bluuebunny/crossref_metadata_2025 huggingface dataset:
Missing digits and good approximations
Authors: Granville Andrew
Published: October 2023

James Maynard has taken the analytic number theory world by storm in the last decade, proving several important and surprising theorems, resolving questions that had seemed far out of reach. He is perhaps best known for his work on small and large gaps between primes (which were discussed, hot off the press, in our 2015Bulletin of the AMSarticle). In this article we will discuss two other Maynard breakthroughs:

— Mersenne numbers take the form2n−12^n-1and so appear as111…111111\dots 111in base 2, having no digit “00”. It is a famous conjecture that there are infinitely many such primes. More generally it was, until Maynard’s work, an open question as to whether there are infinitely many primes that miss any given digit, in any given base. We will discuss Maynard’s beautiful ideas that went into his 2019 partial resolution of this question.

— In 1926, Khinchin gave remarkable conditions for when real numbers can usually be “well approximated” by infinitely many rationals. However Khinchin’s theorem regarded 1/2, 2/4, 3/6 as distinct rationals and so could not be easily modified to cope, say, with approximations by fractions with prime denominators. In 1941 Duffin and Schaeffer proposed an appropriate but significantly more general analogy involving approximation only by reduced fractions (which is much more useful). We will discuss its 2020 resolution by Maynard and Dimitris Koukoulopoulos.
Evolution of the floral nectaries in the Primulaceae sensus lato (Ericales)
Authors: Cano Mauricio J , Ronse De Craene fls Louis
Published: October 2023

The Primuloid clade or Primulaceae sensus lato is well supported and contains several pollination syndromes, including wind pollination and insect pollination with pollen, nectar, or oil as a reward. Previous studies have recognized two types of nectaries (floral and extrafloral) with different distributions (e.g. ovary, stigma, style, pedicel). This study aimed to reassess the diversity of nectary types, and their distribution and evolution within the clade. Flowers were selected to represent the four subfamilies Maesoideae, Theophrastoideae, Primuloideae, and Myrsinoideae. The flowers were investigated for nectary tissue with electron microscopy, light microscopy, and sugar tests. Nectar is mainly exuded by gynoecial nectarostomata (in Maeseoideae, Theophrastoideae, Primuloideae, and a few basal Myrsinoideae, such as Stimpsonia and Coris) distributed at the base, middle, and top part of the ovary. Myrsinoideae is the exception with an absence of a nectary linked to buzz-pollination, or presenting nectariferous or oil-producing trichomes on the perianth and stamens. The evolution of nectaries is variable in the Primuloid clade, with Primuloideae apparently the starting point of an evolutionary reversal in terms of nectary evolution within this clade, and a high diversity of nectaries within the Myrsinoideae representing various trends that are currently under-investigated. The evolution of floral nectaries in Primulaceae presents an exciting shift from nectar-producing flowers towards a loss of nectaries, and an evolutionary reversal with a shift to the co-option of either oil-producing trichomes or nectar-producing trichomes.
The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release
Authors: Zeng Zhuo , Lan Yingying , Zhang Lijuan , Chen Yu , Gong Yali , Zuo Fangqing , Li Junda , Luo Gaoxing , Peng Yizhi , Yuan Zhiqiang
Published: October 2023

Background

Sepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation. YTH domain family 2 (YTHDF2), a well-studied N6-methyladenosine (m6A) reader that specifically recognizes and binds to m6A-modified transcripts to mediate their degradation, is connected to pathogenic and physiological processes in eukaryotes, but its effect on sepsis is still unknown. We aimed to discover the effects and mechanisms of YTHDF2 in sepsis.

Methods

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot analyses were used to measure the expression of YTHDF2, the interleukin 6 receptor (IL-6R), high-mobility group box-1 (HMGB1), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) under different in vitro conditions. Enzyme-linked immunosorbent assays were utilized to evaluate the expression of HMGB1, IL-6, IL-1β and tumor necrosis factor-α. To confirm that YTHDF2 specifically targets IL-6R mRNA, RNA immunoprecipitation and dual-luciferase reporter assays were performed. Finally, we utilized a mouse model of lipopolysaccharide (LPS)-induced sepsis to verify the effects of YTHDF2 in vivo.

Results

According to our findings, YTHDF2 was expressed at a low level in peripheral blood mononuclear cells from septic mice and patients as well as in LPS-induced RAW264.7 cells. Overexpression of YTHDF2 alleviated the inflammatory response by inhibiting HMGB1 release and JAK2/STAT1 signalling in LPS-stimulated cells. Mechanistically, YTHDF2 suppressed JAK2/STAT1 signalling by directly recognizing the m6A-modified site in IL-6R and decreasing the stability of IL-6R mRNA, thereby inhibiting HMGB1 release. In vivo experiments showed that YTHDF2 played a protective role in septic mice by suppressing the IL-6R/JAK2/STAT1/HMGB1 axis.

Conclusions

In summary, these findings demonstrate that YTHDF2 plays an essential role as an inhibitor of inflammation to reduce the release of HMGB1 by inhibiting the IL-6R/JAK2/STAT1 pathway, indicating that YTHDF2 is a novel target for therapeutic interventions in sepsis.
Lnc-PKNOX1-1 inhibits tumor progression in cutaneous malignant melanoma by regulating NF-κB/IL-8 axis
Authors: Hong Anlan , Cao Meng , Li Dongqing , Wang Yixin , Zhang Guoqiang , Fang Fang , Zhao Liang , Wang Qiang , Lin Tong , Wang Yan
Published: October 2023

Cutaneous malignant melanoma is one of the most lethal cutaneous malignancies. Accumulating evidence has demonstrated the potential influence of long non-coding RNAs (lncRNAs) in biological behaviors of melanoma. Herein, we reported a novel lncRNA, lnc-PKNOX1-1 and systematically studied its functions and possible molecular mechanisms in melanoma. Reverse transcription-quantitative PCR assay showed that lnc-PKNOX1-1 was significantly decreased in melanoma cells and tissues. Low lnc-PKNOX1-1 expression was significantly correlated with invasive pathological type and Breslow thickness of melanoma. In vitro and in vivo experiments showed lnc-PKNOX1-1 dramatically inhibited melanoma cell proliferation, migration and invasion. Mechanically, protein microarray analysis suggested that interleukin-8 (IL-8) was negatively regulated by lnc-PKNOX1-1 in melanoma, which was confirmed by western blot and ELISA. Western blot analysis also showed that lnc-PKNOX1-1 could promote p65 phosphorylation at Ser536 in melanoma. Subsequent rescue assays proved IL-8 overexpression could partly reverse the tumor-suppressing function of lnc-PKNOX1-1 overexpression in melanoma cells, indicating that lnc-PKNOX1-1 suppressed the development of melanoma by regulating IL-8. Taken together, our study demonstrated the tumor-suppressing ability of lnc-PKNOX1-1 in melanoma, suggesting its potential as a novel diagnostic biomarker and therapeutic target for melanoma.
Priorities and Progress in Diagnostic Research by the Antibacterial Resistance Leadership Group
Authors: Hanson Kimberly E , Banerjee Ritu , Doernberg Sarah B , Evans Scott R , Komarow Lauren , Satlin Michael J , Schwager Nyssa , Simner Patricia J , Tillekeratne L Gayani , Patel Robin ,   for the Antibacterial Resistance Leadership Group, Tsalik Ephraim , Abbenante Erin , Baum Keri , Souli Maria , Mocka Elizabeth , Hopkins Deborah , Giri Abhigya , Zeng Lijuan , Greenwood-Quaintance Kerryl , Dodd Andrew , Booth Grant , Li Yixuan , Waller Jason , Raza Praneeta , Sund Zoe , Wickward Cathy , Zeng Lijuan , Dai Weixiao , Hamasaki Toshimitsu , Ghazaryan Varduhi , Raterman Erica , Samuel Tamika , Lee Marina
Published: October 2023

The advancement of infectious disease diagnostics, along with studies devoted to infections caused by gram-negative and gram-positive bacteria, is a top scientific priority of the Antibacterial Resistance Leadership Group (ARLG). Diagnostic tests for infectious diseases are rapidly evolving and improving. However, the availability of rapid tests designed to determine antibacterial resistance or susceptibility directly in clinical specimens remains limited, especially for gram-negative organisms. Additionally, the clinical impact of many new tests, including an understanding of how best to use them to inform optimal antibiotic prescribing, remains to be defined. This review summarizes the recent work of the ARLG toward addressing these unmet needs in the diagnostics field and describes future directions for clinical research aimed at curbing the threat of antibiotic-resistant bacterial infections.
High-dimensional asymptotics of Langevin dynamics in spiked matrix models
Authors: Liang Tengyuan , Sen Subhabrata , Sur Pragya
Published: October 2023

We study Langevin dynamics for recovering the planted signal in the spiked matrix model. We provide a ‘path-wise’ characterization of the overlap between the output of the Langevin algorithm and the planted signal. This overlap is characterized in terms of a self-consistent system of integro-differential equations, usually referred to as the Crisanti–Horner–Sommers–Cugliandolo–Kurchan equations in the spin glass literature. As a second contribution, we derive an explicit formula for the limiting overlap in terms of the signal-to-noise ratio and the injected noise in the diffusion. This uncovers a sharp phase transition—in one regime, the limiting overlap is strictly positive, while in the other, the injected noise overcomes the signal, and the limiting overlap is zero.
A local energy-based discontinuous Galerkin method for fourth-order semilinear wave equations
Authors: Zhang Lu
Published: October 2023

This paper proposes an energy-based discontinuous Galerkin scheme for fourth-order semilinear wave equations, which we rewrite as a system of second-order spatial derivatives. Compared to the local discontinuous Galerkin methods, the proposed scheme uses fewer auxiliary variables and is more computationally efficient. We prove several properties of the scheme. For example, we show that the scheme is unconditionally stable and that it achieves optimal convergence in $L^2$ norm for both the solution and the auxiliary variables without imposing penalty terms. A key part of the proof of the stability and convergence analysis is the special choice of the test function for the auxiliary equation involving the time derivative of the displacement variable, which leads to a linear system for the time evolution of the unknowns. Then we can use standard mathematical techniques in discontinuous Galerkin methods to obtain stability and optimal error estimates. We also obtain energy dissipation and/or conservation of the scheme by choosing simple and mesh-independent interelement fluxes. Several numerical experiments are presented to illustrate and support our theoretical results.
Predicting microbial crude protein synthesis in cattle from intakes of dietary energy and crude protein
Authors: Galyean M L , Tedeschi L O
Published: October 2023

Accurate predictions of microbial crude protein (MCP) synthesis are needed to predict metabolizable protein supply in ruminants. Since 1996, the National Academies of Sciences, Engineering, and Medicine series on beef cattle nutrient requirements has used the intake of total digestible nutrients (TDN) to predict ruminal MCP synthesis. Because various tabular energy values for feeds are highly correlated, our objective was to determine whether intakes of digestible energy (DE), metabolizable energy (ME), and net energy for maintenance (NEm) could be used as predictors of MCP synthesis in beef cattle. A published database of 285 treatment means from experiments that evaluated MCP synthesis was updated with 50 additional treatment mean observations. When intakes of TDN, fat-free TDN, DE, ME, NEm, dry matter, organic matter, crude protein (CP), ether extract, neutral detergent fiber, and starch were used in a stepwise regression analysis to predict MCP, only intakes of DE and CP met the P < 0.10 criterion for entry into the model. Mixed-model regression analyses were used to adjust for random intercept and slope effects of citations to evaluate intake of DE alone or in combination with CP intake as predictors of MCP synthesis, and the intakes of TDN, ME, and NEm as alternatives to DE intake. Similar precisions in predicting MCP synthesis were obtained with all measures of energy intake (CV = root mean square error [RMSE] as a percentage of the overall mean MCP varied from 9% to 9.67%), and adding CP intake to statistical models increased precision (CV ranged from 8.43% to 9.39%). Resampling analyses were used to evaluate observed vs. predicted values for the various energy intake models with or without CP intake, as well as the TDN-based equation used in the current beef cattle nutrient requirements calculations. The coefficient of determination, concordance correlation coefficient, and RMSE of prediction as a percentage of the mean averaged 0.595%, 0.730%, and 28.6% for the four measures of energy intake, with average values of 0.630%, 0.757%, and 27.4%, respectively, for equations that included CP intake. The TDN equation adopted by the 2016 beef cattle nutrient requirements system yielded similar results to newly developed equations but had a slightly greater mean bias. We concluded that any of the measures of energy intake we evaluated can be used to predict MCP synthesis by beef cattle and that adding CP intake improves model precision.
Escherichia coli tRNA (Gm18) methyltransferase (TrmH) requires the correct localization of its methylation site (G18) in the D-loop for efficient methylation
Authors: Kohno Yoh , Ito Asako , Okamoto Aya , Yamagami Ryota , Hirata Akira , Hori Hiroyuki
Published: October 2023

TrmH is a eubacterial tRNA methyltransferase responsible for formation of 2’-O-methylguaosine at position 18 (Gm18) in tRNA. In Escherichia coli cells, only 14 tRNA species possess the Gm18 modification. To investigate the substrate tRNA selection mechanism of E. coli TrmH, we performed biochemical and structural studies. Escherichia coli TrmH requires a high concentration of substrate tRNA for efficient methylation. Experiments using native tRNA SerCGA purified from a trmH gene disruptant strain showed that modified nucleosides do not affect the methylation. A gel mobility-shift assay reveals that TrmH captures tRNAs without distinguishing between relatively good and very poor substrates. Methylation assays using wild-type and mutant tRNA transcripts revealed that the location of G18 in the D-loop is very important for efficient methylation by E. coli TrmH. In the case of tRNASer, tRNATyrand tRNALeu, the D-loop structure formed by interaction with the long variable region is important. For tRNAGln, the short distance between G18 and A14 is important. Thus, our biochemical study explains all Gm18 modification patterns in E. coli tRNAs. The crystal structure of E. coli TrmH has also been solved, and the tRNA binding mode of E. coli TrmH is discussed based on the structure.
Molecular insights on the historical dispersion of Piezodorus guildinii (Hemiptera: Pentatomidae) in Brazil
Authors: Moraes Tamara , Santos Larissa Muniz Amaral , Schwertner Cristiano Feldens , Corrêa Alberto Soares
Published: October 2023

Piezodorus guildinii (Westwood, 1837) (Hemiptera: Pentatomidae) is an important arthropod pest of soybean (Glycine max (L.) Merr.) throughout American continents. However, the historical events associated with its dispersion are poorly understood. In this study, we employed a phylogeographic approach to investigate the origin and demographic history of P. guildinii in Brazil. We analyzed the cytochrome c oxidase subunit I and Cytb gene sequences of P. guildinii individuals collected in Brazil’s 5 soybean production macro-regions and cross-referenced this information with sequences available in public databases. Our findings support an older Caribbean basin establishment for the current genealogical strains of P. guildinii, with subsequent dispersion to Brazil around 0.97 Mya. No secondary dispersion of this species from the Caribbean region to soybean areas in Brazil was identified. The Brazilian populations of P. guildinii are genetically structured across the country’s soybean macro-regions and show strong signals of continuous demographic and spatial expansion in Brazil, which may be accelerated by the soybean cropping landscape in the country. The populations from the northern region (MR5) are older than the Central and South populations. The signs of demographic expansion indicate that P. guildinii populations are increasing their effective size in soybean regions, which could reflect its importance as a soybean pest in the coming years.
Short- and long-term effects of season-long infestation of Lycorma delicatula (Hemiptera: Fulgoridae) on young apple (Malus domestica) and peach (Prunus persica) trees
Authors: Nixon Laura J , Barnes Caitlin , Wilson Charlotte , Rugh Anthony , Carper Lee , Leskey Tracy C , Tang Lisa
Published: October 2023

Lycorma delicatula White, commonly called spotted lanternfly, is an invasive fulgorid that was first detected in the United States in Pennsylvania in 2014 and has spread across Eastern states. Lycorma delicatula is a phloem feeder, and feeding of persistent populations can cause wilt and dieback in host plants. Vineyards in infested regions have experienced vine loss, where damage has been attributed to L. delicatula. Nymphal and adult lifestages have been observed on cultivated apple and peach trees, but the feeding effects of this pest on these crops have not been quantified. Here, we caged young potted apple and peach trees and infested them with 50 nymphal or 25 adult L. delicatula per plant for 3 months and tracked plant health. Horticultural measurements including trunk diameter, height, leaf drop, and photosynthesis rates were recorded before, during, and after the infestation. To evaluate the long-term effects of infestation, all apple and peach trees were removed from pots and planted in an orchard block where their phenology, growth, and physiology could be evaluated the following growing season. Short- and long-term measurements showed no significant differences in apple tree health between infested and noninfested trees. There was a significant reduction in the growth of trunk diameter in peach trees during exposure to early-instar nymphs; infested peach trees also had significantly increased frost damage to buds the following spring. However, there were no long-term impacts on peach growth and physiology. These results indicate that L. delicatula likely will not be a major threat to these deciduous fruit crops.
Real-world prostate-specific antigen response and progression to castration-resistant prostate cancer among men with metastatic castration-sensitive prostate cancer treated with apalutamide: a multi-institutional study in the Chu-shikoku Japan Urological Consortium
Authors: Tohi Yoichiro , Kato Takuma , Kobayashi Keita , Daizumoto Kei , Fukuhara Hideo , Ohira Shin , Katayama Satoshi , Shimizu Ryutaro , Takamoto Atsushi , Nishimura Kenichi , Ikeda Kenichiro , Nagami Taichi , Hayashida Yushi , Hirama Hiromi , Naito Hirohito , Tomida Ryotaro , Sasaki Yutaro , Yamamoto Shinkuro , Shimizu Shinjiro , Sugimoto Mikio ,   Chu-shikoku Japan Urological Consortium
Published: October 2023

Background

Japanese men receiving apalutamide often experience skin-adverse events (AEs), possibly requiring treatment interruption or dose reduction. However, concerns have arisen regarding the impact of these adjustments on the efficacy of apalutamide. Our study evaluated the efficacy, safety, and persistence of apalutamide in men with metastatic castration-sensitive prostate cancer (mCSPC).

Methods

We retrospectively reviewed the medical records of 108 men with mCSPC from 14 Japanese institutions. The primary outcomes were the efficacy of apalutamide: prostate-specific antigen (PSA) response (50%, 90% and < 0.2 decline) and progression to castration-resistant prostate cancer (CRPC). The secondary outcomes were the skin-AE and compliance of apalutamide.

Results

PSA50%, PSA90% and PSA < 0.2 declines were observed in 89.8, 84.3 and 65.7%, and the median time to CRPC progression was not reached. PSA < 0.2 decline and an initial full dose of apalutamide were significantly associated with a longer time to CRPC. The most common AE was skin-AE (50.9%), and there was no association between the occurrence of skin-AE and the time to CRPC (P = 0.72). The median apalutamide persistence was 29 months, which was longer in the initial full dose recipients than in the reduced dose recipients. The dosage is reduced in about 60% of patients within the first year of treatment in the initial full dose recipients.

Conclusions

Our findings indicate the effectiveness of apalutamide in Japanese men with mCSPC, despite a substantial portion requiring dose reduction within a year among the initial full dose recipients.
Kinopedagogy as non-conservative education and time as the abode of humans
Authors: Oliverio Stefano
Published: October 2023

In this paper, the endeavour to understand how to think of education ‘after progress’, viz. in an age in which progress has become problematic, is undertaken by focusing on the theme of time. Dovetailing Klaus Mollenhauer’s reflections on the rise of the Bildungszeit at the dawn of modernity with Thomas Popkewitz’s analyses of ‘cosmopolitan time’ presiding over pedagogical reform from the 19th century to the present, I shall, first, explore this temporal configuration of modern schooling (which goes hand in hand with a specific understanding of the child). Against this backdrop, I shall, second, advance an interpretive hypothesis, that of substituting what will be called the ‘child-as-migrant’ for the ‘cosmopolitan child’, by appropriating, in an educational key, some insights of Thomas Nail’s ‘migrant cosmopolitanism’. I shall thereby suggest an alternative view of ‘progressivity’, construed not along modern-developmentalist lines but as a form of non-conservativeness, linked with a recognition of the ekstatikon (that is, destabilizing) character of time. This will require a revisiting of some Aristotelian intuitions about time as the rhythm of movement, reinterpreted as the affective experience of that ek-statikon without which there is no potential for the new. Accordingly, ‘progressive’ education (in the different interpretation investigated here) is the concern to allow all of us as ‘migrants’ to live actively in the abode of our ek-static and unpredictable condition and, therefore, to be vulnerable to the new, without merely remaining in a taken-for-granted ethos, cosmopolitan, inclusive, and progress-oriented though it may be. (Editor's note: This paper forms part of the suite entitled ‘Education After Progress’.)
Psychological Distress Among Parents of Children With Chronic Health Conditions and Its Association With Unmet Supportive Care Needs and Children’s Quality of Life
Authors: Thomas Sangeetha , Ryan Nicholas P , Byrne Linda K , Hendrieckx Christel , White Victoria
Published: October 2023

Objective

To assess parent psychological distress in families of children with common chronic health conditions (CHC) and to explore relationships between parent psychological distress, unmet supportive care needs and children’s quality of life (QoL).

Method

Cross-sectional study involving parents of children diagnosed with a common CHC between 0 and 12 years of age and who had received treatment within the last 5 years. Eligible parents completed an online survey, that included the Depression Anxiety Stress Scale (DASS-21) assessing distress in parents and a 34-item assessment of unmet supportive care needs across 6 domains. Parents completed ratings of their child’s current functioning (QoL) using the 23-item PedsQL. Multivariable regression models examined the relative association between unmet needs, children’s QoL and parents’ depression, anxiety, and stress.

Results

The sample consisted of 194 parents of children with congenital heart disease (n=97; 50%), diabetes (n=50; 26%), cancer (n=39; 20%), and asthma (n=8; 4%). A significant proportion of parents had moderate–severe symptoms of depression (26%), anxiety (38%), and stress (40%). Of the PedsQL scales, the poorest outcomes were found for emotional and school functioning. Multivariable analyses showed that both higher unmet needs and poorer child emotional functioning were associated with parent depression, anxiety, and stress symptoms.

Conclusion

Evidence linking parent distress symptoms to higher unmet needs and poorer child emotional functioning suggests these factors may be targets for interventions to alleviate parent distress. Longitudinal research using larger samples is required to replicate findings, and clarify the magnitude and direction of associations.
Shifting Paradigms, Not Identities: LGBTIQ+ Refugees Queering Temporalities in Denmark
Authors: Schröder Rieke
Published: October 2023

In light of tightening immigration policies, LGBTIQ+ refugees are oftentimes presented as ‘stuck’ in the asylum regime, having to continuously perform their sexual orientation, gender identity, and/or expression (SOGIE) in a fixed way. This article rethinks this narrative, arguing that rather than being stuck, LGBTIQ+ refugees are navigating through spatialized temporalities—during and after their asylum process. Drawing on semi-structured interviews with LGBTIQ+ refugees in Denmark, this article explores how LGBTIQ+ refugees queer temporality in multiple ways: First, I demonstrate how the so-called Danish ‘paradigm shift’ is producing uncertain temporalities for LGBTIQ+ refugees. Second, I analyse how LGBTIQ+ refugees are becoming and remaining queer after having been granted asylum. Finally, I explore how LGBTIQ+ refugees are (un)able to ‘come out’ of the asylum system. By claiming belonging to the Danish nation-state, they seek a change in the asylum system and demand permanent residence to express their SOGIE fluently.
A Rare Presentation of Aggressive Renal Cell Carcinoma and the Utility of Early Molecular Testing in Rapidly Progressing Malignancies: A Case Report
Authors: McLoughlin Daniel E , Chevalier Nicholas , Choy Edwin , Cote Gregory M , Gao Xin , Juric Dejan , Reynolds Kerry L
Published: October 2023

In rapidly progressing cancers, appropriate selection of first-line therapy is essential in prolonging survival. Alongside immunohistochemistry (IHC), comprehensive genomics, including whole exome and transcriptome sequencing (WES/WTS), can improve diagnostic accuracy and guide therapeutic management. Here, we report a young patient with rapidly progressing malignancy and unexpected post-mortem results, a scenario that may have been altered by early, comprehensive genomic sequencing. A 43-year-old man with no relevant medical history presented to the emergency department with progressive cough and dyspnea despite treatment for pneumonia. Radiology revealed enlarged subcarinal, hilar, retroperitoneal, and mesenteric lymph nodes, suspicious for metastasis, and a right kidney mass. Pathologic analysis of a retroperitoneal lymph node was felt to be most consistent with metastatic epithelioid angiomyolipoma (mEAML). Three weeks later, he was urgently treated with an mTOR inhibitor for presumed mEAML due to rapid clinical decline, and a subsequent 4R lymph node biopsy was performed to confirm the diagnosis and identify genomic targets via IHC and WES/WTS. Unfortunately, he developed hypoxic respiratory failure, and only posthumously did WES/WTS reveal pathogenic variants in BAP1 and VHL, consistent with clear cell renal cell carcinoma (ccRCC).

With an earlier ccRCC diagnosis, he would have received combination immunotherapy/tyrosine kinase inhibition, which has significantly greater activity than mTOR inhibition in ccRCC. He could have received systemic treatment earlier, with optimal therapy, while potentially carrying lower tumor burden and greater clinical stability. In cases of rapidly progressing malignancies with complex histopathological presentations, early comprehensive molecular-based testing can aid in diagnosis and critical therapeutic decision-making.
The uncounted casualties of war: suicide in combat veterans
Authors: Sher Leo
Published: October 2023

Military conflicts are ubiquitous. There are a lot of combat veterans around the world. Suicidality in combat veterans is a large and important issue. In this article, the author discusses some aspects of this issue. The combat environment is characterized by violence, physical strains, separation from loved ones and other hardships. Combat deployment may lead to multiple emotional, cognitive, psychosomatic symptoms, suicidal ideation and behavior. Pre-deployment, deployment and post-deployment adversities may increase suicide risk in combat veterans. The act of killing in combat is a stressor which may raise suicide risk. Combat-related injuries are associated with increased suicide risk. Post-deployment difficulties of reintegrating into civilian life may lead to depression and suicidality. Studies suggest that suicidal behavior in combat veterans may have a neurobiological basis. Prevention of suicide among combat veterans should include pre-deployment screening to exclude individuals with psychiatric disorders; psychological support and prevention of harassment and/or abuse during deployment; psychosocial support after deployment; diagnosing and treating psychiatric and medical disorders including neurological disorders; frequent suicide screening; education of mental and non-mental health clinicians, war veterans, their families and friends regarding signs/symptoms of suicidality; and restriction of access to lethal means. We need to study the specific psychobiology of combat veterans to understand how to develop effective suicide prevention interventions for this population.
Multimodal Neuroimaging Summary Scores as Neurobiological Markers of Psychosis
Authors: Rodrigue Amanda L , Hayes Rebecca A , Waite Emma , Corcoran Mary , Glahn David C , Jalbrzikowski Maria
Published: October 2023

Background and Hypothesis

Structural brain alterations are well-established features of schizophrenia but they do not effectively predict disease/disease risk. Similar to polygenic risk scores in genetics, we integrated multifactorial aspects of brain structure into a summary “Neuroscore” and examined its potential as a marker of disease.

Study Design

We extracted measures from T1-weighted scans and diffusion tensor imaging (DTI) models from three studies with schizophrenia and healthy individuals. We calculated individual-level summary scores (Neuroscores) for T1-weighted and DTI measures and a combined score (Multimodal Neuroscore-MM). We assessed each score’s ability to differentiate schizophrenia cases from controls and its relationship to clinical symptomatology, intelligence quotient (IQ), and medication dosage. We assessed Neuroscore specificity by performing all analyses in a more inclusive psychosis sample and by using scores generated from MDD effect sizes.

Study Results

All Neuroscores significantly differentiated schizophrenia cases from controls (T1 d = 0.56, DTI d = 0.29, MM d = 0.64) to a greater degree than individual brain regions. Higher Neuroscores (ie, increased liability) were associated with lower IQ (T1 β = −0.26, DTI β = −0.15, MM β = −0.30). Higher T1-weighted Neuroscores were associated with higher positive and negative symptom severity (Positive β = 0.21, Negative β = 0.16); Higher Multimodal Neuroscores were associated with higher positive symptom severity (β = 0.30). SZ Neuroscores outperformed MDD Neuroscores in predicting IQ (T1: z = 3.5, q = 0.0007; MM: z = 1.8, q = 0.05).

Conclusions

Neuroscores are a step toward leveraging widespread structural brain alterations in psychosis to identify robust neurobiological markers of disease. Future studies will assess ways to improve neuroscore calculation, including developing the optimal methods to calculate neuroscores and considering disorder overlap.
T-Cell Mediated Immune Rejection of Beta-2-Microglobulin Knockout Induced Pluripotent Stem Cell-Derived Kidney Organoids
Authors: Gaykema Lonneke H , van Nieuwland Rianne Y , Lievers Ellen , Moerkerk Wessel B J , de Klerk Juliette A , Dumas Sébastien J , Kers Jesper , Zaldumbide Arnaud , van den Berg Cathelijne W , Rabelink Ton J
Published: October 2023

Immune evasive induced pluripotent stem cell (iPSC)-derived kidney organoids, known as “stealth” organoids, hold promise for clinical transplantation. To address immune rejection, we investigated the impact of genetically modifying human leukocyte antigen (HLA) class I in kidney organoids prior to transplantation. By using CRISPR-Cas9, we successfully knocked out beta-2-microglobulin (B2M), resulting in iPSCs devoid of HLA class I surface expression. In vitro, the B2M knockout protected kidney organoids derived from these iPSCs against T-cell rejection. To assess in vivo protection, unmodified (control) and B2M–/– kidney organoids were transplanted into humanized mice engrafted with human peripheral blood mononuclear cells (PBMCs). Successful engraftment of human PBMCs was confirmed, and after 4 weeks, we observed no discernible difference in the infiltration rate, proliferation, or cytotoxicity of CD4+ and CD8+ T cells between control and B2M–/– organoids. Both groups of organoids showed compromised tissue integrity, displaying tubulitis and loss of tubule integrity. Notably, while B2M–/– organoids failed to express HLA class I on their cell surface, there was preexisting expression of HLA class II in both control and B2M–/– organoids transplanted into mice with human PBMCs. HLA class II expression was not limited to antigen-presenting cells but also evident in epithelial cells of the kidney organoid, posing an additional immunological challenge to its transplantation. Consequently, we conclude that B2M knockout alone is insufficient to protect iPSC-derived kidney organoids from T-cell-mediated immune rejection. Additionally, our findings suggest that modulating HLA class II signaling will be necessary to prevent rejection following transplantation.
A new basal ginglymodian fish (Holostei: Neopterygii) from the Middle Triassic (Anisian) Luoping Biota, Yunnan, China
Authors: Xu Guang-Hui , Ma Xin-Ying
Published: October 2023

Ginglymodians (e.g. gars) are a group of holostean fishes with a rich fossil history in the Mesozoic. The resolution of interrelationships among extinct ginglymodians is central to the problem of understanding the origin of this clade. Here, a new fossil ginglymodian, Diandongichthys ocellatus gen. et sp. nov., is described based on 13 well-preserved specimens from the Early-Middle Triassic (Anisian) marine deposits exposed in Luoping, eastern Yunnan, China. The discovery documents one of the oldest and smallest ginglymodians hitherto known from the Middle Triassic, with a maximum standard length of 41 mm. Diandongichthys, although displaying several synapomorphies of ginglymodians, retains some primitive states with respect to other early ginglymodians (e.g. a short snout without anterior infraorbitals, a maxilla ending below the orbit, and a median gular); consequently, it is nested at the base of the Ginglymodi in this phylogenetic study. Besides body shape, some autapomorphies on the cranial bones and caudal fin easily distinguish Diandongichthys from other members of this clade. The discovery provides new insights into the origin and early diversification of ginglymodian fishes.
Transmission of Spinach Downy Mildew via Seed and Infested Leaf Debris
Authors: Klosterman Steven J. , Clark Kelley J. , Anchieta Amy G. , Kandel Shyam L. , Mou Beiquan , McGrath Margaret T. , Correll James C. , Shishkoff Nina
Published: October 2023

Spinach downy mildew, caused by the obligate oomycete pathogen Peronospora effusa, is a worldwide constraint on spinach production. The role of airborne sporangia in the disease cycle of P. effusa is well established, but the role of the sexual oospores in the epidemiology of P. effusa is less clear and has been a major challenge to examine experimentally. To evaluate seed transmission of spinach downy mildew via oospores in this study, isolated glass chambers were employed in two independent experiments to grow out oospore-infested spinach seed and noninfested seeds mixed with oospore-infested crop debris. Downy mildew diseased spinach plants were observed 37 and 34 days after planting in the two isolator experiments, respectively, in the chambers that contained one of two oospore-infested seed lots or seeds coated with oospore-infested leaves. Spinach plants in isolated glass chambers initiated from seeds without oospores did not show downy mildew symptoms. Similar findings were obtained using the same seed lot samples in a third experiment conducted in a growth chamber. In direct grow out tests to examine oospore infection on seedlings performed in a containment greenhouse with oospore-infested seed of two different cultivars, characteristic Peronospora sporangiophores were observed growing from a seedling of each cultivar. The frequency of seedlings developing symptoms from 82 of these oospore-infested seed indicated that approximately 2.4% of seedlings from infested seed developed symptoms, and 0.55% of seedlings from total seeds assayed developed symptoms. The results provide evidence that oospores can serve as a source of inoculum for downy mildew and provide further evidence of direct seed transmission of the downy mildew pathogen to seedlings in spinach via seedborne oospores.
Enhancing Nix‐dependent mitophagy relieves AKI by restricting TREM‐1‐mediated hyperactivation of inflammasome in platelets
Authors: Pan Pan , Chen Jie , Xie Fei , Guo Yinghua , Liu Xudong , Zhang Dong , Xie Lixin , Su Longxiang
Published: October 2023

Platelets are highly involved in inflammation and organ injury under pathological conditions. The mitophagy in platelets may restrict hyperactivation of the inflammasome and relieve acute kidney injury (AKI). Cecal ligation puncture (CLP)/LPS‐induced AKI Triggering receptor expressed on myeloid cells (TREM‐1)‐knockout mice models were established. Additionally, septic patients with AKI were also included. TREM‐1 expression in platelets and inflammasome activation were examined. Platelet transfer assays were performed to investigate the contribution of platelet TREM‐1 to renal injury. Mitophagy was evaluated in the context of inflammation. BNIP3L/Nix knockout mice were used to examine the relationship between platelet mitophagy and inflammatory activation. The results showed that the level of TREM‐1 was increased and the platelet inflammasome was hyperactivated in CLP mice and septic patients, and TREM‐1 activated platelet inflammasomes. TREM‐1 deletion significantly abrogated hyperactivation of the platelet inflammasome and dramatically reduced AKI, whereas ablation of the mitophagy receptor BNIP3L/Nix induced the accumulation of damaged mitochondria and hyperactivation of platelet inflammasomes in CLP mice. BNIP3L/Nix controlled platelet inflammasome activation, and an amplification loop of platelet inflammasome activation and dysfunctional mitochondria controlled sepsis‐related AKI. Therefore, targeting TREM‐1 and NLRP3/BNIP3L in platelets may represent a novel therapeutic strategy for treating septic AKI.
Autophagy as a therapeutic mechanism to kill drug-resistant cancer cells
Authors: Booth Laurence , Roberts Jane L. , Poklepovic Andrew , Dent Paul
Published: October 2023

Herein we discuss multiple pre-clinical projects developed by our group that have been translated into patients at Massey Cancer Center. Our work has used multi-kinase inhibitors, for example, sorafenib, regorafenib and neratinib, and combined with additional agents, for example, histone deacetylase inhibitors, the thymidylate synthase inhibitor pemetrexed, and PDE5 inhibitors. In broad-brush terms, our experience has been that these drug combinations enhance signaling by ATM-AMPK-ULK-1 and decrease signaling from growth factor receptors and RAS proteins, thereby lowering the activities of the intracellular signaling kinase ERK1/2, AKT, mTOR and p70S6K. This collectively results in reduced protein synthesis and the induction of an endoplasmic reticulum stress response alongside autophagosome formation and autophagic flux. The rupture of autolysosomes, releasing proteases such as cathepsin B into the cytosol results in the cleavage and activation of the toxic BH3 domain protein BID which cooperates with BAX, BAK and BIM to cause mitochondrial dysfunction, leading to the release of cytochrome c and AIF, which then execute the tumor cell. For each of our two-drug combinations, we then performed additional laboratory-based studies to define the development of evolutionary resistance mechanisms, with the long-term concept of performing new three-drug clinical trials to prolong therapeutic efficacy and disease control.
Chidamide plus prednisone, cyclophosphamide, and thalidomide for relapsed or refractory peripheral T-cell lymphoma: A multicenter phase II trial
Authors: Liang Jinhua , Wang Li , Wang Xiaodong , Cui Guohui , Zhou Jianfeng , Xing Tongyao , Du Kaixin , Xu Jingyan , Wang Luqun , Liang Rong , Chen Biyun , Cheng Jian , Shen Haorui , Li Jianyong , Xu Wei
Published: October 2023

Background:

Although the treatment of peripheral T-cell lymphoma (PTCL) has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory—particularly for relapsed or refractory (R/R) patients. This phase II trial was designed to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate the standard chemotherapy for a variety of reasons.

Methods:

We conducted a multicenter phase II clinical trial in which we combined chidamide (30 mg twice weekly) with prednisone (20 mg daily after breakfast), cyclophosphamide (50 mg daily after lunch), and thalidomide (100 mg daily at bedtime) (the CPCT regimen) for a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. Forty-five patients were ultimately enrolled from August 2016 to April 2021 with respect to Chinese patients at nine centers. Our primary objective was to assess the overall response rate (ORR) after the treatment with CPCT.

Results:

Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% (32/45) and 28.9% (13/45), respectively, and after a median follow-up period of 56 months, the median progression-free survival (PFS) and overall survival (OS) were 8.5 months and 17.2 months, respectively. The five-year PFS and OS rates were 21.2% (95% confidence interval [CI], 7.9–34.5%) and 43.8% (95% CI, 28.3–59.3%), respectively. The most common adverse event was neutropenia (20/45, 44.4%), but we observed no treatment-related death.

Conclusion:

The all-oral CPCT regimen was an effective and safe regimen for R/R PTCL patients who could not tolerate standard chemotherapy for various reasons.

Trial Registration:

ClinicalTrials.gov, NCT02879526.
Spindle Cell–Predominant Trichodiscoma With Palisading Arrangement: A Rare Variant
Authors: Linfante Anthony , Carrillo Brenda , Jones Jason , Goodwin Brandon
Published: October 2023

Spindle cell–predominant trichodiscoma (SCPT) is a benign adnexal neoplasm, best categorized within the trichodiscoma–fibrofolliculoma continuum. SCPTs clinically present as dome-shaped papules usually on the face, particularly on the nose or the nasolabial fold. The SCPT variant has been described as a particularly cellular trichodiscoma composed of small interweaving fascicles and sheets of spindle cells. Identical lesions were previously referred to as neurofollicular hamartomas because of their predominantly fascicular stromal cellularity and focal S100 positivity. In this article, we report a rare variant of SCPT with a palisaded arrangement. The patient is a middle-aged man with no significant dermatologic history who presented with a skin-colored papule on the left nasal ala. It had been present for approximately 10 years with only minimal growth over that time. A biopsy was obtained. Histopathological analysis revealed a dermal papule composed of bland spindle cells arranged in a striking palisading pattern within a fibromyxoid stroma with associated peripheral hyperplasia of sebaceous glands. The palisaded pattern shared features reminiscent of Verocay bodies of a schwannoma. Immunohistochemical studies revealed stromal spindled cells with a strong and diffuse pattern of CD34 expression and absent S100 and SOX10 expressions. To our knowledge, only 2 cases of SCPT with a palisaded pattern have been presented. SCPT with a palisaded pattern is a rare histopathologic variant that may resemble a schwannoma but can be recognized by its strong epithelial components and immunohistochemical staining pattern.
A Rare Case of Primary Cutaneous Gamma-Delta T-cell Lymphoma with Aberrant B-cell Marker Expression
Authors: Trivedi Apoorva , Yabe Mariko , Dogan Ahmet , Epstein-Peterson Zachary D. , Myskowski Patricia L. , Arcila Maria E. , Linos Konstantinos
Published: October 2023

Primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) is a rare and diagnostically challenging primary skin lymphoma. We present a case of a 78-year-old otherwise healthy man who developed nonhealing nodules on his right posterior calf. Initial biopsy showed a dense, atypical, lymphoid infiltrate with gamma-delta and cytotoxic T-cell immunophenotypes. The diagnosis of PCGDTL was rendered; however, concurrent flow cytometry revealed expression of aberrant B-cell markers, including CD19 and cytoplasmic CD79a. Subsequent immunohistochemical studies corroborated this result. We report the extremely rare phenomenon of aberrant B-cell marker expression in PCGDTL, the first formally reported case to our knowledge.
Investigating Weekend Effect in the Management of Upper and Lower Extremity Degloving Injuries
Authors: Varagur Kaamya , Sullivan Janessa , Chiang Sarah N. , Skolnick Gary B. , Sacks Justin M. , Christensen Joani M.
Published: October 2023

Background:

Weekend presentation has been associated with adverse outcomes in emergent conditions, including stroke, myocardial infarction, and critical limb ischemia. We examine whether a weekend effect exists in the management of and outcomes after extremity degloving injuries.

Methods:

The cohort included adults presenting with open extremity degloving injuries to a tertiary level one trauma center between June 2018 and May 2022. We collected demographics, comorbidities, injury information, interventions, and complications. Propensity score weighting was used to minimize confounding differences between those presenting on weekends (Sat–Sun) versus weekdays (Mon–Fri). Weighted regressions were used to examine differences in interventions by day of presentation. Multivariable weighted regressions accounting for differences in interventions received were used to examine whether weekend presentation was associated with amputation risk, complications, or functional deficits.

Results:

Ninety-five patients with 100 open extremity degloving injuries were included. In total, 39% of injuries were weekend-presenting. There was a higher rate of noninsulin-dependent diabetes among patients presenting on weekends (P = 0.03). Weekend-presenting injuries had higher median Injury Severity Scores (P = 0.04). Propensity-weighted regression analysis revealed differences in interventions received on weekends, including lower rates of pedicled and free flaps and bone graft, and increased rates of negative-pressure wound therapy (P ≤ 0.02). Multivariable regression analysis revealed weekend presentation was a significant independent risk factor for amputation of the affected extremity [odds ratio 2.27, 95% CI (1.01–5.33), P = 0.05].

Conclusion:

Weekend presentation may impact interventions received and amputation risk in patients presenting with open extremity degloving injuries.