Cortical response tracking the conscious experience of threshold duration visual stimuli indicates visual perception is all or none

At perceptual threshold, some stimuli are available for conscious access whereas others are not. Such threshold inputs are useful tools for investigating the events that separate conscious awareness from unconscious stimulus processing. Here, viewing unmasked, threshold-duration images was combined with recording magnetoencephalography to quantify differences among perceptual states, ranging from no awareness to ambiguity to robust perception. A four-choice scale was used to assess awareness: “didn’t see” (no awareness), “couldn’t identify” (awareness without identification), “unsure” (awareness with low certainty identification), and “sure” (awareness with high certainty identification). Stimulus-evoked neuromagnetic signals were grouped according to behavioral response choices. Three main cortical responses were elicited. The earliest response, peaking at ∼100 ms after stimulus presentation, showed no significant correlation with stimulus perception. A late response (∼290 ms) showed moderate correlation with stimulus awareness but could not adequately differentiate conscious access from its absence. By contrast, an intermediate response peaking at ∼240 ms was observed only for trials in which stimuli were consciously detected. That this signal was similar for all conditions in which awareness was reported is consistent with the hypothesis that conscious visual access is relatively sharply demarcated.     

Comprehensive analysis of prognostic immune-related genes in the tumor microenvironment of hepatocellular carcinoma (HCC)

Growing evidence supports that the tumor microenvironment plays a key role in the development and progression of tumors. But immune microenvironment of hepatocellular carcinoma (HCC) has not yet been fully explored. In the present investigation, the clinical value and prognostic significance of immune-related genes in HCC were investigated.The immune and stromal scores of HCC were calculated through the application of Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data Algorithm based on the Cancer Genome Atlas database. Differentially expressed genes were identified using the “edgeR” package of the R software. Functional annotation and pathway enrichment were performed using “ggplots2” and “clusterProfiler” packages in R software. Protein-protein interaction network was constructed using STRING, and the hub genes were identified through the Cytoscape. Survival analysis was performed using Kaplan-Meier methods. Tumor Immune Estimation Resource algorithm was used to view the immune landscape of the microenvironment in HCC.Firstly, the immune and stromal scores of HCC were calculated and we found that the immune and stromal scores of HCC were closely related to the patients’ prognosis. Then the differentially expressed genes were identified respectively stratified by the median value of the immune and stromal scores, and the immune-related genes that related to the prognosis in HCC patients were further identified. Functional enrichment analysis and protein-protein interaction networks further showed that these genes mainly participated in immune-related biological process. In addition, dendritic cells were found to be the most abundant in the microenvironment of HCC through Tumor Immune Estimation Resource algorithm and were significantly associated with the patients’ prognosis. To robust the results, the immune-related genes were validated in an independent dataset from the Gene Expression Omnibus database.We arrived at a more comprehensive understanding of the microenvironment of HCC and extracted 7 immune-related genes that were significantly associated with the recurrence survival of HCC.     

Kissing and nanotunneling mediate intermitochondrial communication in the heart

Mitochondria in many types of cells are dynamically interconnected through constant fusion and fission, allowing for exchange of mitochondrial contents and repair of damaged mitochondria. However, constrained by the myofibril lattice, the ∼6,000 mitochondria in the adult mammalian cardiomyocyte display little motility, and it is unclear how, if at all, they communicate with each other. By means of target-expressing photoactivatable green fluorescent protein (PAGFP) in the mitochondrial matrix or on the outer mitochondrial membrane, we demonstrated that the local PAGFP signal propagated over the entire population of mitochondria in cardiomyocytes on a time scale of ∼10 h. Two elemental steps of intermitochondrial communications were manifested as either a sudden PAGFP transfer between a pair of adjacent mitochondria (i.e., “kissing”) or a dynamic nanotubular tunnel (i.e., “nanotunneling”) between nonadjacent mitochondria. The average content transfer index (fractional exchange) was around 0.5; the rate of kissing was 1‰ s⁻¹ per mitochondrial pair, and that of nanotunneling was about 14 times smaller. Electron microscopy revealed extensive intimate contacts between adjacent mitochondria and elongated nanotubular protrusions, providing a structural basis for the kissing and nanotunneling, respectively. We propose that, through kissing and nanotunneling, the otherwise static mitochondria in a cardiomyocyte form one dynamically continuous network to share content and transfer signals.     

Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. The pathophysiology of FSHD is unknown and, as a result, there is currently no effective treatment available for this disease. To better understand the pathophysiology of FSHD and develop mRNA-based biomarkers of affected muscles, we compared global analysis of gene expression in two distinct muscles obtained from a large number of FSHD subjects and their unaffected first-degree relatives. Gene expression in two muscle types was analyzed using GeneChip Gene 1.0 ST arrays: biceps, which typically shows an early and severe disease involvement; and deltoid, which is relatively uninvolved. For both muscle types, the expression differences were mild: using relaxed cutoffs for differential expression (fold change ≥1.2; nominal P value <0.01), we identified 191 and 110 genes differentially expressed between affected and control samples of biceps and deltoid muscle tissues, respectively, with 29 genes in common. Controlling for a false-discovery rate of <0.25 reduced the number of differentially expressed genes in biceps to 188 and in deltoid to 7. Expression levels of 15 genes altered in this study were used as a “molecular signature” in a validation study of an additional 26 subjects and predicted them as FSHD or control with 90% accuracy based on biceps and 80% accuracy based on deltoids.     

Genetic and archaeological perspectives on the initial modern human colonization of southern Asia

It has been argued recently that the initial dispersal of anatomically modern humans from Africa to southern Asia occurred before the volcanic “supereruption” of the Mount Toba volcano (Sumatra) at ∼74,000 y before present (B.P.)—possibly as early as 120,000 y B.P. We show here that this “pre-Toba” dispersal model is in serious conflict with both the most recent genetic evidence from both Africa and Asia and the archaeological evidence from South Asian sites. We present an alternative model based on a combination of genetic analyses and recent archaeological evidence from South Asia and Africa. These data support a coastally oriented dispersal of modern humans from eastern Africa to southern Asia ∼60–50 thousand years ago (ka). This was associated with distinctively African microlithic and “backed-segment” technologies analogous to the African “Howiesons Poort” and related technologies, together with a range of distinctively “modern” cultural and symbolic features (highly shaped bone tools, personal ornaments, abstract artistic motifs, microblade technology, etc.), similar to those that accompanied the replacement of “archaic” Neanderthal by anatomically modern human populations in other regions of western Eurasia at a broadly similar date.     

Small open reading frames associated with morphogenesis are hidden in plant genomes

It is likely that many small ORFs (sORFs; 30–100 amino acids) are missed when genomes are annotated. To overcome this limitation, we identified ∼8,000 sORFs with high coding potential in intergenic regions of the Arabidopsis thaliana genome. However, the question remains as to whether these coding sORFs play functional roles. Using a designed array, we generated an expression atlas for 16 organs and 17 environmental conditions among 7,901 identified coding sORFs. A total of 2,099 coding sORFs were highly expressed under at least one experimental condition, and 571 were significantly conserved in other land plants. A total of 473 coding sORFs were overexpressed; ∼10% (49/473) induced visible phenotypic effects, a proportion that is approximately seven times higher than that of randomly chosen known genes. These results indicate that many coding sORFs hidden in plant genomes are associated with morphogenesis. We believe that the expression atlas will contribute to further study of the roles of sORFs in plants.     

Polar front shift and atmospheric CO2 during the glacial maximum of the Early Paleozoic Icehouse

Our new data address the paradox of Late Ordovician glaciation under supposedly high pCO₂ (8 to 22× PAL: preindustrial atmospheric level). The paleobiogeographical distribution of chitinozoan (“mixed layer”) marine zooplankton biotopes for the Hirnantian glacial maximum (440 Ma) are reconstructed and compared to those from the Sandbian (460 Ma): They demonstrate a steeper latitudinal temperature gradient and an equatorwards shift of the Polar Front through time from 55°–70° S to ∼40° S. These changes are comparable to those during Pleistocene interglacial-glacial cycles. In comparison with the Pleistocene, we hypothesize a significant decline in mean global temperature from the Sandbian to Hirnantian, proportional with a fall in pCO₂ from a modeled Sandbian level of ∼8× PAL to ∼5× PAL during the Hirnantian. Our data suggest that a compression of midlatitudinal biotopes and ecospace in response to the developing glaciation was a likely cause of the end-Ordovician mass extinction.     

Differential expression of transfer RNA-derived small RNAs in IgA nephropathy

Background:IgA nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. Recent studies have indicated that small noncoding RNAs, such as tRNA-derived small RNAs (tsRNAs), might be novel biomarkers for glomerulonephritis. We therefore investigated the potential roles and possible functions of the tsRNAs in IgAN.Method:Peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of the patients with IgAN and healthy control groups. The expression profiles of tsRNAs were assessed by small RNA sequencing (RNA-Seq) in PBMCs of the IgAN and control groups. Dysregulated tsRNAs were selected for validation by quantitative real-time polymerase chain reaction (qRT-PCR). Target gene prediction and enrichment were performed by bioinformatics analysis.Results:The results revealed that 143 significantly upregulated and 202 significantly downregulated tsRNAs were differentially altered in the IgAN group compared with the control group. Five upregulated tsRNAs (tRF-Val-AAC-007, tRF-Ala-AGC-063, tRF-Gln-CTG-010, tRF-Tyr-GTA-011 and tRF-Thr-AGT-007) and 3 downregulated tsRNAs (tiRNA-Val-TAC-004, tRF-Gly-CCC-005 and tRF-His-GTG-006) were selected for validation by qRT-PCR; the results were consistent with the sequencing data. Gene Ontology (GO) analysis revealed that the target genes predicted by upregulated tsRNAs were mostly enriched in “nucleic acid metabolic process," “intracellular part," and “ion binding," whereas the target genes predicted by downregulated tsRNAs were mostly enriched in “regulation of cellular component organization," “membrane-bound organelle," and “ion binding." Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes predicted by upregulated tsRNAs were mostly enriched in “herpes simplex virus 1 infection," whereas the target genes predicted by downregulated tsRNAs were mostly enriched in “circadian rhythmConclusions:The present study confirmed the differential expression of tsRNAs in patients with IgAN, and these dysregulated tsRNAs might be novel potential targets for the diagnosis and treatment of IgAN.     

Space can substitute for time in predicting climate-change effects on biodiversity

“Space-for-time” substitution is widely used in biodiversity modeling to infer past or future trajectories of ecological systems from contemporary spatial patterns. However, the foundational assumption—that drivers of spatial gradients of species composition also drive temporal changes in diversity—rarely is tested. Here, we empirically test the space-for-time assumption by constructing orthogonal datasets of compositional turnover of plant taxa and climatic dissimilarity through time and across space from Late Quaternary pollen records in eastern North America, then modeling climate-driven compositional turnover. Predictions relying on space-for-time substitution were ∼72% as accurate as “time-for-time” predictions. However, space-for-time substitution performed poorly during the Holocene when temporal variation in climate was small relative to spatial variation and required subsampling to match the extent of spatial and temporal climatic gradients. Despite this caution, our results generally support the judicious use of space-for-time substitution in modeling community responses to climate change.     

Regulative recovery in the sea urchin embryo and the stabilizing role of fail-safe gene network wiring

Design features that ensure reproducible and invariant embryonic processes are major characteristics of current gene regulatory network models. New cis-regulatory studies on a gene regulatory network subcircuit activated early in the development of the sea urchin embryo reveal a sequence of encoded “fail-safe” regulatory devices. These ensure the maintenance of fate separation between skeletogenic and nonskeletogenic mesoderm lineages. An unexpected consequence of the network design revealed in the course of these experiments is that it enables the embryo to “recover” from regulatory interference that has catastrophic effects if this feature is disarmed. A reengineered regulatory system inserted into the embryo was used to prove how this system operates in vivo. Genomically encoded backup control circuitry thus provides the mechanism underlying a specific example of the regulative development for which the sea urchin embryo has long been famous.     

Adaptation to herbivory by the Tammar wallaby includes bacterial and glycoside hydrolase profiles different from other herbivores

Metagenomic and bioinformatic approaches were used to characterize plant biomass conversion within the foregut microbiome of Australia''s “model” marsupial, the Tammar wallaby (Macropus eugenii). Like the termite hindgut and bovine rumen, key enzymes and modular structures characteristic of the “free enzyme” and “cellulosome” paradigms of cellulose solubilization remain either poorly represented or elusive to capture by shotgun sequencing methods. Instead, multigene polysaccharide utilization loci-like systems coupled with genes encoding β-1,4-endoglucanases and β-1,4-endoxylanases—which have not been previously encountered in metagenomic datasets—were identified, as were a diverse set of glycoside hydrolases targeting noncellulosic polysaccharides. Furthermore, both rrs gene and other phylogenetic analyses confirmed that unique clades of the Lachnospiraceae, Bacteroidales, and Gammaproteobacteria are predominant in the Tammar foregut microbiome. Nucleotide composition-based sequence binning facilitated the assemblage of more than two megabase pairs of genomic sequence for one of the novel Lachnospiraceae clades (WG-2). These analyses show that WG-2 possesses numerous glycoside hydrolases targeting noncellulosic polysaccharides. These collective data demonstrate that Australian macropods not only harbor unique bacterial lineages underpinning plant biomass conversion, but their repertoire of glycoside hydrolases is distinct from those of the microbiomes of higher termites and the bovine rumen.     

Sensitivity of the Predictive Hypoglycemia Minimizer System to the Algorithm Aggressiveness Factor

Background:

The Predictive Hypoglycemia Minimizer System (“Hypo Minimizer”), consisting of a zone model predictive controller (the “controller”) and a safety supervision module (the “safety module”), aims to mitigate hypoglycemia by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The “aggressiveness factor,” a pivotal variable in the system, governs the speed and magnitude of the controller’s insulin dosing characteristics in response to changes in CGM levels.

Methods:

Twelve adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 24 hours. This analysis focused primarily on the effect of the aggressiveness factor on the automated insulin-delivery characteristics of the controller, and secondarily on the glucose control results.

Results:

As aggressiveness increased from “conservative” to “medium” to “aggressive,” the controller recommended less insulin (–3.3% vs –14.4% vs –19.5% relative to basal) with a higher frequency (5.3% vs 14.4% vs 20.3%) during the critical times when the CGM was reading 90-120 mg/dl and decreasing. Blood glucose analyses indicated that the most aggressive setting resulted in the most desirable combination of the least time spent <70 mg/dl and the most time spent 70-180 mg/dl, particularly in the overnight period. Hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia did not occur with any of the aggressiveness values.

Conclusion:

The Hypo Minimizer’s controller took preemptive action to prevent hypoglycemia based on predicted changes in CGM glucose levels. The most aggressive setting was quickest to take action to reduce insulin delivery below basal and achieved the best glucose metrics.     

Liver retraction using n-butyl-2-cyanoacrylate glue during laparoscopic cholecystectomy

There might be a thick “protrusion” in the visceral surface of hepatic quadrate lobe during the laparoscopic cholecystectomy (LC), which affects the surgical fields and consequently triggers high risks of biliary tract injury. Although n-butyl-2-cyanoacrylate (NBCA) glue has been applied to laparoscopic upper abdominal surgery for liver retraction, there is still no consensus on its safety and feasibility in LC. In this study, we investigated the safety, feasibility, and effectiveness of liver retraction using NBCA glue for these patients which have the thick “protrusion” on the square leaf surface of the liver during LC.Fifty-seven patients presenting thick “protrusion” hepatic quadrate lobe were included in our retrospective study. We performed LC in the presence of NBCA glue (n = 30, NBCA group) and absence of NBCA glue (n = 27, non-NBCA group), respectively. NBCA was used to fix the thick “protrusion” of the liver leaves to the hepatic viscera surface, which contributed to the revelation of the gallbladder triangle. The operation time, blood loss, postoperative hospitalization, and liver function were compared between the 2 groups.Both the groups’ patients accomplished the operation in the laparoscopy. There was no mortality and no additional incision during operation. No severe complications including bile duct injury were available after surgery and no postoperative NBCA-related complications occurred after 9- to 30 months’ follow-up. The time of operation in NBCA group showed significant decrease compared with that of non-NBCA group (48.33 ± 16.15 vs 65.00 ± 22.15 minutes, P < .01). There were no significant differences in blood loss, postoperative hospital stays, and the preoperative and postoperative liver function between the two groups (P > .05). Besides, no significant differences were noticed in major clinical characteristics between the 2 groups (P > .05).Liver retraction using NBCA during LC for thick “protrusion” hepatic quadrate lobe patients is safe, effective, and feasible.