Sea-surface temperature pattern effects have slowed global warming and biased warming-based constraints on climate sensitivity.

The observed rate of global warming since the 1970s has been proposed as a strong constraint on equilibrium climate sensitivity (ECS) and transient climate response (TCR)-key metrics of the global climate response to greenhouse-gas forcing. Using CMIP5/6 models, we show that the inter-model relationship between warming and these climate sensitivity metrics (the basis for the constraint) arises from a similarity in transient and equilibrium warming patterns within the models, producing an effective climate sensitivity (EffCS) governing recent warming that is comparable to the value of ECS governing long-term warming under CO[Formula: see text] forcing. However, CMIP5/6 historical simulations do not reproduce observed warming patterns. When driven by observed patterns, even high ECS models produce low EffCS values consistent with the observed global warming rate. The inability of CMIP5/6 models to reproduce observed warming patterns thus results in a bias in the modeled relationship between recent global warming and climate sensitivity. Correcting for this bias means that observed warming is consistent with wide ranges of ECS and TCR extending to higher values than previously recognized. These findings are corroborated by energy balance model simulations and coupled model (CESM1-CAM5) simulations that better replicate observed patterns via tropospheric wind nudging or Antarctic meltwater fluxes. Because CMIP5/6 models fail to simulate observed warming patterns, proposed warming-based constraints on ECS, TCR, and projected global warming are biased low. The results reinforce recent findings that the unique pattern of observed warming has slowed global-mean warming over recent decades and that how the pattern will evolve in the future represents a major source of uncertainty in climate projections.

Familiarity enhances functional connectivity between visual and nonvisual regions of the brain during natural viewing.

We explored the neural correlates of familiarity with people and places using a naturalistic viewing paradigm. Neural responses were measured using functional magnetic resonance imaging, while participants viewed a movie taken from Game of Thrones. We compared inter-subject correlations and functional connectivity in participants who were either familiar or unfamiliar with the TV series. Higher inter-subject correlations were found between familiar participants in regions, beyond the visual brain, that are typically associated with the processing of semantic, episodic, and affective information. However, familiarity also increased functional connectivity between face and scene regions in the visual brain and the nonvisual regions of the familiarity network. To determine whether these regions play an important role in face recognition, we measured responses in participants with developmental prosopagnosia (DP). Consistent with a deficit in face recognition, the effect of familiarity was significantly attenuated across the familiarity network in DP. The effect of familiarity on functional connectivity between face regions and the familiarity network was also attenuated in DP. These results show that the neural response to familiarity involves an extended network of brain regions and that functional connectivity between visual and nonvisual regions of the brain plays an important role in the recognition of people and places during natural viewing.

Mapping the functional and structural connectivity of the scene network.

The recognition and perception of places has been linked to a network of scene-selective regions in the human brain. While previous studies have focussed on functional connectivity between scene-selective regions themselves, less is known about their connectivity with other cortical and subcortical regions in the brain. Here, we determine the functional and structural connectivity profile of the scene network. We used fMRI to examine functional connectivity between scene regions and across the whole brain during rest and movie-watching. Connectivity within the scene network revealed a bias between posterior and anterior scene regions implicated in perceptual and mnemonic aspects of scene perception respectively. Differences between posterior and anterior scene regions were also evident in the connectivity with cortical and subcortical regions across the brain. For example, the Occipital Place Area (OPA) and posterior Parahippocampal Place Area (PPA) showed greater connectivity with visual and dorsal attention networks, while anterior PPA and Retrosplenial Complex showed preferential connectivity with default mode and frontoparietal control networks and the hippocampus. We further measured the structural connectivity of the scene network using diffusion tractography. This indicated both similarities and differences with the functional connectivity, highlighting biases between posterior and anterior regions, but also between ventral and dorsal scene regions. Finally, we quantified the structural connectivity between the scene network and major white matter tracts throughout the brain. These findings provide a map of the functional and structural connectivity of scene-selective regions to each other and the rest of the brain.

Substratifying the risk of covert malignancy in significant rectal polyps: Outcomes from a specialist multidisciplinary team (MDT).

AIM: A treatment strategy for patients with a significant polyp or early colon cancer (SPECC) of the rectum presents a challenge due to the significant rate of covert malignancy and lack of standardized assessment. For this reason, NICE recommends multidisciplinary meetings to improve outcomes. The primary aim of the present study was to report the performance of our specialist early rectal cancer (SERC) multidisciplinary team (MDT) in correctly substratifying the risk of cancer and to discuss the limitations of staging investigations in those patients with "poor outcomes". METHOD: This was a retrospective review of patients referred to our SERC MDT from 2014 to 2019. Lesions were assigned by the MDT to three pre-resection categories (low, intermediate, high) according to the risk of covert malignancy. Resection method and final histology were compared to the pre-resection categories. RESULTS: Of 350 SPECC lesions, 174 were assessed as low-risk, 108 intermediate-risk and 68 high-risk. The cancer incidence was 4.8%, 8.3% and 53%, respectively (15.5% overall). Eight lesions were categorized as low-risk but following piecemeal resection were found to be malignant. Five lesions, three of which were categorized as high-risk, were ultimately benign following conventional surgery. One pT1sm1 cancer, removed by anterior resection, may have been treated by local excision. CONCLUSION: A total of 83% of malignant polyps were triaged to an en bloc resection technique and surgical resection avoided for nearly all benign lesions. However, 12 patients from this cohort were deemed to have a poor outcome because of miscategorization. Further comparative research is needed to establish the optimum strategy for rectal SPECC lesion assessment. ORIGINALITY STATEMENT: There is currently no consensus for staging significant polyps of the rectum. This paper reports the effectiveness of a specialist early rectal cancer MDT to correctly risk-stratify significant rectal polyps. It underscores the importance of accurate categorization for treatment decision-making, while acknowledging the limitations of current staging modalities.

No evidence for an other-race effect in dominance and trustworthy judgements from faces.

A variety of evidence shows that social categorization of people based on their race can lead to stereotypical judgements and prejudicial behaviour. Here, we explore the extent to which trait judgements of faces are influenced by race. To address this issue, we measured the reliability of first impressions for own-race and other-race faces in Asian and White participants. Participants viewed pairs of faces and were asked to indicate which of the two faces was more dominant or which of the two faces was more trustworthy. We measured the consistency (or reliability) of these judgements across participants for own-race and other-races faces. We found that judgements of dominance or trustworthiness showed similar levels of reliability for own-race and other-race faces. Moreover, an item analysis showed that the judgements on individual trials were very similar across participants from different races. Next, participants made overall ratings of dominance and trustworthiness from own-race and other-race faces. Again, we found that there was no evidence for an ORE. Together, these results provide a new approach to measuring trait judgements of faces and show that in these conditions there is no ORE for the perception of dominance and trustworthiness.

Connectopic mapping techniques do not reflect functional gradients in the brain.

Functional gradients, in which response properties change gradually across a brain region, have been proposed as a key organising principle of the brain. Recent studies using both resting-state and natural viewing paradigms have indicated that these gradients may be reconstructed from functional connectivity patterns via "connectopic mapping" analyses. However, local connectivity patterns may be confounded by spatial autocorrelations artificially introduced during data analysis, for instance by spatial smoothing or interpolation between coordinate spaces. Here, we investigate whether such confounds can produce illusory connectopic gradients. We generated datasets comprising random white noise in subjects' functional volume spaces, then optionally applied spatial smoothing and/or interpolated the data to a different volume or surface space. Both smoothing and interpolation induced spatial autocorrelations sufficient for connectopic mapping to produce both volume- and surface-based local gradients in numerous brain regions. Furthermore, these gradients appeared highly similar to those obtained from real natural viewing data, although gradients generated from real and random data were statistically different in certain scenarios. We also reconstructed global gradients across the whole-brain - while these appeared less susceptible to artificial spatial autocorrelations, the ability to reproduce previously reported gradients was closely linked to specific features of the analysis pipeline. These results indicate that previously reported gradients identified by connectopic mapping techniques may be confounded by artificial spatial autocorrelations introduced during the analysis, and in some cases may reproduce poorly across different analysis pipelines. These findings imply that connectopic gradients need to be interpreted with caution.

The representation of shape and texture in category-selective regions of ventral-temporal cortex.

Neuroimaging studies using univariate and multivariate approaches have shown that the fusiform face area (FFA) and parahippocampal place area (PPA) respond selectively to images of faces and places. The aim of this study was to determine the extent to which this selectivity to faces or places is based on the shape or texture properties of the images. Faces and houses were filtered to manipulate their texture properties, while preserving the shape properties (spatial envelope) of the images. In Experiment 1, multivariate pattern analysis (MVPA) showed that patterns of fMRI response to faces and houses in FFA and PPA were predicted by the shape properties, but not by the texture properties of the image. In Experiment 2, a univariate analysis (fMR-adaptation) showed that responses in the FFA and PPA were sensitive to changes in both the shape and texture properties of the image. These findings can be explained by the spatial scale of the representation of images in the FFA and PPA. At a coarser scale (revealed by MVPA), the neural selectivity to faces and houses is sensitive to variation in the shape properties of the image. However, at a finer scale (revealed by fMR-adaptation), the neural selectivity is sensitive to the texture properties of the image. By combining these neuroimaging paradigms, our results provide insights into the spatial scale of the neural representation of faces and places in the ventral-temporal cortex.

Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration.

BACKGROUND AND AIMS: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration. APPROACH AND RESULTS: Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients. CONCLUSIONS: Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.

Long-term outcomes of patients with poor prognostic factors following transanal endoscopic microsurgery for early rectal cancer.

AIM: Management of early rectal cancer following transanal microscopic anal surgery poses a management dilemma when the histopathology reveals poor prognostic features, due to high risk of local recurrence. The aim of this study is to evaluate the oncological outcomes of such patients who undergo surgery with total mesorectal excision (TME), receive adjuvant chemo/radiotherapy (CRDT/RT) or receive close surveillance only (no further treatment). METHODS: We identified patients with poor prognostic factors-pT2 adenocarcinoma, poor differentiation, deep submucosal invasion (Kikuchi SM3), lymphovascular invasion, tumour budding or R1 resection margin-between 1 September 2012 and 31 January 2020 and report their oncological outcomes. RESULTS: Of the 53 patients, 18 had TME, 14 had CRDT and 14 had RT; seven patients did not have any further treatment. The median follow-up was 48 months, 12 developed recurrence and six died. Overall, 5-year survival (OS) was 88.9% and disease-free survival (DFS) was 79.2%. Compared to the surgical group, in which there were eight recurrences and two deaths, there were zero recurrences or deaths in the CRDT group, log-rank test P = 0.206 for OS and P = 0.005 for DFS. The 5-year survival rates in the RT and surveillance only groups were OS 78.6%, DFS 85.7% and OS 71.5%, DFS 71% respectively. TME assessment in the surgical group revealed Grade 3 quality in seven of the 16 available reports. CONCLUSION: These findings support the strategy of adjuvant CRDT as first line treatment for patients undergoing transanal endoscopic microsurgery for early rectal cancer with poor prognostic factors on initial histological assessment.

Long-term outcomes of open versus closed rectal defect after transanal endoscopic microscopic surgery.

AIM: Management of the rectal defect after transanal endoscopic microsurgery (TEM) is a matter of debate. Data are lacking on long term outcomes and continence of patients with open or closed rectal defect. We sought to analyse these in a retrospective cohort study. METHODS: Patients undergoing TEM via the Specialist Early Rectal Cancer (SERC) MDT between 2012 and 2019 were included from a prospectively maintained database. These were divided into two groups - open and closed, based on management of rectal defect. Patient demographics and outcomes, including pre- and postoperative oncological staging, morbidity, mortality, length of stay and faecal incontinence severity score (FISI) scores were assessed. RESULTS: A total of 170 matched patients were included (70-open, 100-closed rectal defects). Short-term complications (bleeding, infection, urinary retention and infection, length of stay and pain) were 18.8% with no significant difference between the two groups (22% vs. 16%). Most of the defects were well healed upon endoscopic follow-up; more unhealed/sinus formation was noticed in the open group (p = 0.01); more strictures were encountered in the closed group (p = 0.04). Comparing the open and closed defect groups, there was no difference in the functional outcome of patients in those who developed sinus (p = 0.87) or stricture (p = 0.79) but a significant difference in post-TEMS FISI scores in those with healed scar, with those in closed rectal defect group with worsening function (p = 0.02). CONCLUSION: There are pros and cons associated with both rectal defect management approaches. Long-term complications should be expected and actively followed up. Patients should be thoroughly counselled about these and possible deterioration in continence post-TEM.

Symmetrical Viewpoint Representations in Face-Selective Regions Convey an Advantage in the Perception and Recognition of Faces.

Learning new identities is crucial for effective social interaction. A critical aspect of this process is the integration of different images from the same face into a view-invariant representation that can be used for recognition. The representation of symmetrical viewpoints has been proposed to be a key computational step in achieving view-invariance. The aim of this study was to determine whether the representation of symmetrical viewpoints in face-selective regions is directly linked to the perception and recognition of face identity. In Experiment 1, we measured fMRI responses while male and female human participants viewed images of real faces from different viewpoints (-90, -45, 0, 45, and 90° from full-face view). Within the face regions, patterns of neural response to symmetrical views (-45 and 45° or -90 and 90°) were more similar than responses to nonsymmetrical views in the fusiform face area and superior temporal sulcus, but not in the occipital face area. In Experiment 2, participants made perceptual similarity judgements to pairs of face images. Images with symmetrical viewpoints were reported as being more similar than nonsymmetric views. In Experiment 3, we asked whether symmetrical views also convey an advantage when learning new faces. We found that recognition was best when participants were tested with novel face images that were symmetrical to the learning viewpoint. Critically, the pattern of perceptual similarity and recognition across different viewpoints predicted the pattern of neural response in face-selective regions. Together, our results provide support for the functional value of symmetry as an intermediate step in generating view-invariant representations.SIGNIFICANCE STATEMENT The recognition of identity from faces is crucial for successful social interactions. A critical step in this process is the integration of different views into a unified, view-invariant representation. The representation of symmetrical views (e.g., left profile and right profile) has been proposed as an important intermediate step in computing view-invariant representations. We found view symmetric representations were specific to some face-selective regions, but not others. We also show that these neural representations influence the perception of faces. Symmetric views were perceived to be more similar and were recognized more accurately than nonsymmetric views. Moreover, the perception and recognition of faces at different viewpoints predicted patterns of response in those face regions with view symmetric representations.

Neural Correlates of Group Bias During Natural Viewing.

Individuals from different social groups interpret the world in different ways. This study explores the neural basis of these group differences using a paradigm that simulates natural viewing conditions. Our aim was to determine if group differences could be found in sensory regions involved in the perception of the world or were evident in higher-level regions that are important for the interpretation of sensory information. We measured brain responses from 2 groups of football supporters, while they watched a video of matches between their teams. The time-course of response was then compared between individuals supporting the same (within-group) or the different (between-group) team. We found high intersubject correlations in low-level and high-level regions of the visual brain. However, these regions of the brain did not show any group differences. Regions that showed higher correlations for individuals from the same group were found in a network of frontal and subcortical brain regions. The interplay between these regions suggests a range of cognitive processes from motor control to social cognition and reward are important in the establishment of social groups. These results suggest that group differences are primarily reflected in regions involved in the evaluation and interpretation of the sensory input.

Selectivity for mid-level properties of faces and places in the fusiform face area and parahippocampal place area.

Regions in the ventral visual pathway, such as the fusiform face area (FFA) and parahippocampal place area (PPA) are selective for images from specific object categories. Yet images from different object categories differ in their image properties. To investigate how these image properties are represented in the FFA and PPA, we compared neural responses to locally-SCRAMBLED images (in which mid-level, spatial properties are preserved) and globally-SCRAMBLED images (in which mid-level, spatial properties are not preserved). There was a greater response in the FFA and PPA to images from the preferred CATEGORY relative to their non-preferred category for the scrambled conditions. However, there was a greater selectivity for locally-scrambled compared to globally-scrambled images. Next, we compared the magnitude of fMR-adaptation to intact and scrambled images. fMR-adaptation was evident to locally-scrambled images from the preferred category. However, there was no adaptation to globally-scrambled images from the preferred category. These results show that the selectivity to faces and places in the FFA and PPA is dependent on mid-level properties of the image that are preserved by local-scrambling.

A data-driven approach to stimulus selection reveals an image-based representation of objects in high-level visual areas.

The ventral visual pathway is directly involved in the perception and recognition of objects. However, the extent to which the neural representation of objects in this region reflects low-level or high-level properties remains unresolved. A problem in resolving this issue is that only a small proportion of the objects experienced during natural viewing can be shown during a typical experiment. This can lead to an uneven sampling of objects that biases our understanding of how they are represented. To address this issue, we developed a data-driven approach to stimulus selection that involved describing a large number objects in terms of their image properties. In the first experiment, clusters of objects were evenly selected from this multi-dimensional image space. Although the clusters did not have any consistent semantic features, each elicited a distinct pattern of neural response. In the second experiment, we asked whether high-level, category-selective patterns of response could be elicited by objects from other categories, but with similar image properties. Object clusters were selected based on the similarity of their image properties to objects from five different categories (bottle, chair, face, house, and shoe). The pattern of response to each metameric object cluster was similar to the pattern elicited by objects from the corresponding category. For example, the pattern for bottles was similar to the pattern for objects with similar image properties to bottles. In both experiments, the patterns of response were consistent across participants providing evidence for common organising principles. This study provides a more ecological approach to understanding the perceptual representations of objects and reveals the importance of image properties.

Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability.

Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean. These links are extensive, influencing a range of climate processes such as hurricane activity and African Sahel and Amazonian droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures, but climate models have so far failed to reproduce these interactions and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860-2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910-1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol-cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol-cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions.

UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis.

The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ∼70% of PDAC cases. Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels. UHRF1 expression was observed in 20% (5 of 25) of benign pancreatic ducts compared to 86% (114 of 132) of pancreatic tumours, and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours (n = 124) was apparent (p = 0.002). We also provide evidence that UHRF1-mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC. Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest. UHRF1 depletion also led to reduced levels of Nrf2-regulated downstream proteins and was accompanied by heightened oxidative stress, in the form of lower glutathione levels and increased reactive oxygen species. Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species. Mechanistically, depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines, and KEAP1 gene promoter methylation was reduced in one of three cell lines examined. Thus, methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1, although our data suggest that additional mechanisms need to be explored. Finally, we demonstrate that K-Ras drives UHRF1 expression, establishing a novel link between this oncogene and Nrf2-mediated cellular protection. Since UHRF1 over-expression occurs in other cancers, its ability to regulate the Keap1-Nrf2 pathway may be critically important to the malignant behaviour of these cancers.

Distinct but Overlapping Patterns of Response to Words and Faces in the Fusiform Gyrus.

Converging evidence suggests that the fusiform gyrus is involved in the processing of both faces and words. We used fMRI to investigate the extent to which the representation of words and faces in this region of the brain is based on a common neural representation. In Experiment 1, a univariate analysis revealed regions in the fusiform gyrus that were only selective for faces and other regions that were only selective for words. However, we also found regions that showed both word-selective and face-selective responses, particularly in the left hemisphere. We then used a multivariate analysis to measure the pattern of response to faces and words. Despite the overlap in regional responses, we found distinct patterns of response to both faces and words in the left and right fusiform gyrus. In Experiment 2, fMR adaptation was used to determine whether information about familiar faces and names is integrated in the fusiform gyrus. Distinct regions of the fusiform gyrus showed adaptation to either familiar faces or familiar names. However, there was no adaptation to sequences of faces and names with the same identity. Taken together, these results provide evidence for distinct, but overlapping, neural representations for words and faces in the fusiform gyrus.