative amount of obstructive apnea was positively correlated with age and body mass index (BMI). The relative amount of central sleep apnea was associated with younger age in the very youngest group (0–3 years). Hypoventilation was common occurring in more than 22% of patients and there was a positive correlation between the maximum CO2 and BMI. Sleep disordered breathing, including hypoventilation, was common in patients with DS. The obstructive component increased significantly with age and BMI, while the central component occurred most in the very young age group. Due to the high risk of hypoventilation, which has not been previously highlighted, it may be helpful to consider therapies to target both apnea and hypoventilation in this population.

Treatment of ethanethiol esters with triethylsilane and palladium on carbon at ambient temperature furnished aldehydes. In addition, a variety of ketones have been prepared by a palladium-catalyzed reaction of ethanethiol esters with organozinc reagents. Various functional groups, including esters, ketones, aromatic halides and aldehydes, tolerate both transformation reactions. These novel reactions can also be applied to the synthesis of alpha-amino aldehyde and alpha-amino ketone derivatives using the corresponding L-alpha-amino thiol esters without causing racemization.

Vezatin (VEZT), an adherens junctions transmembrane protein, was identified as a putative tumor suppressor in our previous study. However, the role of VEZT in tumorigenesis remains elusive. We aimed to clarify its epigenetic regulation and biological functions in gastric cancer. In this study, we show that the expression level of VEZT is involved in lymphatic metastasis, depth of cancer invasion and TNM stage in 104 gastric cancer patients. Bisulfate sequencing polymerase chain reaction (BSP) methods showed that VEZT was hypermethylated in tissues and corresponding blood of gastric cancer patients compared with healthy controls. Helicobacter pylori (H. pylori) infection induces the methylation and silencing of VEZT in GES-1 cells. Restoring VEZT expression in MKN-45 and NCI-N87 gastric cancer cells inhibited growth, invasion and tumorigenesis in vitro and in vivo. Global microarray analysis was applied to analyze the molecular basis of the biological functions of VEZT after VEZT transfection combined with real-time PCR and chromatin immunoprecipitation assay. G protein-coupled receptor 56(GPR56), cell growth, cell division cycle 42(CDC42), migration/invasion and transcription factor 19(TCF19), cell cycle progression, were identified as direct VEZT target genes. TCF19, a novel target of VEZT, was functionally validated. Overexpression of TCF19 in MKN-45 cells increased cell cycle progress and growth ability. This study provides novel insight into the regulation of the VEZT gene, which could represent a potential target for therapeutic anti-cancer strategies.

ChIP-Seq has become the standard method for genome-wide profiling DNA association of transcription factors. To simplify analyzing and interpreting ChIP-Seq data, which typically involves using multiple applications, we describe an integrated, open source, R-based analysis pipeline. The pipeline addresses data input, peak detection, sequence and motif analysis, visualization, and data export, and can readily be extended via other R and Bioconductor packages. Using a standard multicore computer, it can be used with datasets consisting of tens of thousands of enriched regions. We demonstrate its effectiveness on published human ChIP-Seq datasets for FOXA1, ER, CTCF and STAT1, where it detected co-occurring motifs that were consistent with the literature but not detected by other methods. Our pipeline provides the first complete set of Bioconductor tools for sequence and motif analysis of ChIP-Seq and ChIP-chip data.

Background: For gastric cancer with total gastrectomy, the usual laparoscopic surgical approaches are totally laparoscopic total gastrectomy (TLTG) and laparoscopic-assisted total gastrectomy (LATG). Due to its difficult anastomotic technique, the adoption of TLTG is limited. Therefore, surgeons prefer using LATG, which also led to TLTG being somewhat overlooked, so there is no clear conclusion today as to which surgical procedure is more favorable to the patient's recovery. This article aimed to compare the safety and short-term outcomes of the two surgical approaches. Materials and methods: Studies comparing TLTG and LATG, published up to December 2022, were searched in PubMed, Web of Science, and Embase databases. The study outcomes, including operative time, blood loss, anastomosis time, number of retrieved lymph nodes, proximal and distal resection margins, time to first fluid and soft diet, hospitalization duration, time to first flatus, and postsurgical and anastomotic complications, were compared between these two different surgical procedures. Statistics were analyzed with RevMan 5.4 and Stata 13.1. Results: Fifteen publications were included in this study. The total sample included 3023 cases. The meta-analysis revealed no significant difference in overall postoperative complications between the two surgical approaches (P>0.05). Compared with LATG, TLTG led to reduced intraoperative blood loss (P< 0.0001), an increased number of lymphatic node dissections (P<0.0001), and decreased hospitalization duration (P=0.002). However, operative time, anastomosis time, pulmonary infection, resection margins, time to first fluid and soft diet, time to first flatus and anastomosis-related complications were no significant difference between TLTG and LATG groups (P> 0.05). Conclusion: TLTG did not lead to an increase in overall postoperative complications, which is a reliable surgical approach for treatment of gastric cancer. Moreover, it may reduce harm to patients and enable them to obtain better surgical outcomes. [ABSTRACT FROM AUTHOR]