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Abstract Background Grade 3 neuroendocrine tumor (G3 PanNET) and poorly differentiated neuroendocrine carcinoma (PanNEC) of the pancreas are considered distinct entities from a biological and prognostic perspective but may have overlapping features complicating a definitive diagnosis. Case Presentation A 52-year-old female presented with a pancreatic body mass and liver lesions. Initial biopsies showed variable lower- and higher-grade morphologies and modestly elevated Ki67 proliferation index up to 30%, leading to a diagnosis of G3 PanNET. The patient underwent everolimus treatment followed by surgical resection, revealing a complex tumor with features of both G3 PanNET and PanNEC, including admixed well- and poorly differentiated morphologies, modestly elevated hotspot Ki67 of 28%, retained ATRX/DAXX expression, and loss of RB expression. The final diagnosis rendered was “high-grade neuroendocrine neoplasm” with discussion of both entities in the differential. Post-operatively, the patient remains alive with stable metastases. Conclusions This case highlights the diagnostic complexities of distinguishing G3 PanNET and PanNEC even with the support of ancillary immunohistochemical and molecular studies. In addition, such cases raise the possibility that G3 PanNET and PanNEC may lie on a spectrum of disease with potential biological overlap.

Digital agriculture supports farmers’ decision making to improve productivity and profitability. However, adoption of digital technology is uneven. Through interviews with 21 medium acreage almond growers and crop consultants in California’s Central Valley, we examine barriers to adoption through the lens of technology acceptance models, Technology Acceptance Model (TAM-3) and Unified Theory of Acceptance and Use of Technology (UTAUT-2). Not surprisingly, farmers are willing to adopt technology when profitability and ease of use are shown, with economic returns (either anticipated or demonstrated) from the technology investment serving as the primary factor influencing adoption. Trust operates as a moderating factor to the desire for economic returns that influences adoption. There may be trust, or lack of trust, in technology performance or in the advisors who recommend it. Producer trust is affected by expectations of technology relevance and usefulness, and it is influenced by prior experience. Concerns about data management (e.g., governance, quality, privacy, security) take a back seat to more practical issues such as profitability, leaving producers in an imbalanced position with tech companies who have an interest in their agricultural data. We assert that producer acceptance of data management practices (despite their uncertainty in how to utilize the data being generated) implies that there is a basic level of trust in tech companies’ data management practices that is consistent with models of moralistic trust behaviors for precision ag adoption. Our findings contribute to the growing research on digital agriculture that debates the benefits and downsides of digital agriculture.

Background and Aims: Typical immune checkpoint inhibitor-induced colitis (T-ICI) has significant histomorphologic overlap with inflammatory bowel disease (IBD), a distinction further complicated in ICI-treated patients with pre-existing inflammatory bowel disease (P-IBD) and those with potentially “unmasked” inflammatory bowel disease (U-IBD) after ICI therapy. This study describes histopathologic findings seen in U-IBD colonic biopsies and assesses for distinguishing features from T-ICI and P-IBD biopsies. Methods: Initial colon biopsies after symptom onset from 34 patients on ICI therapy were reviewed, and histopathologic features were tabulated. U-IBD patients were identified clinically based on rapid toxicity development post-ICI treatment with multiple recurrences after immune suppression, frequently with regional colitis (versus pancolitis). Results: The study cohort was classified into T-ICI (n = 20), P-IBD (n = 9), and U-IBD (n = 5) groups. The predominant histological patterns were diffuse active colitis (35%) in the T-ICI, and chronic active colitis in both the P-IBD (67%) and U-IBD (60%) groups (overall P = .003, P > .05 between the two IBD groups). None of the T-ICI biopsies demonstrated chronicity features (ie, architectural distortion score 2, basal lymphoplasmacytosis, or Paneth cell metaplasia). Only U-IBD biopsies demonstrated basal lymphoplasmacytosis (60% vs 0% in T-ICI/P-IBD, P = .002). Among available follow-up biopsies, chronicity features were present in all (4/4) U-IBD patients, including those without chronicity seen in the initial biopsy, but none (0/7) of T-ICI patients. Conclusion: These early results show that no definite features of chronicity were seen in colon biopsies from T-ICI patients, suggesting that the presence of those features may be a clue to U-IBD in patients without a known IBD diagnosis. Frequent basal lymphoplasmacytosis seen in U-IBD may support a recent onset of mucosal injury and early architectural remodeling.

Physiological matching of blood flow to the demand for oxygen by the heart is required for sustained cardiac health, yet the underlying mechanisms are obscure. Here, the authors report a key role for acute modifications to the redox state of intracellular pyridine nucleotides in coronary smooth muscle and their impact on voltage-gated K + channels in metabolic vasodilation

The Mogollon Highlands, Arizona/New Mexico, USA, spans a large biogeographical region of 11 biotic communities, 63 land cover types, and 7 ecoregions. This 11.3 M ha region has high levels of beta diversity across topo-edaphic gradients that span deserts to mountain tops. The main stressors affecting the region’s forests and woodlands include climate change, livestock grazing, and frequent mechanical removals of large amounts of forest biomass for fire concerns. We present an ecoregion conservation assessment for robust conservation area design that factors in appropriate wildfire response to protect communities from increasing threats of climate-induced wildfires spreading into urban areas. We focused mainly on maintaining connectivity for endangered focal species (grizzly bear (Ursus arctos horribilis) and Mexican wolf (Canis lupus baileyi)) along with protecting mature and old-growth (MOG) forests, Piñon (Pinus spp.)–Juniper (Juniperus spp.) Woodlands, and riparian areas. Over half the region is managed by federal agencies where new protected areas can be integrated with tribal co-management and prescribed burning, defensible space, and home hardening to protect communities from the growing threat of climate-induced wildfires. However, just 9% of the study area is currently protected, and even with the inclusion of proposed protected areas, only 24% would be protected, which is below 30 × 30 targets. The potential grizzly bear habitat, wolf habitat connectivity, and MOG forests (1.6 M ha (14.2%) of the study area; 18% protected) are concentrated mainly in the central and eastern portions of the MHE. There were 824 fires (2 to 228,065 ha) from 1984–2021, with 24% overlapping the wildland–urban interface. Regional temperatures have increased by 1.5 °C, with a 16% reduction in precipitation and stream flow since 1970 that under worst-case emission scenarios may increase temperatures another 3 to 8 °C by the century’s end. The unique biodiversity of the MHE can be better maintained in a rapidly changing climate via at least a three-fold increase in protected areas, co-management of focal species with tribes, and strategic use of fuel treatments nearest communities.

Abstract Fire regimes in North American forests are diverse and modern fire records are often too short to capture important patterns, trends, feedbacks, and drivers of variability. Tree‐ring fire scars provide valuable perspectives on fire regimes, including centuries‐long records of fire year, season, frequency, severity, and size. Here, we introduce the newly compiled North American tree‐ring fire‐scar network (NAFSN), which contains 2562 sites, >37,000 fire‐scarred trees, and covers large parts of North America. We investigate the NAFSN in terms of geography, sample depth, vegetation, topography, climate, and human land use. Fire scars are found in most ecoregions, from boreal forests in northern Alaska and Canada to subtropical forests in southern Florida and Mexico. The network includes 91 tree species, but is dominated by gymnosperms in the genus Pinus. Fire scars are found from sea level to >4000‐m elevation and across a range of topographic settings that vary by ecoregion. Multiple regions are densely sampled (e.g., >1000 fire‐scarred trees), enabling new spatial analyses such as reconstructions of area burned. To demonstrate the potential of the network, we compared the climate space of the NAFSN to those of modern fires and forests; the NAFSN spans a climate space largely representative of the forested areas in North America, with notable gaps in warmer tropical climates. Modern fires are burning in similar climate spaces as historical fires, but disproportionately in warmer regions compared to the historical record, possibly related to under‐sampling of warm subtropical forests or supporting observations of changing fire regimes. The historical influence of Indigenous and non‐Indigenous human land use on fire regimes varies in space and time. A 20th century fire deficit associated with human activities is evident in many regions, yet fire regimes characterized by frequent surface fires are still active in some areas (e.g., Mexico and the southeastern United States). These analyses provide a foundation and framework for future studies using the hundreds of thousands of annually‐ to sub‐annually‐resolved tree‐ring records of fire spanning centuries, which will further advance our understanding of the interactions among fire, climate, topography, vegetation, and humans across North America.

Purpose: Seasonality and periodicity of influenza in human and animal populations is not well characterized in tropical and subtropical regions globally. In Bangladesh, where over 90% of poultry products are marketed through live poultry markets, avian influenza is prevalent in poultry and epidemics of influenza occur in humans. We sought to empirically examine the timing and intensity of influenza seasonality in humans and avian influenza in poultry in Bangladesh using time series methods. Methods & Materials: We evaluated 8,790 cases of human influenza occurring between January 2010 and December 2019 obtained from 32 hospital-based sentinel surveillance sites across Bangladesh. Avian influenza positive samples (n=2,274) were obtained from environmental surveillance across 106 live poultry markets in Dhaka between January 2016 and December 2019. We applied wavelet analysis to determine influenza periodicity, and conducted Poisson regression with harmonic terms adjusting for trend and an offset for samples tested to estimate the average timing and intensity of the primary influenza peak in each population. We examine co-seasonality by estimating the time lag between the annual influenza peak in humans and the annual avian influenza peak in poultry. Results: Over the 10-year period there was consistent annual periodicity of influenza in humans with peak incidence occurring in early July (peak calendar-week: 27.3, 95%CI: 27.0-27.5) and intense seasonality (amplitude: 14.7, 95%CI: 13.4-16.2). Large metropolitan centers displayed earlier epidemic timing, with epidemic spread following a spatial diffusion pattern based on geographic proximity. Comparatively, avian influenza displayed weak seasonality, with moderate year-round transmission and only a small peak in late March to early April (peak calendar-week: 13.5, 95%CI: 11.5-16.8; amplitude: 1.5, 95%CI: 1.3-1.7). Peak avian influenza preceded peak human influenza by 13.8 calendar-weeks (95%CI: 10.7-15.5). Conclusion: Our findings suggest that while influenza epidemics in humans are highly seasonal and take off faster in metropolitan areas, avian influenza in poultry does not display a strong seasonal trend in Bangladesh. Although influenza peaks do not coincide, endemic avian influenza continues to pose a risk for viral reassortment throughout the year. These co-seasonality results provide evidence for more quantitative risk assessments of viral reassortment and inform timing of sequencing-based surveillance.

Since the release of The Paris System for Reporting Urinary Cytology (TPS), the assessment of urine cytology specimens has primarily focused on the detection of high-grade urothelial carcinoma (HGUC) and carcinoma in situ (CIS). Fortunately, the malignant cells in these lesions tend to be loosely cohesive, resulting in the natural exfoliation of individual malignant cells into the urine. However, HGUC/CIS lesions occasionally exfoliate larger fragments which can be difficult to assess due to cellular overlap and fragment three-dimensionality. Furthermore, reactive benign urothelial fragments and fragments from low-grade urothelial neoplasms (LGUN) may also be seen in urine specimens and contain atypical cytomorphologic features. As a result, the significance of urothelial tissue fragments (UTFs) is often unclear. Herein, we discuss the literature on UTFs before and after the implementation of TPS, as well as strategies to help overcome this diagnostic challenge.

Organization-sponsored sharing platforms extend the sharing economy to workplaces by connecting employees in a private online community where they can socially exchange goods and services with coworkers. Employees share costs but do not earn income during this collaborative consumption. Furthermore, employers pay for their employees to have access to the platform technology and any related transaction fees. Trust is a crucial antecedent for engagement on sharing platforms because it helps mitigate risks during collaborative consumption. However, the literature on trust in the sharing economy has focused almost exclusively on platforms that broker peer-to-peer rental transactions rather than social exchanges. There is also a lack of research about providers’ perspectives. We address these gaps by investigating the nature of trust among employees who initially provide goods and services on an organization-sponsored sharing platform. We also explore how these employees’ initial trust influences their collaborative consumption with coworkers. Through abductive analysis of 22 interviews with 15 providers on an organization-sponsored sharing platform, we shed light on how employees initially develop trust when providing goods and services to coworkers. By integrating prior research on initial trust among employees and cognitive framing with in-depth qualitative insights, we develop a conceptual model depicting how identity, interaction and issue frames shape these providers’ beliefs about coworker trustworthiness and intended sharing strategy. In particular, our empirical findings reveal that employees’ social categorization, illusions of control and engagement motive framed their initial trust and enactment of collaborative consumption as citizens in a community or consumers in a marketplace.

Glaucoma is a neurodegenerative disease of which the etiology is still unclear. Here the authors show that elevation of intraocular pressure induces T cell infiltration in the eyes. Furthermore, they show that T cell cross-reactivity between endogenous and commensal antigens contributes to disease onset in mice.

Objective: Glucose is the major energy substrate of the brain and crucial for normal brain function. In diabetes, the brain is subject to episodes of hypo- and hyperglycemia resulting in acute outcomes ranging from confusion to seizures, while chronic metabolic dysregulation puts patients at increased risk for depression and Alzheimer's disease. In the present study, we aimed to determine how glucose is metabolized in different regions of the brain using imaging mass spectrometry (IMS). Methods: To examine the relative abundance of glucose and other metabolites in the brain, mouse brain sections were subjected to imaging mass spectrometry at a resolution of 100 μm. This was correlated with immunohistochemistry, qPCR, western blotting and enzyme assays of dissected brain regions to determine the relative contributions of the glycolytic and pentose phosphate pathways to regional glucose metabolism. Results: In brain, there are significant regional differences in glucose metabolism, with low levels of hexose bisphosphate (a glycolytic intermediate) and high levels of the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) and PPP metabolite hexose phosphate in thalamus compared to cortex. The ratio of ATP to ADP is significantly higher in white matter tracts, such as corpus callosum, compared to less myelinated areas. While the brain is able to maintain normal ratios of hexose phosphate, hexose bisphosphate, ATP, and ADP during fasting, fasting causes a large increase in cortical and hippocampal lactate. Conclusion: These data demonstrate the importance of direct measurement of metabolic intermediates to determine regional differences in brain glucose metabolism and illustrate the strength of imaging mass spectrometry for investigating the impact of changing metabolic states on brain function at a regional level with high resolution. Keywords: Brain imaging, Glucose metabolism, Pentose phosphate pathway, Glycolysis, ATP, Mass spectrometry

Activation of brown adipose tissue (BAT) reduces the development of atherosclerosis in animal models. Here the authors show that BAT activation also increases reverse cholesterol transport and turnover of high-density lipoprotein, which likely contributes to the anti-atherosclerotic effect of BAT activation.

Tissue, cell, and nucleus morphology change during tumor progression. In 2D confluent cell cultures, different tissue states, such as fluid (unjammed) and solid (jammed), are correlated with cell shapes. These results do not have to apply a priori to three dimensions. Cancer cell motility requires and corresponds to a fluidization of the tumor tissue on the bulk level. Here, we investigate bulk tissue fluidity in 3D and determine how it correlates with cell and nucleus shape. In patient samples of mamma and cervix carcinoma, we find areas where cells can move or are immobile. We compare 3D cell spheroids composed of cells from a cancerous and a noncancerous cell line. Through bulk mechanical spheroid-fusion experiments and single live-cell tracking, we show that the cancerous sample is fluidized by active cells moving through the tissue. The healthy, epithelial sample with immobile cells behaves more solidlike. 3D segmentations of the samples show that the degree of tissue fluidity correlates with elongated cell and nucleus shapes. This correlation links cell shapes to cell motility and bulk mechanical behavior. We find two active states of matter in solid tumors: an amorphous glasslike state with characteristics of 3D cell jamming and a disordered fluid state. Individual cell and nucleus shape may serve as a marker for metastatic potential to foster personalized cancer treatment.

Digital agriculture supports farmers’ decision making to improve productivity and profitability. However, adoption of digital technology is uneven. Through interviews with 21 medium acreage almond growers and crop consultants in California’s Central Valley, we examine barriers to adoption through the lens of technology acceptance models, Technology Acceptance Model (TAM-3) and Unified Theory of Acceptance and Use of Technology (UTAUT-2). Not surprisingly, farmers are willing to adopt technology when profitability and ease of use are shown, with economic returns (either anticipated or demonstrated) from the technology investment serving as the primary factor influencing adoption. Trust operates as a moderating factor to the desire for economic returns that influences adoption. There may be trust, or lack of trust, in technology performance or in the advisors who recommend it. Producer trust is affected by expectations of technology relevance and usefulness, and it is influenced by prior experience. Concerns about data management (e.g., governance, quality, privacy, security) take a back seat to more practical issues such as profitability, leaving producers in an imbalanced position with tech companies who have an interest in their agricultural data. We assert that producer acceptance of data management practices (despite their uncertainty in how to utilize the data being generated) implies that there is a basic level of trust in tech companies’ data management practices that is consistent with models of moralistic trust behaviors for precision ag adoption. Our findings contribute to the growing research on digital agriculture that debates the benefits and downsides of digital agriculture.

Contact changes in packings of sheared hard spheres invariably trigger instabilities and irreversible rearrangements, providing an archetypal scenario for plasticity of disordered media. Here we show that the plasticity of jammed soft spheres at any finite pressure follows a different scenario, with only 14% of contact changes leading to irreversible rearrangements, irrespective of pressure, size, dimension or interaction potential. Moreover, we find that for sheared soft spheres, the nonlinear quantities associated with either contact changes or irreversible events exhibit the same finite-size scaling with pressure and system size as linear response quantities such as the shear modulus, suggesting an unexpected connection between curvature and saddle points in the potential energy landscape. Together our results indicate that soft spheres at finite pressure are not a smooth perturbation away from hard spheres, and that the nonlinear response of soft spheres is singular at zero pressure.

An amendment to this paper has been published and can be accessed via the original article.

The originally published version of this Article contained an error in Figure 4. The bar chart in panel f was inadvertently replaced with a duplicate of the bar chart in panel e. This error has now corrected in both the PDF and HTML versions of the Article.

Innovation is a very important concern for both managers and governmental policy makers. There is an important interplay between security and technology innovation that is largely unrecognized in the literature. This research considers the case where technology innovation in the form of additional product features increases demand through greater functionality. However, the likelihood of a security breach increases with the number of product features as the features interact in unintended ways, thereby increasing the attack surface. Using a two-stage game, we demonstrate how potential demand changes (from direct risk or externalities) impact firm technology innovation strategy. The analysis shows that the type and extent of customer demand reaction has a significant impact on innovative feature development. This research identifies two potential impacts on the level of innovation that can be strategically managed - the impact of externalities on demand and industry risk - explaining how these forces alter the level of innovation in the product ecosystem. Additionally, high-security development is disincentivized, and leads to a type of competitive behavior where the opportunity window for high-security development for all firms is small.

Cell motion inside dense tissues governs many biological processes, including embryonic development and cancer metastasis, and recent experiments suggest that these tissues exhibit collective glassy behavior. To make quantitative predictions about glass transitions in tissues, we study a self-propelled Voronoi model that simultaneously captures polarized cell motility and multibody cell-cell interactions in a confluent tissue, where there are no gaps between cells. We demonstrate that the model exhibits a jamming transition from a solidlike state to a fluidlike state that is controlled by three parameters: the single-cell motile speed, the persistence time of single-cell tracks, and a target shape index that characterizes the competition between cell-cell adhesion and cortical tension. In contrast to traditional particulate glasses, we are able to identify an experimentally accessible structural order parameter that specifies the entire jamming surface as a function of model parameters. We demonstrate that a continuum soft glassy rheology model precisely captures this transition in the limit of small persistence times and explain how it fails in the limit of large persistence times. These results provide a framework for understanding the collective solid-to-liquid transitions that have been observed in embryonic development and cancer progression, which may be associated with epithelial-to-mesenchymal transition in these tissues.

We report innovative scalable, vertical, ultra-sharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. Stable amplitudes of intracellular potentials from 3D tissue-like networks of neurons and cardiomyocytes are obtained. Individual electrical addressability is necessary for high-fidelity intracellular electrophysiological recordings. This study paves the way toward predictive, high-throughput, and low-cost electrophysiological drug screening platforms.

The purpose of this study was to fill a gap in the literature on student learning and use participant feedback to improve the pedagogical effectiveness in mathematics and literacy classrooms. To this end, an anonymous, semi-structured Qualtrics survey was developed and administered to 1,212 recent high school graduates asking about the best way to learn mathematics. Respondents said they preferred printed textbooks, although 30% rarely read them. They found instructional videos helpful and that guided notes kept them engaged. Students wanted practice problems and examples, in an environment where they were unafraid to ask questions. Their learning benefited from both collaboration and independent work. They knew that participation in math clubs improved their learning, but they admitted not participating. Although no survey items focused on teachers, half of those providing open-ended feedback made clear, the necessity of a "good," "patient," "experienced," teacher, "excited to teach math," with whom students could work "face-to-face."