bluuebunny/crossref_metadata_2025 huggingface dataset:
Next-generation genetic sexing strain establishment in the agricultural pestCeratitis capitata
Authors: Davydova Serafima , Liu Junru , Kandul Nikolay P. , Braswell W. Evan , Akbari Omar S. , Meccariello Angela
Published: October 2023

Tephritid fruit fly pests pose an increasing threat to the agricultural industry due to their global dispersion and a highly invasive nature. Here we showcase the feasibility of an early-detection SEPARATOR sex sorting approach through using the non-model Tephritid pest,Ceratitis capitata. This system relies on female-only fluorescent marker expression, accomplished through the use of a sex-specific intron of the highly-conservedtransformergene fromC. capitataandAnastrepha ludens. The herein characterized strains have 100% desired phenotype outcomes, allowing accurate male-female separation during early development. Overall, we describe an antibiotic and temperature-independent sex-sorting system inC. capitata, which, moving forward, may be implemented in other non-model Tephritid pest species. This strategy can facilitate the establishment of genetic sexing systems with endogenous elements exclusively, which, on a wider scale, can improve pest population control strategies like sterile insect technique.
Early steps of multi-receptor viral interactions dissected by high-density, multi-color single molecule mapping in living cells
Authors: Mateos Nicolas , Gutierrez-Martinez Enric , Angulo-Capel Jessica , Carlon-Andres Irene , Padilla-Parra Sergi , Garcia-Parajo Maria F. , Torreno-Pina Juan Andres
Published: October 2023

Direct visualization of the early steps of multi-receptor viral interactions at the singlemolecule level has been largely impeded by the technical challenges associated to imaging individual multi-molecular systems at relevant spatial (nanometer) and temporal (millisecond) scales. Here, we present a four-color, high-density single-molecule spatiotemporal mapping methodology to capture real-time interactions between individual viruses and three different viral (co-)receptors on the membrane of living immune cells derived from donors. Together with quantitative tools, our approach revealed the existence of a coordinated spatiotemporal diffusion of the three different (co-)receptors prior to viral-engagement. By varying the temporal-windows of cumulated single-molecule localizations, we discovered that such a concerted diffusion impacts on the residence time of viruses on the host membrane and potential viral infectivity. Overall, our methodology opens a new door to the systematic analysis of the initial steps of viralhost interactions and paves the way to the investigation of other multi-molecular systems at the single-molecule level.
RAG1 and RAG2 Non-core Regions Are Implicated in Leukemogenesis and Off-target V(D)J Recombination in BCR-ABL1-driven B-cell Lineage Lym-phoblastic Leukemia
Authors: Yu Xiaozhuo , Zhou Wen , Chen Xiaodong , He Shunyu , Qin Mengting , Yuan Meng , Wang Yang , Odhiambo Woodvine otieno , Miao Yinsha , Ji Yanhong
Published: October 2023

The evolutionary conservation of non-core RAG regions suggests significant roles that might involve quantitative or qualitative alterations in RAG activity. Off-target V(D)J recombination contributes to lymphomagenesis and is exacerbated by RAG2’ C-terminus absence in Tp53-/-mice thymic lymphomas. However, the genomic stability effects of non-core regions from both cRAG1 and cRAG2 inBCR-ABL1+Blymphoblastic leukemia (BCR-ABL1+B-ALL), the characteristics, and mechanisms of non-core regions in suppressing off-target V(D)J recombination remains unclear. Here, we established three mouse models ofBCR-ABL1+B-ALL in mice expressing full-length RAG (fRAG), core RAG1 (cRAG1), and core RAG2 (cRAG2). The cRAG (cRAG1 and cRAG2) leukemia cells exhibited greater malignant tumor characteristics compared to fRAG cells. Additionally, cRAG cells showed higher frequency of off-target V(D)J recombination and oncogenic mutations than fRAG. We also revealed decreased RAG cleavage accuracy in cRAG cells and a smaller recombinant size in cRAG1 cells, which could potentially exacerbate off-target V(D)J recombination in cRAG cells. In conclusion, these findings indicate that the non-core RAG regions, particularly the non-core region of RAG1, play a significant role in preserving V(D)J recombination precision and genomic stability inBCR-ABL1+B-ALL.
A dicer-like3 protein affects paramutation at multiple loci inZea mays
Authors: Narain Ankur S. , Liao Irene T. , Talbot Joy-El R.B. , Deans Natalie C. , Hollick Jay B.
Published: October 2023

Paramutation is a process by which meiotically-heritable gene regulation is altered bytrans-homolog interactions. InZea mays, genetic screens for functions maintaining paramutation-induced repressed states have identified loci encoding small RNA biogenesis components, thus implicating small RNAs in mediating thesetrans-homolog communications. Here we report that therequired to maintain repression5locus encodes the sole dicer-like3 protein responsible for non-anther-specific 24-nucleotide RNA production. We found dicer-like3 is essential for mediating paramutation at thebooster1locus and for the meiotic maintenance of transcriptionally repressed states at thepurple plant1locus. Despite an expected role in mediating RNA-directed DNA methylation, we found 5-methylcytosine levels largely unchanged at multiple repetitive sequences indicer-like3mutants, with minimal compensation from other small RNA sizes. The minor effects on plant heights and flowering time seen in the absence of dicer-like3 contrasts with other paramutation mutants and we highlight one specific allele repressed by RNA polymerase IV yet unaffected by dicer-like3 loss. These findings highlight diverse regulatory functions for individual components of 24-nucleotide biogenesis occurring in the grasses and support a working model in which this small RNA size class mediatestrans-homolog interactions that drive meiotically-heritable changes in gene regulation.
ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer
Authors: Wee Yinshen , Wang Junhua , Wilson Emily C. , Rich Coulson P. , Rogers Aaron , Tong Zongzhong , DeGroot Evelyn , Gopal Y.N. Vashisht , Davies Michael A. , Ekiz H. Atakan , Tay Joshua K.H. , Stubben Chris , Boucher Kenneth M. , Oviedo Juan M. , Fairfax Keke C. , Williams Matthew A. , Holmen Sheri L. , Wolff Roger K. , Grossmann Allie H.
Published: October 2023

Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.
Hydrogel-polyurethane fiber composites with enhanced microarchitectural control for heart valve replacement
Authors: Robinson Andrew , Nkansah Abbey , Bhat Sanchita , Karnik Shweta , Jones Sarah , Fairley Ashauntee , Leung Jonathan , Wancura Megan , Sacks Michael , Dasi Lakshmi , Cosgriff-Hernandez Elizabeth
Published: October 2023

Polymeric heart valves offer the potential to overcome the limited durability of tissue based bioprosthetic valves and the need for anticoagulant therapy of mechanical valve replacement options. However, developing a single-phase material with requisite biological properties and target mechanical properties remains a challenge. In this study, a composite heart valve material was developed where an electrospun mesh provides tunable mechanical properties and a hydrogel coating confers an antifouling surface for thromboresistance. Key biological responses were evaluated in comparison to glutaraldehyde-fixed pericardium. Platelet and bacterial attachment were reduced by 38% and 98%, respectively, as compared to pericardium that demonstrated the antifouling nature of the hydrogel coating. There was also a notable reduction (59%) in the calcification of the composite material as compared to pericardium. A custom 3D printed hydrogel coating setup was developed to make valve composites for device-level hemodynamic testing. Regurgitation fraction (9.6 ± 1.8%) and effective orifice area (1.52 ± 0.34 cm2) met ISO 5840-2:2021 requirements. Additionally, the mean pressure gradient was comparable to current clinical bioprosthetic heart valves demonstrating preliminary efficacy. Although the hemodynamic properties are promising, it is anticipated that the random microarchitecture will result in suboptimal strain fields and peak stresses that may accelerate leaflet fatigue and degeneration. Previous computational work has demonstrated that bioinspired fiber microarchitectures can improve strain homogeneity of valve materials toward improving durability. To this end, we developed advanced electrospinning methodologies to achieve polyurethane fiber microarchitectures that mimic or exceed the physiological ranges of alignment, tortuosity, and curvilinearity present in the native valve. Control of fiber alignment from a random fiber orientation at a normalized orientation index (NOI) 14.2 ± 6.9% to highly aligned fibers at a NOI of 85.1 ± 1.4%. was achieved through increasing mandrel rotational velocity. Fiber tortuosity and curvilinearity in the range of native valve features were introduced through a post-spinning annealing process and fiber collection on a conical mandrel geometry, respectively. Overall, these studies demonstrate the potential of hydrogel-polyurethane fiber composite as a heart valve material. Future studies will utilize the developed advanced electrospinning methodologies in combination with model-directed fabrication toward optimizing durability as a function of fiber microarchitecture.
Repurposing of Glatiramer Acetate to Treat Heart Diseases
Authors: Aviel Gal , Elkahal Jacob , Umansky Kfir Baruch , Bueno-Levy Hanna , Miyara Shoval , Lendengolts Daria , Zhang Lingling , Petrover Zachary , Kain David , Shalit Tali , Aharoni Rina , Arnon Ruth , Mishaly David , Katz Uriel , Nachman Dean , Ammar Mahdi , Asleh Rabea , Amir Offer , Tzahor Eldad , Sarig Rachel
Published: October 2023

Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer-acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction, as well as in a rat model of ischemic HF. We provide bothin vivoandin vitromechanistic evidence indicating that in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis, mediated partially by extracellular vesicles carrying a pro-reparative cargo. Finally, as GA is a widely used drug with established efficacy and safety history, we conducted a small, prospective, randomized trial to determine its effect on patients admitted to the hospital with acute decompensated HF (ADHF). Strikingly, a short-term add-on administration of GA, resulted in marked reduction in the cytokine surge and NT-proBNP levels, both associated with acute HF exacerbations. Overall, these findings demonstrate the efficacy of GA in attenuating acute myocardial injury and modulating the inflammatory process in animal models and humans and highlight the potential of GA as a future therapy for a myriad of heart diseases.

One Sentence Summary

Glatiramer acetate promotes reparative processes in rodent models of cardiac injury and reduces the inflammatory process in ADHF patients.
Methylomic, proteomic, and metabolomic correlates of traffic-related air pollution: A systematic review, pathway analysis, and network analysis relating traffic-related air pollution to subclinical and clinical cardiorespiratory outcomes
Authors: Casella Cameron , Kiles Frances , Urquhart Catherine , Michaud Dominique S. , Kirwa Kipruto , Corlin Laura
Published: October 2023

A growing body of literature has attempted to characterize how traffic-related air pollution (TRAP) affects molecular and subclinical biological processes in ways that could lead to cardiorespiratory disease. To provide a streamlined synthesis of what is known about the multiple mechanisms through which TRAP could lead cardiorespiratory pathology, we conducted a systematic review of the epidemiological literature relating TRAP exposure to methylomic, proteomic, and metabolomic biomarkers in adult populations. Using the 139 papers that met our inclusion criteria, we identified the omic biomarkers significantly associated with short-or long-term TRAP and used these biomarkers to conduct pathway and network analyses. We considered the evidence for TRAP-related associations with biological pathways involving lipid metabolism, cellular energy production, amino acid metabolism, inflammation and immunity, coagulation, endothelial function, and oxidative stress. Our analysis suggests that an integrated multi-omics approach may provide critical new insights into the ways TRAP could lead to adverse clinical outcomes. We advocate for efforts to build a more unified approach for characterizing the dynamic and complex biological processes linking TRAP exposure and subclinical and clinical disease, and highlight contemporary challenges and opportunities associated with such efforts.
circulating tumor DNA in the immediate post-operative setting
Authors: Efthymiou Vasileios , Queenan Natalia , Haas Markus , Naegele Saskia , Goss Deborah , Faden Daniel L.
Published: October 2023

Background

Circulating tumor DNA (ctDNA) has emerged as an accurate real-time biomarker of disease status across most solid tumor types. Most studies evaluating the utility of ctDNA have focused on time points weeks to months after surgery, which for many cancer types, is significantly later than decision-making time points for adjuvant treatment. In this systematic review, we summarize the state of the literature on the feasibility of using ctDNA as a biomarker in the immediate postoperative period.

Methods

We performed a systematic review evaluating the early kinetics, defined here as three days, of ctDNA in patients who underwent curative-intent surgery across several cancer types.

Results

Among the 2057 studies identified, we evaluated eight cohort studies with ctDNA levels measured within the first three days after surgery. Across six different cancer types, all studies showed an increased risk of cancer recurrence in patients with a positive early postoperative ctDNA level.

Discussion

While ctDNA clearance kinetics appear to vary based on tumor type, across all studies-detectable ctDNA after surgery was predictive of recurrence, suggesting early post-operative timepoints could be feasibly used for determining minimal residual disease. However, larger studies need to be performed to better understand the precise kinetics of ctDNA clearance across different cancer types as well as to determine optimal postoperative time points.

Synopsis

This systematic review analyzed the use of ctDNA as a biomarker for minimal residual disease detection in the early postoperative setting and found that ctDNA detection within three days after surgery is associated with an increased risk of recurrence.
Reliable detection and quantification of plasmodesmal callose inNicotiana benthamianaleaves during defense responses
Authors: Sankoh Amie F. , Adjei Joseph , Roberts Daniel M. , Burch-Smith Tessa M.
Published: October 2023

Callose, a beta-(1,3)-D-glucan polymer, is essential for regulating intercellular trafficking via plasmodesmata (PD). Pathogens manipulate PD-localized proteins to enable intercellular trafficking by removing callose at PD, or conversely by increasing callose accumulation at PD to limit intercellular trafficking during infection. Plant defense hormones like salicylic acid regulate PD-localized proteins to control PD and intercellular trafficking during innate immune defense responses such as systemic acquired resistance. Measuring callose deposition at PD in plants has therefore emerged as a popular parameter for assessing the intercellular trafficking activity during plant immunity. Despite the popularity of this metric there is no standard for how these measurements should be made. In this study, three commonly used methods for identifying and quantifying PD callose by aniline blue staining were evaluated to determine the most effective in theNicotiana benthamianaleaf model. The results reveal that the most reliable method used aniline blue staining and fluorescent microscopy to measure callose deposition in fixed tissue. Manual or semi-automated workflows for image analysis were also compared and found to produce similar results although the semi-automated workflow produced a wider distribution of data points.
Inhalable point-of-care urinary diagnostic platform
Authors: Zhong Qian , Tan Edward K.W. , Martin-Alonso Carmen , Parisi Tiziana , Hao Liangliang , Kirkpatrick Jesse D. , Fadel Tarek , Fleming Heather E. , Jacks Tyler , Bhatia Sangeeta N.
Published: October 2023

The late-stage detection of lung cancer leads to a high global mortality rate. Although low-dose computed tomography screening improves lung cancer survival in at-risk groups, this test still suffers from high rates of false positive results. In addition, inequality remains in the diagnosis of lung cancer as access to medical imaging infrastructure is limited. Here, we designed a needleless and imaging-free platform, termed PATROL (point-of-careaerosolizable nanosensors withtumor-responsiveoligonucleotide barcodes), to increase detection accuracy, to reduce resource disparities for early detection of lung cancer, and to enable timely interception. PATROL formulates a set of DNA-barcoded, activity-based nanosensors (ABNs) into inhalable formats that can be delivered using clinical nebulizers or inhalers. Lung cancer-associated proteases in the tumor microenvironment selectively cleave the ABNs, releasing synthetic DNA reporters that are eventually excreted via the urine. The barcoded nanosensor signatures present in urine samples are quantified within 20 minutes using a multiplexable paper-based lateral flow assay at room temperature. PATROL detects early-stage tumors in an autochthonous lung adenocarcinoma mouse model with high sensitivity and specificity. Tailoring the library of ABNs may enable the modular PATROL platform to not only lower the resource thresholds required for early detection of lung cancer, but also enable rapid detection of chronic pulmonary disorders and infections.
Geometry of navigation identifies genetic-risk and clinical Alzheimer’s disease
Authors: Lim Uzu , Cervantes Rodrigo Leal , Coughlan Gillian , Lambiotte Renaud , Spiers Hugo J. , Hornberger Michael , Harrington Heather A.
Published: October 2023

Recent research evidence demonstrates that the inability to orient oneself and navigate space is an early indicator of Alzheimer’s Disease. The video game Sea Hero Quest (SHQ) was designed to assess the players’ navigation ability, and several research works analysed the SHQ data using simple metrics such as length and time of navigation paths. Expanding these analyses, we propose new performance metrics that capture the geometry of paths, and analyse datasets of more than 60,000 navigators. The metrics identify players who failed the navigation task, the dementia patients, and carriers of the at-risk allele of the Apolipoprotein-E [APOE]. Furthermore the metrics detect weak navigation ability when only a fraction of navigation paths are used, with superior performance to baseline methods. Our findings demonstrate that the proposed performance metrics pave the way to a comprehensive pre-clinical screening toolbox for Alzheimer’s Disease.

TEASER

We propose geometric methods to capture decline in navigation ability from dementia.
Neoadjuvant Immunotherapy and Chemoradiation Followed by Esophagectomy for Esophageal Cancer
Authors: Panda Nikhil , Fu Beverly , Potter Alexandra , Auchincloss Hugh G. , Klempner Samuel J. , Lanuti Michael , Yang Chi-Fu , Schumacher Lana
Published: October 2023

Background

Treatment of locally advanced esophageal cancer includes neoadjuvant chemoradiation (chemoRT) and esophagectomy. We evaluated perioperative and oncologic outcomes among patients who received neoadjuvant chemoRT and immunotherapy (I/O).

Methods

Adults who underwent esophagectomy following neoadjuvant chemoRT or chemoRT+I/O for T1-4, N0-3, M0 esophageal cancer were identified from the National Cancer Database (2012-2020). Unadjusted, propensity score-matched, and Cox proportional hazards analyses compared perioperative outcomes and three-year overall survival (OS) between neoadjuvant chemoRT versus chemoRT+I/O cohorts.

Results

Among 17,937 patients, 261 (1.5%) received neoadjuvant chemoRT+I/O. ChemoRT+I/O patients were younger (62 versus 64 years, p=0.002) and had a longer interval between chemotherapy and surgery (104.5 versus 97.0 days, p<0.001) compared with chemoRT patients. Among the chemoRT+I/O cohort, there were more undifferentiated tumors (46.4% versus 34.3%, p<0.001) with adenocarcinoma histology (93.9% versus 81.2%, p<0.001) compared with the chemoRT cohort. On unadjusted analysis, there were no significant differences regarding margin positivity, 30-day readmission, 30-day mortality, or 90-day mortality. ChemoRT+I/O patients had higher 3-year OS (61.4% 95%CI [54.2-67.7] versus 55.1% [54.3-55.9], p=0.02), more lymph nodes resected (median 17.0 IQR [11.0-25.0] versus 15.0 [10.0-22.0], p=0.007), and less pathologic nodal downstaging from N2 to N1/N0 (36.8% vs 48.4%, p<0.001) than chemoRT patients. Propensity score-matched analyses (n=217) revealed no differences in perioperative outcomes and 3-year OS (65.0% 95%CI [57.1-71.8] versus 56.0% [48.0-63.3], p=0.11) between the chemoRT+I/O and chemoRT cohort.

Conclusions

There were similar perioperative outcomes and 3-year OS between patients who received neoadjuvant chemoRT+I/O and chemoRT, supporting the feasibility of adding immunotherapy to neoadjuvant regimens.
Urinary bisphenol A exposure in relation to liver function abnormalities among U.S. adults: results from the National Health and Nutrition Examination Survey, 2003-2016
Authors: Zhang Tiantian , Huang Guang , Wang Tongshuai , Chen Jie , Zhou Xiangyu , Shi Wenming
Published: October 2023

Background

Bisphenol A (BPA) is an endocrine-disrupting chemical that has been linked with various health outcomes. However, few studies using nationally representative data have assessed the association between BPA exposure with liver function. In addition, whether behavior characteristics of smoking and alcohol use modify such association has been underexplored.

Methods

Using data from seven cycles of the National Health and Nutrition Examination Surveys (NHANES) among 11,750 adults from 2003 to 2016, we investigated the relationship between urinary BPA with liver function indicators. BPA concentration in urine was measured by using high performance liquid chromatography with atmospheric pressure chemical ionization–mass spectrometry.

We estimated BPA concentration after controlling for creatinine and normalized the asymmetrical distribution using natural logarithmic transformation (ln-BPA/Cr). Eight liver function indicators in serum were examined. Multivariate linear regression models were performed to explore the association between urinary BPA with changes in liver indicators. Stratified analyses examined whether these associations varied by sex, age, smoking, or drinking.

Findings

Of the 11,750 participants (49.5% men), the mean age was 43.9 years. Per unit increment in ln-BPA/Cr was positively related to alkaline phosphotase (ALP) and total bilirubin (TBIL), while inversely with albumin (ALB). In quartile analysis, the highest BPA exposure was associated with higher aspartate aminotransferase (AST), ALP, and TBIL, while with decreased ALB (all Ptrend< 0.01). These associations for specific liver indicators (i.e., ALT, AST, Gamma-glutamyl transferase [GGT], and TBIL) were stronger in smokers and alcohol drinkers. Moreover, we found that BPA exposure with higher ALP in older adults (≥ 60 years) but no sex difference.

Interpretation

This nationally representative study suggested that urinary BPA was associated with elevated AST, ALP, TBIL, and inversely with ALB among U.S. adults. The associations were more evident in smokers and drinkers but no sex difference. Better understanding of the mechanisms is needed for improving liver and planetary health.

Funding

National Natural Science Foundation of China.
FBXO24 modulates mRNA alternative splicing and MIWI degradation and is required for normal sperm formation and piRNA production
Authors: Li Zhiming , Liu Xingping , Zhang Yan , Li Yuanyuan , Zhou Liquan , Yuan Shuiqiao
Published: October 2023

Spermiogenesis is a critical, post-meiotic phase of male gametogenesis, in which the proper gene expression is essential for sperm maturation. However, the underlying molecular mechanism that controls mRNA expression in the round spermatids remains elusive. Here, we identify that FBXO24, an orphan F-box protein, is highly expressed in the testis of humans and mice and interacts with the splicing factors (SRSF2, SRSF3, and SRSF9) to modulate the gene alternative splicing in the round spermatids. Genetic mutation of FBXO24 in mice causes many abnormal splicing events in round spermatids, thus affecting a large number of critical genes related to sperm formation that were dysregulated. Further molecular and phenotypical analyses revealed that FBXO24 deficiency results in aberrant histone retention, incomplete axonemes, oversized chromatoid body (CB), and abnormal mitochondrial coiling along sperm flagella, ultimately leading to male sterility. In addition, we discovered that FBXO24 interacts with MIWI and SCF subunits and mediates the degradation of MIWI via K48-linked polyubiquitination. Furthermore, we show that FBXO24 depletion could lead to aberrant piRNA production in testes, which suggests FBXO24 is required for normal piRNA counts. Collectively, these data demonstrate that FBXO24 is essential for sperm formation and piRNA production by regulating mRNA alternative splicing and MIWI degradation during spermiogenesis.
Molecular dynamics simulations of HIV-1 matrix-membrane interactions at different stages of viral maturation
Authors: Banerjee Puja , Qu Kun , Briggs John A. G. , Voth Gregory A.
Published: October 2023

Although the structural rearrangement of the membrane-bound matrix (MA) protein trimers upon HIV-1 maturation has been reported, the consequences of MA maturation on the MA-lipid interactions are not well understood. Long-timescale molecular dynamics (MD) simulations of the MA multimeric assemblies of immature and mature virus particles with our realistic asymmetric membrane model have explored MA-lipid interactions and lateral organization of lipids around MA complexes. The number of stable MA-PS and MA-PIP2 interactions at the trimeric interface of the mature MA complex is observed to be greater compared to that of the immature MA complex. Our simulations identified an alternative PIP2 binding site in the immature MA complex where the multivalent headgroup of a PIP2 lipid with a greater negative charge binds to multiple basic amino acid residues such as, ARG3 residues of both the MA monomers at the trimeric interface, and HBR residues (LYS29, LYS31) of one of the MA monomers. Our enhanced sampling simulations have explored the conformational space of phospholipids at different binding sites of the trimeric interface of MA complexes. Unlike the immature MA complex, the 2’ acyl tail of two PIP2 lipids at the trimeric interface of the mature MA complex is observed to sample stable binding pockets of MA consisting of helix4 residues. Together, our results provide molecular-level insights into the interactions of MA trimeric complexes with membrane and different lipid conformations at the specific binding sites of MA protein before and after viral maturation.

Significance

HIV-1 maturation facilitates the conversion of a newly formed immature virus particle to a mature infectious virion and initiates a new round of infection. The contributions of specific protein-lipid interactions in the HIV-1 assembly process are well recognized, however, the interactions of matrix protein lattice with the membrane before and after HIV-1 maturation are yet to be fully understood. Based on our simulated data, supported by prior experimental observations, the present study provides a molecular-level understanding of possible altered binding mode of PIP2 lipids after viral maturation. Identification of protein-lipid specific interactions, and lipid sorting data obtained from our long-time and large-scale atomistic MD simulations advance the understanding of the HIV-1 matrix and membrane maturation.
Epididymal acquired sperm microRNAs modify post-fertilization embryonic gene expression
Authors: Trigg Natalie A. , Conine Colin C.
Published: October 2023

Sperm small RNAs have emerged as important non-genetic contributors to embryogenesis and offspring health. A subset of sperm small RNAs are thought to be acquired during epididymal transit. However, the transfer of RNAs from the somatic epididymis to sperm has been questioned, and the identity of the specific small RNAs transferred remains unclear. Here, we employCre/Loxgenetics to generate germline- and epididymal-specificDgcr8conditional knockout mice to investigate the dynamics of sperm microRNAs and their function in the early embryo. Testicular sperm from germline specificDgcr8knockout mice have reduced levels of 98 microRNAs. Enthrallingly, following epididymal transit the abundance of 59% of these microRNAs are restored to control levels. Conversely, sperm from epididymalDgcr8knockouts displayed a reduction of > 3.4-fold in 25 miRNAs. This substantial loss of epididymal miRNAs in sperm was accompanied by transcriptomic changes in the embryo which was rescued by microinjection of epididymal miRNAs. These findings ultimately demonstrate the acquisition of miRNAs from the soma by sperm during epididymal transit and their subsequent regulation of post-fertilization embryonic gene expression.
Objects, Faces, and Spaces: Organizational Principles of Visual Object Perception as Evidenced by Individual Differences in Behavior
Authors: Sigurdardottir Heida Maria , Ólafsdóttir Inga María
Published: October 2023

What are the diagnostic dimensions on which objects differ visually? We constructed a two-dimensional object space based on such attributes captured by a deep convolutional neural network. These attributes can be approximated as stubby/spiky and animate-/inanimate-looking. If object space contributes to human visual cognition, this should have a measurable effect on object discrimination abilities. We administered an object foraging task to a large, diverse sample (N=511). We focused on the stubby animate-looking “face quadrant” of object space given known variations in face discrimination abilities. Stimuli were picked out of tens of thousands of images to either match or not match with the coordinates of faces in object space. Results show that individual differences in face perception can to a large part be explained by variability in general object perception abilities (o-factor). However, additional variability in face processing can be attributed to visual similarity with faces as captured by dimensions of object space; people who struggle with telling apart faces also have difficulties with discriminating other objects with the same object space attributes. This study is consistent with a contribution of object space to human visual cognition.

Public Significance Statement

The study emphasizes individual differences in visual cognition, a relatively neglected field of research. Unlike differences in other cognitive traits (e.g., Big Five personality traits, g-factor of general intelligence), we have limited knowledge on how people differ in their object processing capacity, and whether such abilities are fractionated or unitary. In this study, we ask whether visual object perception abilities are organized around an object space as evidenced by individual differences in behavior.
Can a leader's ethical leadership and abusive supervision be a gain? Workplace emotions as mediators
Authors: Huang Danyu , Zhou Hao
Published: October 2023

Purpose

The main objectives of this study were to examine the congruent/incongruent effects of ethical leadership–abusive supervision (EL-AS) on employees' job performance (JP), mediated by employees' workplace emotions.

Design/methodology/approach

In this study, multiphase data were collected from 276 frontline employees at a large automobile manufacturing company in southwest China. The hypotheses were tested performing polynomial regression and response surface analysis.

Findings

The results revealed that employees in “high–high” and “high–low” EL-AS experienced more positive emotions (PE), while “low–high” EL-AS triggered more negative emotions. Furthermore, employees' workplace emotions mediate the effect of EL-AS's congruence/incongruence on employees' JP.

Practical implications

Leaders should notice the paradoxical effects of EL and AS and adopt ambidextrous thinking to enhance subordinates' PE.

Originality/value

This study enriches the literature on paradoxical leadership by exploring the complex consequences that may result from the incongruent practice of two leadership behaviors that are often considered paradoxical in nature. Furthermore, it shifts from the previous leader-centered perspective to a subordinate-centered perspective, complementing the theoretical perspectives of EL and AS research. And it deepens the understanding of the relationship between paradoxical leadership and employees' work outcomes by exploring the intrinsic affective mechanism.
An evaluation of behaviour monitoring charts for behaviours that challenge in an older adult inpatients dementia service
Authors: King Nicole , Asquith Ian
Published: October 2023

Purpose

This study aims to evaluate the quality of information recorded in Behaviour Monitoring Charts (BMC) for Behaviours that Challenge (BtC) in dementia in an older adult inpatient dementia service in the North of England (Aim I) and to understand staff perceptions and experiences of completing BMC for BtC in dementia (Aim II).

Design/methodology/approach

Descriptive statistics and graphs were used to analyse and interpret quantitative data gathered from BMC (Aim I) and Likert-scale survey responses (Aim II). Thematic analysis (Braun and Clarke, 2006) was used to analyse and interpret qualitative data collected from responses to open-ended survey questions and, separately, focus group discussions (Aim II).

Findings

Analysis of the BMCs revealed that some of the data recorded relating to antecedents, behaviours and consequences lacked richness and used vague language (i.e. gave reassurance), which limited its clinical utility. Overall, participants and respondents found BMC to be problematic. For them, completing BMCs were not viewed as worthwhile, the processes that followed their completion were unclear, and they left staff feeling disempowered in the systemic hierarchy of an inpatient setting.

Originality/value

Functional analysis of BMC helps identify and inform appropriately tailored interventions for BtC in dementia. Understanding how BMCs are used and how staff perceive BMC provides a unique opportunity to improve them. Improving BMC will support better functional analysis of BtC, thus allowing for more tailored interventions to meet the needs of people with dementia.
Alternative direct‐to‐amplification cell lysis techniques for forensically relevant non‐sperm cells
Authors: Arya Rhea , Hudson Brittany C. , Green Tracey Dawson
Published: October 2023

While efforts have been made to reduce the pervasive backlog of sexual assault evidence collection kits, the actual laboratory process remains very time‐consuming due to the requirement of a differential lysis step before DNA purification, as well as intricate mixture analysis towards the end of the DNA workflow. Recently, an alternative, direct‐to‐amplification sperm lysis method (using 1 M NaOH) was identified. However, a direct cell lysis method for non‐sperm cells has not been identified yet. Thus, the primary objective of this work was to find an alternative method that is quick, inexpensive, and does not require multiple purification steps for the lysis of non‐sperm cells in sexual assault samples. In this study, vaginal swab samples were lysed with the control method, prepGEM™, as well as six alternative reagents: alkaline buffer with 25–200 mM NaOH, high‐salt stain extraction buffer, modified radioimmunoprecipitation assay (RIPA) buffer, mammalian protein extraction reagent (M‐PER™), digitonin buffer, and urea/thiourea buffer. Quantification using Quantifiler® Trio of vaginal and semen lysates revealed that the alkaline (25 mM NaOH) and M‐PER™ methods were efficient for the lysis of vaginal epithelial cells without substantial sperm cell lysis. Following quantification, analysis of STR profiles from vaginal lysates revealed that the M‐PER™ method showed promising results across all metrics examined, including the percentage of detected STR alleles, mean peak heights, peak height ratio, and interlocus balance. Thus, this method was recommended as an alternative to the traditional differential lysis method for non‐sperm cells given its ability to produce amplification‐ready lysates without any DNA purification step.
Pulmonary pleomorphic carcinoma treated with PD‐1 inhibitor: Two case reports
Authors: Jiang Tao , Wang Hao , Xue Fei , Wu Xuanpeng , Ni Ming , Wang Yuanyuan , Chen Nanzheng , Zhang Yong , Zhang Guangjian , Fu Junke , Liu Xi , Wu Qifei
Published: October 2023

Pulmonary polymorphic carcinoma (PPC) is a rare and poorly differentiated form of non‐small cell lung cancer (NSCLC), accounting for just approximately 0.1% to 0.4% of all NSCLC cases. Historically, the conventional treatments for PPC have been linked to a grim prognosis. However, with the advent of immune checkpoint inhibitors (ICIs), including PD‐1 inhibitors, for the management of NSCLC, our center has witnessed encouraging outcomes in two PPC patients who underwent PD‐1 inhibitor therapy. The first patient was a 70‐year‐old male who initially came to our attention after the discovery of a lung mass during a routine physical examination. A lung biopsy confirmed the diagnosis of PPC, and further complications included brain metastasis. Surgical intervention was conducted for the brain metastases, while PD‐1 inhibitor therapy was employed for the lung tumors. The second patient was a 60‐year‐old male who was admitted with a history of persistent coughing and hemoptysis, which led to the diagnosis of a left lung tumor. Subsequent postoperative pathology revealed pulmonary adenocarcinoma coexisting with PPC. However, 2 months later, distant metastases were detected during a follow‐up examination. The patient encountered difficulty in tolerating the adverse effects of chemotherapy, prompting the initiation of PD‐1 inhibitor treatment. Notably, both patients underwent one cycle of PD‐1 inhibitor therapy without encountering significant adverse reactions, and their responses proved to be promising during re‐examinations. These findings suggest that surgery combined with immunotherapy PD‐1 inhibitor therapy may represent an effective approach for the treatment of PPC.
Speaking the Language of Friendship: Partnerships in the Political Construction of the Late Sixteenth‐Century South‐East Charcas Frontier
Authors: Graña Taborelli Mario
Published: October 2023

The present article discusses the importance of partnerships in the political construction of the south‐east frontier of late sixteenth‐century Charcas, focused on foundation and destruction of San Miguel de la Laguna. In a challenge to the narrative of ‘constant war zone’, the events are here framed as part of a process described as territorialisation, which transformed geographies into territories of the polycentric Catholic Monarchy, politically equipping the land with relations that were expressed through institutions. San Miguel was the product of the ‘friendship’ between its founder and the Chiriguanaes who inhabited the area. Its fate was not the result of untrustworthy natives.
RALY participates in nerve trauma‐induced nociceptive hypersensitivity through triggering Eif4g2 gene expression in primary sensory neurons
Authors: Huang Lina , Sharma Dilip , Feng Xiaozhou , Pan Zhiqiang , Wu Shaogen , Munoz Daisy , Bekker Alex , Hu Huijuan , Tao Yuan‐Xiang
Published: October 2023

Background and Purpose

Peripheral nerve trauma‐induced dysregulation of pain‐associated genes in the primary sensory neurons of dorsal root ganglion (DRG) contributes to neuropathic pain genesis. RNA‐binding proteins participate in gene transcription. We hypothesized that RALY, an RNA‐binding protein, participated in nerve trauma‐induced dysregulation of DRG pain‐associated genes and nociceptive hypersensitivity.

Methods and Results

Immunohistochemistry staining showed that RALY was expressed exclusively in the nuclei of DRG neurons. Peripheral nerve trauma caused by chronic constriction injury (CCI) of unilateral sciatic nerve produced time‐dependent increases in the levels of Raly mRNA and RALY protein in injured DRG. Blocking this increase through DRG microinjection of adeno‐associated virus 5 (AAV5)‐expressing Raly shRNA reduced the CCI‐induced elevation in the amount of eukaryotic initiation factor 4 gamma 2 (Eif4g2) mRNA and Eif4g2 protein in injured DRG and mitigated the development and maintenance of CCI‐induced nociceptive hypersensitivity, without altering basal (acute) response to noxious stimuli and locomotor activity. Mimicking DRG increased RALY through DRG microinjection of AAV5 expressing Raly mRNA up‐regulated the expression of Eif4g2 mRNA and Eif4g2 protein in the DRG and led to hypersensitive responses to noxious stimuli in the absence of nerve trauma. Mechanistically, CCI promoted the binding of RALY to the promoter of Eif4g2 gene and triggered its transcriptional activity.

Conclusion and Implications

Our findings indicate that RALY participates in nerve trauma‐induced nociceptive hypersensitivity likely through transcriptionally triggering Eif4g2 expression in the DRG. RALY may be a potential target in neuropathic pain management.
Head‐to‐head comparison of three chelates reveals DOTAGA promising for 225Ac labeling of anti‐FZD10 antibody OTSA101
Authors: Sudo Hitomi , Tsuji Atsushi B. , Sugyo Aya , Harada Yosuke , Nagayama Satoshi , Katagiri Toyomasa , Nakamura Yusuke , Higashi Tatsuya
Published: October 2023

To select the most suitable chelate for 225Ac radiolabeling of the anti‐FZD10 antibody OTSA101, we directly compared three chelates: S‐2‐(4‐isothiocyanatobenzyl)‐1,4,7,10‐tetraazacyclododecane tetraacetic acid (p‐SCN‐Bn‐DOTA), 2,2′,2″‐(10‐(1‐carboxy‐4‐((4‐isothiocyanatobenzyl)amino)‐4‐oxobutyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl) triacetic acid (p‐SCN‐Bn‐DOTAGA), and 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid mono‐N‐hydroxysuccinimide ester (DO3A‐NHS‐ester). We evaluated the binding affinity of the chelate‐conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225Ac‐labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate‐conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO‐1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA‐OTSA101 and DO3A‐OTSA101 were 1.8‐fold higher than that of DOTA‐OTSA101 (p < 0.01). The stabilities were similar between 225Ac‐labeled DOTA‐OTSA101, DOTAGA‐OTSA101, and DO3A‐OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor‐absorbed doses by 225Ac‐labeled DOTA‐OTSA101 and DOTAGA‐OTSA101 compared with 225Ac‐DO3A‐OTSA101 (p < 0.05). 225Ac‐DOTAGA‐OTSA101 exhibited the highest tumor‐to‐bone marrow ratio, with bone marrow being the dose‐limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225Ac‐labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow.
‘I never win’: How children and staff in residential facilities experience meaningful participation
Authors: Slaatto Ane , Baugerud Gunn Astrid , Mellblom Anneli V.
Published: October 2023

Policymakers increasingly emphasize the importance of achieving meaningful participation of children living in residential care. To achieve the goal of participation, children must be adequately informed, have opportunities to express themselves freely and to be heard, and be given the opportunity to influence decisions about their lives. This study investigated the views and experiences of both children and staff with respect to children's participation in residential facilities in Norway. We conducted both focus‐group and individual interviews with 6 children and 18 staff members at different facilities. Qualitative interview data were analysed using the dimensions of meaningful participation: informing, hearing and involving. The study offers three main findings. First, children's initiatives determine if staff inform them of their rights, with two exceptions: children are presented with information by staff when they arrive at a facility and/or after staff use coercion that requires protocols. Second, staff members expressed the importance of listening to children's opinions in a standardized way, following bureaucratic guidelines and structures. Third, several children stated that, no matter what they say, they cannot change the minds of staff members. These findings reveal that the dimensions of meaningful participation (informing, hearing and involving) are not all fully present at these facilities. Further research is needed to determine how to achieve in practice the policy goal of participation of children in residential care.
1073. Euonymus chibae Makino
Authors: Mochizuki Ko , Takegami Minako , Yamanaka Masumi
Published: October 2023

The widely‐distributed genus Euonymus, the spindle‐tree, includes over 140 accepted species, many of which are well known in cultivation. Here we describe and illustrate one of the tallest species, Euonymus chibae Makino. The discovery, pollination biology, and conservation of this species is discussed, and a lectotype is proposed in addition to the detailed description.