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Programmed cell death (PCD) is a crucial genetically-encoded and evolutionarily-conserved process for development and homeostasis. We previously identified a genetically non-apoptotic, highly ordered, and stereotyped killing program called Compartmentalized Cell Elimination (CCE) in the C. elegans tail-spike epithelial cell (TSC). Here we identify the transcription factor EOR-1/PLZF as promoting CCE. Loss of EOR-1 results in a persisting un-engulfed large soma with enlarged nuclei. We find that EOR-1 and its partners positively regulate the transcription of the Apoptosis Inducing Factor AIF homolog, WAH-1/AIF. We report stereotyped and sequential spatiotemporal dynamics of WAH-1/AIF1 during phagocytosis, with defined roles early and late. Mitochondrial to plasma membrane translocation is required for internalization, and plasma membrane to nuclear translocation for DNA degradation and ultimate corpse resolution. Our study expands our knowledge of PCD by describing a mechanistic contribution of EOR-1/PLZF and functional relevance to specific spatiotemporal contexts for WAH-1/AIF function, and by implying a correlation between DNA degradation with nuclear morphology during cell elimination., Summary Statement: This work describes the genetic control and cellular dynamics of a factor linked to cancer, metabolic and degenerative disease acting in developmentally dying cells to instruct their own removal.

The nematode Caenorhabditis elegans is a powerful experimental setting for uncovering fundamental tenets of nervous system organization and function. Its nearly invariant and simple anatomy, coupled with a plethora of methodologies for interrogating single-gene functions at single-cell resolution in vivo, have led to exciting discoveries in glial cell biology and mechanisms of glia-neuron interactions. Findings over the last two decades reinforce the idea that insights from C. elegans can inform our understanding of glial operating principles in other species. Here, we summarize the current state-of-the-art, and describe mechanistic insights that have emerged from a concerted effort to understand C. elegans glia. The remarkable acceleration in the pace of discovery in recent years paints a portrait of striking molecular complexity, exquisite specificity, and functional heterogeneity among glia. Glial cells affect nearly every aspect of nervous system development and function, from generating neurons, to promoting neurite formation, to animal behavior, and to whole-animal traits, including longevity. We discuss emerging questions where C. elegans is poised to fill critical knowledge gaps in our understanding of glia biology., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Primary (non-motile) cilia represent structurally and functionally diverse organelles whose roles as specialized cellular antenna are central to animal cell signaling pathways, sensory physiology and development. An ever-growing number of ciliary proteins, including those found in vertebrate photoreceptors, have been uncovered and linked to human disorders termed ciliopathies. Here, we demonstrate that an evolutionarily-conserved PPEF-family serine-threonine phosphatase, not functionally linked to cilia in any organism but associated with rhabdomeric (non-ciliary) photoreceptor degeneration in the Drosophila rdgC (retinal degeneration C) mutant, is a bona fide ciliary protein in C. elegans. The nematode protein, PEF-1, depends on transition zone proteins, which make up a 'ciliary gate' in the proximal-most region of the cilium, for its compartmentalization within cilia. Animals lacking PEF-1 protein function display structural defects to several types of cilia, including potential degeneration of microtubules. They also exhibit anomalies to cilium-dependent behaviors, including impaired responses to chemical, temperature, light, and noxious CO 2 stimuli. Lastly, we demonstrate that PEF-1 function depends on conserved myristoylation and palmitoylation signals. Collectively, our findings broaden the role of PPEF proteins to include cilia, and suggest that the poorly-characterized mammalian PPEF1 and PPEF2 orthologs may also have ciliary functions and thus represent ciliopathy candidates., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Programmed cell death (PCD) is an essential component of animal development, and aberrant cell death underlies many disorders. Understanding mechanisms that govern PCD during development can provide insight into cell death programs that are disrupted in disease. Key steps mediating apoptosis, a highly conserved cell death program employing caspase proteases, were first uncovered in the nematode Caenorhabditis elegans , a powerful model system for PCD research. Recent studies in C. elegans also unearthed conserved nonapoptotic caspase-independent cell death programs that function during development. Here, we discuss recent advances in understanding cell death during C. elegans development. We review insights expanding the molecular palette behind the execution of apoptotic and nonapoptotic cell death, as well as new discoveries revealing the mechanistic underpinnings of dying cell engulfment and clearance. A number of open questions are also discussed that will continue to propel the field over the coming years.

Introduction: Current literature lacks data regarding the influence of serous fluid volume (SFV) on next-generation sequencing (NGS) performed on malignant cases. In this study, we highlight the impact of SFV and other parameters influencing the outcome of NGS analysis., Materials and Methods: We evaluated 827 samples of serous fluids from 607 patients. Of these, 72 samples underwent NGS analysis. Effusion volume, tumor cellularity, DNA, and RNA quality metrics, as well as clinicopathologic and molecular data were evaluated. Pleural fluid accounted for 56.3% of the fluid samples collected. The most common primary tumor site was gastrointestinal/pancreatobiliary, adenocarcinoma was the most common histologic type. Overall mean volume was 293 mL. The mean Qubit DNA of the 72 effusion samples that underwent NGS analysis was 14.3 ng/μL and mean Qubit RNA was 28.2 ng/μL. The mean Qubit DNA concentration increases in SFV up to 100 mL only., Results: No correlation exists between SFV and mean tumor cellularity. In addition, 74.6% (50 of 67) of sequenced samples showed oncogenic drivers; KRAS was the most common driver followed by EGFR. Three cases displayed ALK fusions, and 1 case displayed NTRK1 fusion. The DNA yield is higher in SFV of 100 mL as a cutoff. Beyond 100 mL, there is no impact of SFV on DNA yield. SFV does not impact RNA yield and mean tumor cellularity. Effusion samples should be submitted for molecular testing despite low tumor cellularity., Conclusions: Our results as a pilot study are important in optimization of SFV for both diagnosis as well as NGS analysis for improving management., (Copyright © 2024 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Few cytologically indeterminate thyroid fine-needle aspirations (FNAs) harbor BRAF V600E. Here, we assess interobserver agreement for The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III (atypia of undetermined significance [AUS]) FNAs harboring BRAF V600E and contrast their features with those harboring non-BRAF V600E alterations, with attention to cytopathology experience., Methods: Seven reviewers evaluated 5 AUS thyroid FNAs harboring BRAF V600E. To blind reviewers, cases were intermixed with 19 FNAs falling within other TBSRTC categories and in which genetic alterations other than BRAF V600E had been identified (24 FNAs total). Interobserver agreement against both "index" and most popular ("mode") diagnoses was calculated. Four additional BRAF V600E cases were independently reviewed., Results: Reviewers included 3 trainees and 3 American Board of Pathology (board)-certified cytopathologists. Board-certified cytopathologists, whose experience ranged from 2 to more than 15 subspecialty practice years, had known AUS rates. BRAF V600E was identified in 5 of 260 (2%) AUS FNAs. Interobserver agreement was higher among cytopathologists with more experience. Mode diagnosis differed from index diagnosis in 6 of 11 cases harboring RAS-like alterations; mode diagnosis was AUS in 4 of 5 BRAF V600E FNAs., Conclusions: Atypia of undetermined significance of thyroid FNAs harboring BRAF V600E is uncommon yet relatively reproducible, particularly among pathologists with experience. It is advisable to sequence BRAF across V600 in such cases., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Metal-semiconductor nanocomposites have emerged as a viable strategy for concurrently tailoring both thermal and electronic transport properties of established thermoelectric materials, ultimately achieving synergistic performance. In this investigation, a series of nanocomposite thin films were synthesized, embedding metallic cobalt telluride (CoTe 2 ) nanophase within the nanocrystalline ternary skutterudite (Co(Ge 1.22 Sb 0.22 )Te 1.58 or CGST) matrix. Our approach harnessed composition fluctuation-induced phase separation and in situ growth during thermal annealing to seamlessly integrate the metallic phase. The distinctive band structures of both materials have developed an ohmic-type contact characteristic at the interface, which raised carrier density considerably yet negligibly affected the mobility counterpart, leading to a substantial improvement in electrical conductivity. The intricate balance in transport properties is further influenced by the metallic CoTe 2 phase's role in diminishing lattice thermal conductivity. The presence of the metallic phase instigates enhanced phonon scattering at the interface boundaries. Consequently, a 2-fold enhancement in the thermoelectric figure of merit (zT ∼ 1.30) is attained with CGST-7 wt. % CoTe 2 nanocomposite film at 655 K compared to that of pristine CGST.

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient., (© 2024. The Author(s).)

While most glial cell types in the central nervous system (CNS) arise from neuroectodermal progenitors, some, like microglia, are mesodermally derived. To understand mesodermal glia development and function, we investigated C. elegans GLR glia, which envelop the brain neuropil and separate it from the circulatory system cavity. Transcriptome analysis shows that GLR glia combine astrocytic and endothelial characteristics, which are relegated to separate cell types in vertebrates. Combined fate acquisition is orchestrated by LET-381/FoxF, a fate-specification/maintenance transcription factor also expressed in glia and endothelia of other animals. Among LET-381/FoxF targets, the UNC-30/Pitx2 transcription factor controls GLR glia morphology and represses alternative mesodermal fates. LET-381 and UNC-30 co-expression in naive cells is sufficient for GLR glia gene expression. GLR glia inactivation by ablation or let-381 mutation disrupts locomotory behavior and promotes salt-induced paralysis, suggesting brain-neuropil activity dysregulation. Our studies uncover mechanisms of mesodermal glia development and show that like neuronal differentiation, glia differentiation requires autoregulatory terminal selector genes that define and maintain the glial fate., (© 2024. The Author(s).)

Machine learning (ML) is playing an increasing role in decision-making tasks that directly affect individuals, e.g., loan approvals, or job applicant screening. Significant concerns arise that, without special provisions, individuals from under-privileged backgrounds may not get equitable access to services and opportunities. Existing research studies fairness with respect to protected attributes such as gender, race or income, but the impact of location data on fairness has been largely overlooked. With the widespread adoption of mobile apps, geospatial attributes are increasingly used in ML, and their potential to introduce unfair bias is significant, given their high correlation with protected attributes. We propose techniques to mitigate location bias in machine learning. Specifically, we consider the issue of miscalibration when dealing with geospatial attributes. We focus on spatial group fairness and we propose a spatial indexing algorithm that accounts for fairness. Our KD-tree inspired approach significantly improves fairness while maintaining high learning accuracy, as shown by extensive experimental results on real data.

Mobile apps that use location data are pervasive, spanning domains such as transportation, urban planning and healthcare. Important use cases for location data rely on statistical queries, e.g., identifying hotspots where users work and travel. Such queries can be answered efficiently by building histograms. However, precise histograms can expose sensitive details about individual users. Differential privacy (DP) is a mature and widely-adopted protection model, but most approaches for DP-compliant histograms work in a data-independent fashion, leading to poor accuracy. The few proposed data-dependent techniques attempt to adjust histogram partitions based on dataset characteristics, but they do not perform well due to the addition of noise required to achieve DP. In addition, they use ad-hoc criteria to decide the depth of the partitioning. We identify density homogeneity as a main factor driving the accuracy of DP-compliant histograms, and we build a data structure that splits the space such that data density is homogeneous within each resulting partition. We propose a self-tuning approach to decide the depth of the partitioning structure that optimizes the use of privacy budget. Furthermore, we provide an optimization that scales the proposed split approach to large datasets while maintaining accuracy. We show through extensive experiments on large-scale real-world data that the proposed approach achieves superior accuracy compared to existing approaches.

Accessing realistic human movements (aka trajectories) is essential for many application domains, such as urban planning, transportation, and public health. However, due to privacy and commercial concerns, real-world trajectories are not readily available, giving rise to an important research area of generating synthetic but realistic trajectories. Inspired by the success of deep neural networks (DNN), data-driven methods learn the underlying human decision-making mechanisms and generate synthetic trajectories by directly fitting real-world data. However, these DNN-based approaches do not exploit people's moving behaviors (e.g., work commute, shopping purpose), significantly influencing human decisions during the generation process. This paper proposes MBP-GAIL, a novel framework based on generative adversarial imitation learning that synthesizes realistic trajectories that preserve moving behavior patterns in real data. MBP-GAIL models temporal dependencies by Recurrent Neural Networks (RNN) and combines the stochastic constraints from moving behavior patterns and spatial constraints in the learning process. Through comprehensive experiments, we demonstrate that MBP-GAIL outperforms state-of-the-art methods and can better support decision making in trajectory simulations.

Introduction: Detection of malignant cells in serous fluids is an indicator of advanced stage of malignancy and is critical in clinical management decisions and prompt treatment initiation. The minimum volume which is ideal for detecting malignancy in serous fluid is not well established. In this study, we aim to identify optimal volume that will be ideal for adequate cytopathological diagnosis., Materials and Methods: A total of 1597 samples of serous fluids from 1134 patients were included in the study. Samples were diagnosed based on International System for Reporting Serous Fluid Cytopathology (ISRSFC). Clinicopathologic results from different diagnostic groups were compared and statistically analyzed., Results: Pleural fluids comprised 890 (55.7%) specimens, followed by 456 (28.6%) peritoneal, 128 (8%) ascites, and 123 (7.7%) pericardial fluid specimens. The majority were negative for malignancy (1138, 71.3%), followed by malignant (376, 23.5%), atypical (59, 3.7%), and suspicious for malignancy (24, 1.5%). Malignancy was identified in sample with volumes from 5 mL to 5000 mL. Rate of detection of malignant cells increased significantly with higher sample volumes. For malignancy detection the optimal volume for overall serous fluid is 70 mL. Pericardial fluid is an exception, with lower mean volume and significantly lower proportion of cases with malignant diagnosis., Conclusions: Our study indicates that higher fluid volumes have a higher rate of malignancy detection and a low false-negative rate. We recommend a minimum of 70 mL of serous fluid for optimal cytopathologic examination and malignancy detection. Pericardial fluid is an exception, with lower mean volume and thus lower requirement., (Copyright © 2023 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

In Caenorhabditis elegans worms, epigenetic information transmits transgenerationally. Still, it is unknown whether the effects transfer to the next generation inside or outside of the nucleus. Here, we use the tractability of gene-specific double-stranded RNA-induced silencing to demonstrate that RNA interference can be inherited independently of any nuclear factors via mothers that are genetically engineered to transmit only their ooplasm but not the oocytes' nuclei to the next generation. We characterize the mechanisms and, using RNA sequencing, chimeric worms, and sequence polymorphism between different isolates, identify endogenous small RNAs which, similarly to exogenous siRNAs, are inherited in a nucleus-independent manner. From a historical perspective, these results might be regarded as partial vindication of discredited cytoplasmic inheritance theories from the 19th century, such as Darwin's "pangenesis" theory.

Interview with Shai Shaham, who studies glia-neuron interactions in C. elegans at The Rockefeller University., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2023.)

Introduction: Noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP), represents a distinct class of thyroid neoplasms with very low risk of adverse outcome and a set of strict histologic criteria. Introduction of NIFTP as a non-cancer has had an appreciable decrease in risk of malignancy and body of literature on this entity continues to grow. In this study, we reviewed clinical, fine-needle aspiration cytology (FNAC), imaging, and molecular findings of histologically proven NIFTPs at our institution., Materials and Methods: Thyroid resections during an 11-year period, with histologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC), were retrospectively reviewed to identify NIFTP. Ultrasonographic appearance, FNA findings, and molecular findings were also reviewed., Results: Of 244 cases of FVPTC identified, 74 (30%) cases were reclassified as NIFTP. Mean tumor size was 2.5 cm. Of 33 patients with lymph node dissection, none had lymph node metastases. On imaging, 36 NIFTP (49%) showed vascularity, 25 (33%) were isoechoic to hypoechoic, there were calcifications in 14 cases (19%), and 7 cases (9%) showed a hypoechoic rim. Bethesda III/IV was the most common interpretation rendered on FNAC (31%). Seven cases had NRAS mutations and 1 case had BRAF V600E mutation. The remaining cases were either negative for BRAF V600E or had no identifiable molecular alterations., Conclusions: A significant percentage of tumors previously diagnosed as FVPTC were reclassified as NIFTP. This tumor cannot be reliably diagnosed preoperatively on FNAC, shows no characteristic features on ultrasound and has low suspicion of malignancy. BRAF V600E mutations are infrequent in NIFTP., (Copyright © 2022 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Fairness in data-driven decision-making studies scenarios where individuals from certain population segments may be unfairly treated when being considered for loan or job applications, access to public resources, or other types of services. In location-based applications, decisions are based on individual whereabouts, which often correlate with sensitive attributes such as race, income, and education. While fairness has received significant attention recently, e.g., in machine learning, there is little focus on achieving fairness when dealing with location data. Due to their characteristics and specific type of processing algorithms, location data pose important fairness challenges. We introduce the concept of spatial data fairness to address the specific challenges of location data and spatial queries. We devise a novel building block to achieve fairness in the form of fair polynomials . Next, we propose two mechanisms based on fair polynomials that achieve individual spatial fairness, corresponding to two common location-based decision-making types: distance-based and zone-based . Extensive experimental results on real data show that the proposed mechanisms achieve spatial fairness without sacrificing utility.

This paper aims to examine the direct and indirect impact of ambient air pollution (AAP) on employees' performance. This study has used cross sectional survey design to collect the data from the outdoor employees of the pharmaceutical industry of Pakistan. The data were collected in time lags from 299. Partial least squares- structural equation modeling (PLS-SEM) approach was applied to analyze the data. The results show that AAP has a significant negative impact on the employees' performance, and anxiety partially mediates the association between AAP and employees' performance. This study reveals that AAP brings anxiety among outdoor employees, which in turn decreases their working performance. The implications, limitations, and future research directions are presented in the last section of this study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bari, Saleem, Bashir and Ahmad.)

Motoneurons and motoneuron-like pancreatic β cells arise from radial glia and ductal cells, respectively, both tube-lining progenitors that share molecular regulators. To uncover programs underlying motoneuron formation, we studied a similar, cell-division-independent transformation of the C. elegans tube-lining Y cell into the PDA motoneuron. We find that lin-12/Notch acts through ngn-1/Ngn and its regulator hlh-16/Olig to control transformation timing. lin-12 loss blocks transformation, while lin-12(gf) promotes precocious PDA formation. Early basal expression of ngn-1/Ngn and hlh-16/Olig depends on sem-4/Sall and egl-5/Hox. Later, coincident with Y cell morphological changes, ngn-1/Ngn expression is upregulated in a sem-4/Sall and egl-5/Hox-dependent but hlh-16/Olig-independent manner. Subsequently, Y cell retrograde extension forms an anchored process priming PDA axon extension. Extension requires ngn-1-dependent expression of the cytoskeleton organizers UNC-119, UNC-44/ANK, and UNC-33/CRMP, which also activate PDA terminal-gene expression. Our findings uncover cell-division-independent regulatory events leading to motoneuron generation, suggesting a conserved pathway for epithelial-to-motoneuron/motoneuron-like cell differentiation., Competing Interests: Declaration of interests S.S. is a member of the Cell Reports advisory board., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer., (© 2022 Raman et al.)

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Background: Molecular testing (MT) of thyroid fine-needle aspiration (FNA)-derived genetic material is commonly used to assess malignancy risk for indeterminate cases. The Bethesda System for Reporting Thyroid Cytopathology (TBS) provides limited guidance for the appropriate use of category III (atypia of undetermined significance [AUS]). The authors combined MT with cytomorphology to monitor AUS diagnoses in a cytopathology laboratory., Methods: Neoplasia-associated genetic alterations (NGAs) were determined by MT of preoperative FNA biopsies or resected malignancies and were categorized as BRAF V600E mutations, RAS-like mutations (HRAS, NRAS, or KRAS mutations or non-V600E BRAF mutations), or other mutations., Results: Among 7382 thyroid FNA biopsies, the AUS rate was 9.3% overall and ranged from 4.3% to 24.2% among 6 cytopathologists (CPs) who evaluated >150 cases. The ratio of specimens falling into TBS category III to specimens falling into category VI (malignant) (the III:VI ratio) was 2.4 overall (range, 1.1-8.1), and the ratio of specimens falling into TBS categories III and IV (follicular neoplasm or suspicious for follicular neoplasm) combined (III+IV) to specimens falling into category VI (the [III+IV]:VI ratio) was 2.9 overall (range, 1.4-9.5). MT was performed on 588 cases from 560 patients (79% women) with a median age of 56 years (range, 8-89 years). BRAF V600E mutation was the most common (76% of cases) in TBS category VI and was rare (3%) in category III. RAS-like mutations were most common in TBS categories III (13%), IV (25%), and V (suspicious for malignancy) (17.5%). The NGA rate in AUS cases fell between 5% and 20% for 5 of 6 CPs and did not correlate with the III:VI ratio or the (III+IV):VI ratio., Conclusions: Lack of correlation between the NGA rate and easily calculable diagnostic ratios enables the calibration of diagnostic thresholds, even for CPs who have normal metrics. Specifically, calculation of the NGA rate and the III:VI ratio may allow individual CPs to determine whether they are overcalling or undercalling cases that other CPs might otherwise recategorize., (© 2021 American Cancer Society.)

Ascertaining the function of in-plane intrinsic defects and edge atoms is necessary for developing efficient low-dimensional photocatalysts. We report the wireless photocatalytic CO 2 reduction to CH 4 over reconstructed edge atoms of monolayer 2H-WSe 2 artificial leaves. Our first-principles calculations demonstrate that reconstructed and imperfect edge configurations enable CO 2 binding to form linear and bent molecules. Experimental results show that the solar-to-fuel quantum efficiency is a reciprocal function of the flake size. It also indicates that the consumed electron rate per edge atom is two orders of magnitude larger than the in-plane intrinsic defects. Further, nanoscale redox mapping at the monolayer WSe 2 -liquid interface confirms that the edge is the most preferred region for charge transfer. Our results pave the way for designing a new class of monolayer transition metal dichalcogenides with reconstructed edges as a non-precious co-catalyst for wired or wireless hydrogen evolution or CO 2 reduction reactions., (© 2022. The Author(s).)

Background: It is unclear if different genetic drivers in papillary thyroid cancer (PTC) confer different phenotypic tumor behavior leading to more aggressive disease. We hypothesized that RET-driven cancers are more aggressive., Patients and Methods: We reviewed records of consecutive patients treated for newly diagnosed PTC at this single institution from 2015 to 2016. Tumor samples from these patients were genotyped to identify RET-translocated, BRAF V600E mutant, and HRAS, KRAS, and NRAS mutant tumors. Patient demographic, clinicopathologic, and outcomes data were compared to identify genotype-specific patterns of disease., Results: Of the 327 patients who underwent initial surgery for PTC during the study period, 192 (58.7%) had BRAF V600E mutant tumors (BRAF), 14 (4.3%) had RET-rearranged tumors (RET), 46 (14.1%) had RAS mutant tumors (RAS), and 75 (22.9%) had BRAF, RET, and RAS wildtype tumors. RET-driven tumors were more likely to have extrathyroidal extension (50.0% versus 27.0% for BRAF and 2.2% for RAS, P < 0.001), multifocal disease (85.7% versus 60.3%, and 44.4%, respectively, P = 0.017), and distant metastases (14.3% versus 1.1%, and 0%, respectively, P = 0.019). RET and BRAF patients also had worse disease-free survival than RAS patients (Kaplan-Meier log rank, P = 0.027)., Conclusions: Patients with RET-driven PTCs had higher rates of extrathyroidal extension, multifocal disease, and distant metastases than patients whose tumors had BRAF V600E or RAS mutations. Patients with RET-rearranged tumors had similar disease-free survival to patients with BRAF V600E mutant tumors. RET rearrangement may confer an aggressive phenotype in PTC., (© 2022. Society of Surgical Oncology.)

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

It is unknown whether transient transgenerational epigenetic responses to environmental challenges affect the process of evolution, which typically unfolds over many generations. Here, we show that in C. elegans, inherited small RNAs control genetic variation by regulating the crucial decision of whether to self-fertilize or outcross. We found that under stressful temperatures, younger hermaphrodites secrete a male-attracting pheromone. Attractiveness transmits transgenerationally to unstressed progeny via heritable small RNAs and the Argonaute Heritable RNAi Deficient-1 (HRDE-1). We identified an endogenous small interfering RNA pathway, enriched in endo-siRNAs that target sperm genes, that transgenerationally regulates sexual attraction, male prevalence, and outcrossing rates. Multigenerational mating competition experiments and mathematical simulations revealed that over generations, animals that inherit attractiveness mate more and their alleles spread in the population. We propose that the sperm serves as a "stress-sensor" that, via small RNA inheritance, promotes outcrossing in challenging environments when increasing genetic variation is advantageous., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Salivary gland acinic cell carcinoma (AciCC) has recognizable cytomorphologic features that can overlap with benign and malignant entities, creating a diagnostic challenge. AciCC harbors a t(4;9) translocation increasing nuclear receptor subfamily 4 group A member 3 (NR4A3) expression, detectable by immunohistochemistry (IHC) on surgical resection (SR). NR4A3 IHC cytology data are limited. Here, we examine NR4A3 IHC on smears, cell blocks (CBs), and SRs of AciCC and its mimickers., Methods: Our cohort comprised AciCC (including high-grade transformation), secretory carcinoma, mucoepidermoid carcinoma (MEC), Warthin tumor, pleomorphic adenoma (PA), cellular PA, carcinoma ex-PA, oncocytic carcinoma, oncocytoma, and nodular oncocytosis. NR4A3 IHC (Santa Cruz Biotechnology and Origene antibodies) was positive if more than 5% tumor cells showed nuclear staining., Results: Among CBs, 90% of AciCC cases and none of the mimickers expressed NR4A3. Among SRs, 100% of AciCC cases showed diffuse NR4A3, whereas one high-grade MEC expressed focal NR4A3. Concordance was 95% with two antibody clones. Sensitivity, specificity, positive predictive value, and negative predictive value were 90%, 100%, 100%, and 94.7% for CBs and 100%, 98.8%, 92.3%, and 100% for SRs, respectively. NR4A3 immunostaining was demonstrable on smears from an AciCC case., Conclusions: NR4A3 IHC can be a robust diagnostic tool to identify AciCC, especially for cytology specimens., (© American Society for Clinical Pathology, 2021. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Animals encounter microorganisms in their habitats, adapting physiology and behavior accordingly. The nematode Caenorhabditis elegans is found in microbe-rich environments; however, its responses to fungi are not extensively studied. Here, we describe interactions of C. elegans and Penicillium brevicompactum, an ecologically relevant mold. Transcriptome studies reveal that co-culture upregulates stress response genes, including xenobiotic-metabolizing enzymes (XMEs), in C. elegans intestine and AMsh glial cells. The nuclear hormone receptors (NHRs) NHR-45 and NHR-156 are induction regulators, and mutants that cannot induce XMEs in the intestine when exposed to P. brevicompactum experience mitochondrial stress and exhibit developmental defects. Different C. elegans wild isolates harbor sequence polymorphisms in nhr-156, resulting in phenotypic diversity in AMsh glia responses to microbe exposure. We propose that P. brevicompactum mitochondria-targeting mycotoxins are deactivated by intestinal detoxification, allowing tolerance to moldy environments. Our studies support the idea that C. elegans NHRs may be regulated by environmental cues., Competing Interests: Declarations of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)