Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion

SummaryGlutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer patients. Treatment of a tumor-derived cell line with NMDAR antagonists impaired cancer cell proliferation and invasion. Flow conditions mimicking interstitial fluid pressure induced autologous glutamate secretion, activating NMDAR and its downstream MEK-MAPK and CaMK effectors, thereby promoting invasiveness. Congruently, pharmacological inhibition of NMDAR in mice with PNET reduced tumor growth and invasiveness. Therefore, beyond its traditional role in neurons, NMDAR may be activated in human tumors by fluid flow consequent to higher interstitial pressure, inducing an autocrine glutamate signaling circuit with resultant stimulation of malignancy

Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells.

N-Methyl-d-aspartate receptor (NMDAR) activation is implicated in the malignant progression of many cancer types, as previously shown by the growth-inhibitory effects of NMDAR antagonists. NMDAR-mediated calcium influx and its downstream signalling depend critically, however, on the dynamics of membrane potential and ambient glutamate concentration, which are poorly characterized in cancer cells. Here, we have used low-noise whole-cell patch-clamp recording to investigate the electrophysiology of glutamate signalling in pancreatic neuroendocrine tumour (PanNET) cells derived from a genetically-engineered mouse model (GEMM) of PanNET, in which NMDAR signalling is known to promote cancer progression. Activating NMDARs caused excitation and intracellular calcium elevation, and intracellular perfusion with physiological levels of glutamate led to VGLUT-dependent autocrine NMDAR activation. Necrotic cells, which are often present in rapidly-growing tumours, were shown to release endogenous cytoplasmic glutamate, and necrosis induced by mechanical rupture of the plasma membrane produced intense NMDAR activation in nearby cells. Computational modelling, based on these results, predicts that NMDARs in cancer cells can be strongly activated in the tumour microenvironment by both autocrine glutamate release and necrosis

A User-Friendly Protocol for Mandibular Segmentation of CBCT Images for Superimposition and Internal Structure Analysis

Background: Since cone-beam computed tomography (CBCT) technology has been widely adopted in orthodontics, multiple attempts have been made to devise techniques for mandibular segmentation and 3D superimposition. Unfortunately, as the software utilized in these methods are not specifically designed for orthodontics, complex procedures are often necessary to analyze each case. Thus, this study aimed to establish an orthodontist-friendly protocol for segmenting the mandible from CBCT images that maintains access to the internal anatomic structures. Methods: The “sculpting tool” in the Dolphin 3D Imaging software was used for segmentation. The segmented mandible images were saved as STL files for volume matching in the 3D Slicer to validate the repeatability of the current protocol and were exported as DICOM files for internal structure analysis and voxel-based superimposition. Results: The mandibles of all tested CBCT datasets were successfully segmented. The volume matching analysis showed high consistency between two independent segmentations for each mandible. The intraclass correlation coefficient (ICC) analysis on 20 additional CBCT mandibular segmentations further demonstrated the high consistency of the current protocol. Moreover, all of the anatomical structures for superimposition identified by the American Board of Orthodontics were found in the voxel-based superimposition, demonstrating the ability to conduct precise internal structure analyses with the segmented images. Conclusion: An efficient and precise protocol to segment the mandible while retaining access to the internal structures was developed on the basis of CBCT images. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion

Glutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer patients. Treatment of a tumor-derived cell line with NMDAR antagonists impaired cancer cell proliferation and invasion. Flow conditions mimicking interstitial fluid pressure induced autologous glutamate secretion, activating NMDAR and its downstream MEK-MAPK and CaMK effectors, thereby promoting invasiveness. Congruently, pharmacological inhibition of NMDAR in mice with PNET reduced tumor growth and invasiveness. Therefore, beyond its traditional role in neurons, NMDAR may be activated in human tumors by fluid flow consequent to higher interstitial pressure, inducing an autocrine glutamate signaling circuit with resultant stimulation of malignancy

Interplay of Support, Comparison, and Surveillance in Social Media Weight Management Interventions: Qualitative Study

Background:The trend of using social media as a platform to deliver weight management interventions is substantial. This illustrates a need to develop a holistic understanding of doctor-patient communication and patient-patient communication in social media and the impacts on overweight and obese adults’ weight management. Studies like this will shed light on how social media can be more effectively integrated into weight management programs to enhance individuals’ short-term and long-term weight management behaviors and to improve the end result of preferred weight outcomes. Objective:This qualitative study explored the interplay of three social influence factors: social support, social comparison, and surveillance derived from two sources: doctor-patient communication and peer interactions in a social media-based weight management program. The study aimed to address how social media support, comparison, and surveillance affect overweight and obese adults’ self-regulation of weight management. The program, designed and implemented by the research team based in a tertiary referral hospital in a southeastern province in China, included both diet and physical activity components. Methods:We conducted in-depth interviews with 32 program participants with variations in age (M = 35.59, SD = 7.67), gender, duration of program membership (M = 1.4 years), and weight loss outcomes (-9.4% to 54.2% weight loss). All interview data were audio-recorded, transcribed, and translated using the translation-back-translation technique. Nvivo software was used to facilitate the coding process. Results:Results of thematic analysis indicated the distinct functions of professionally-led support and peer support. Professional support was presented in the form of capacity building. Peer support fostered empathy and sense of belonging and had a mutually constitutive relationship with peer comparison and peer-based surveillance. Peer comparison enhanced motivation and positive competition. However, it could also reinforce negative group norms and resulted in downturns in reference standards. Social media surveillance prompted participants’ reactions to the gaze from medical professionals and peers that could be cooperative or resisting. Findings from this study illustrated the interrelated and fluctuant influences of support, comparison, and surveillance. Conclusions:This study revealed that the interactive characteristics of social media eased the practices of social support and social comparison and created new forms of surveillance related to weight management. The theoretical contribution of the study was an in-depth understanding of social media influences on individuals’ weight management behaviors. Practical implications of the study concerned improved strategies for maintaining the positive dynamics of social media interactions and preventing negative resistance to surveillance technology

The Role of Carbonate Factories and Sea Water Chemistry on Basin-Wide Ramp to High-Relief Carbonate Platform Evolution: Triassic, Nanpanjiang Basin, South China

The end-Permian extinction and its aftermath altered carbonate factories globally for millions of years, but its impact on platform geometries remains poorly understood. Here, the evolution in architecture and composition of two exceptionally exposed platforms in the Nanpanjiang Basin are constrained and compared with geochemical proxies to evaluate controls on platform geometries. Geochemical proxies indicate elevated siliciclastic and nutrient fluxes in the basal Triassic, at the Induan—Olenekian boundary and in the uppermost Olenekian. Cerium/Ce* shifts from high Ce/Ce* values and a lack of Ce anomaly indicating anoxia during the Lower Triassic to a negative Ce anomaly indicating oxygenation in the latest Olenekian and Anisian. Uranium and Mo depletion represents widespread anoxia in the world\u27s oceans in the Early Triassic with progressive oxygenation in the Anisian. Carbonate factories shifted from skeletal in the Late Permian to abiotic and microbial in the Early Triassic before returning to skeletal systems in the Middle Triassic, Anisian coincident with declining anoxia. Margin facies shifted to oolitic grainstone in the Early Triassic with development of giant ooids and extensive marine cements. Anisian margins, in contrast, are boundstone with a diverse skeletal component. The shift in platform architecture from ramp to steep, high-relief, flat-topped profiles is decoupled from carbonate compositions having occurred in the Olenekian prior to the onset of basin oxygenation and biotic stabilisation of the margins. A basin-wide synchronous shift from ramp to high-relief platforms points to a combination of high subsidence rate and basin starvation coupled with high rates of abiotic and microbial carbonate accumulation and marine cement stabilisation of oolitic margins as the primary causes for margin up-building. High sea water carbonate saturation resulting from a lack of skeletal sinks for precipitation, and basin anoxia promoting an expanded depth of carbonate supersaturation, probably contributed to marine cement stabilisation of margins that stimulated the shift from ramp to high-relief platform architecture

Interval-censored Hawkes processes

Interval-censored data solely records the aggregated counts of events during specific time intervals - such as the number of patients admitted to the hospital or the volume of vehicles passing traffic loop detectors - and not the exact occurrence time of the events. It is currently not understood how to fit the Hawkes point processes to this kind of data. Its typical loss function (the point process log-likelihood) cannot be computed without exact event times. Furthermore, it does not have the independent increments property to use the Poisson likelihood. This work builds a novel point process, a set of tools, and approximations for fitting Hawkes processes within interval-censored data scenarios. First, we define the Mean Behavior Poisson process (MBPP), a novel Poisson process with a direct parameter correspondence to the popular self-exciting Hawkes process. We fit MBPP in the interval-censored setting using an interval-censored Poisson log-likelihood (IC-LL). We use the parameter equivalence to uncover the parameters of the associated Hawkes process. Second, we introduce two novel exogenous functions to distinguish the exogenous from the endogenous events. We propose the multi-impulse exogenous function - for when the exogenous events are observed as event time - and the latent homogeneous Poisson process exogenous function - for when the exogenous events are presented as interval-censored volumes. Third, we provide several approximation methods to estimate the intensity and compensator function of MBPP when no analytical solution exists. Fourth and finally, we connect the interval-censored loss of MBPP to a broader class of Bregman divergence-based functions. Using the connection, we show that the popularity estimation algorithm Hawkes Intensity Process (HIP) is a particular case of the MBPP. We verify our models through empirical testing on synthetic data and real-world data

Measuring the effect of Think Aloud Protocols on workload using fNIRS

The Think Aloud Protocol (TAP) is a verbalisation technique widely employed in HCI user studies to give insight into user experience, yet little work has explored the impact that TAPs have on participants during user studies. This paper utilises a brain sensing technique, fNIRS, to observe the effect that TAPs have on participants. Functional Near-Infrared Spectroscopy (fNIRS) is a brain sensing technology that offers the potential to provide continuous, detailed insight into brain activity, enabling an objective view of cognitive processes during complex tasks. Participants were asked to perform a mathematical task under 4 conditions: nonsense verbalisations, passive concurrent think aloud protocol, invasive concurrent think aloud protocol, and a baseline of silence. Subjective ratings and performance measures were collected during the study. Our results provide a novel view into the effect that different forms of verbalisation have on workload during tasks. Further, the results provide a means for estimating the effect of spoken artefacts when measuring workload, which is another step towards our goal of proactively involving fNIRS analysis in ecologically valid user studies

Effects of dietary macronutrients on the hepatic transcriptome and serum metabolome in mice

ACKNOWLEDGMENTS The study was funded by National Key R&D Program of China (2019YFA0801900), National Postdoctoral Program for Innovative Talents (BX2021357), Postdoctoral Science Foundation (2021M693393) the Chinese Academy of Sciences Strategic Program (XDB13030100), the National Natural Science Foundation of China (91649108), a PIFI professorial fellowship from CAS and a Wolfson merit award from the UK Royal Society (all to J.R.S unless stated).Peer reviewedPublisher PD

Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model

The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge for malaria control and elimination in endemic countries. This study aims to directly determine the contribution of relapses to the burden of P. vivax and P. ovale infection, illness, and transmission in Papua New Guinean children.; From 17 August 2009 to 20 May 2010, 524 children aged 5-10 y from East Sepik Province in Papua New Guinea (PNG) participated in a randomised double-blind placebo-controlled trial of blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], 3 d; and primaquine [PQ], 20 d, 10 mg/kg total dose) (261 children) or blood-stage drugs only (CQ, 3 d; AL, 3 d; and placebo [PL], 20 d) (263 children). Participants, study staff, and investigators were blinded to the treatment allocation. Twenty children were excluded during the treatment phase (PQ arm: 14, PL arm: 6), and 504 were followed actively for 9 mo. During the follow-up time, 18 children (PQ arm: 7, PL arm: 11) were lost to follow-up. Main primary and secondary outcome measures were time to first P. vivax infection (by qPCR), time to first clinical episode, force of infection, gametocyte positivity, and time to first P. ovale infection (by PCR). A basic stochastic transmission model was developed to estimate the potential effect of mass drug administration (MDA) for the prevention of recurrent P. vivax infections. Targeting hypnozoites through PQ treatment reduced the risk of having at least one qPCR-detectable P. vivax or P. ovale infection during 8 mo of follow-up (P. vivax: PQ arm 0.63/y versus PL arm 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; P. ovale: 0.06 versus 0.14, HR = 0.31 [95% CI 0.13, 0.77], p = 0.011) and the risk of having at least one clinical P. vivax episode (HR = 0.25 [95% CI 0.11, 0.61], p = 0.002). PQ also reduced the molecular force of P. vivax blood-stage infection in the first 3 mo of follow-up (PQ arm 1.90/y versus PL arm 7.75/y, incidence rate ratio [IRR] = 0.21 [95% CI 0.15, 0.28], p < 0.001). Children who received PQ were less likely to carry P. vivax gametocytes (IRR = 0.27 [95% CI 0.19, 0.38], p < 0.001). PQ had a comparable effect irrespective of the presence of P. vivax blood-stage infection at the time of treatment (p = 0.14). Modelling revealed that mass screening and treatment with highly sensitive quantitative real-time PCR, or MDA with blood-stage treatment alone, would have only a transient effect on P. vivax transmission levels, while MDA that includes liver-stage treatment is predicted to be a highly effective strategy for P. vivax elimination. The inclusion of a directly observed 20-d treatment regime maximises the efficiency of hypnozoite clearance but limits the generalisability of results to real-world MDA programmes.; These results suggest that relapses cause approximately four of every five P. vivax infections and at least three of every five P. ovale infections in PNG children and are important in sustaining transmission. MDA campaigns combining blood- and liver-stage treatment are predicted to be a highly efficacious intervention for reducing P. vivax and P. ovale transmission.; ClinicalTrials.gov NCT02143934